Current Immunology Reviews, 2010, 6, 000-000 1
1573-3955/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections
of the Fetus and Newborn
William J. Muller*,1, Cheryl A. Jones2,3 and David M. Koelle4,5,6,7,8
1Department of Pediatrics, Division of Pediatric Infectious Diseases, Northwestern University Feinberg School of
Medicine, Chicago, Illinois, USA
2Centre for Perinatal Infection Research, The Children’s Hospital at Westmead, Westmead, Australia
3Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
4Department of Medicine, University of Washington, Seattle, Washington, USA
5Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA
6Department of Global Health Medicine, University of Washington, Seattle, Washington, USA
7Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
8Benaroya Research Institute, Seattle, Washington, USA
Abstract: Immunologic “immaturity” is often blamed for the increased susceptibility of newborn humans to infection, but
the precise mechanisms and details of immunologic development remain somewhat obscure. Herpes simplex virus (HSV)
and cytomegalovirus (CMV) are two of the more common severe infectious agents of the fetal and newborn periods. HSV
infection in the newborn most commonly occurs after exposure to the virus during delivery, and can lead to a spectrum of
clinical disease ranging from isolated skin-eye-mucous membrane infection to severe disseminated multiorgan disease,
often including encephalitis. In contrast to HSV, clinically severe CMV infections early in life are usually acquired during
the intrauterine period. These infections can result in a range of clinical disease, including hearing loss and
neurodevelopmental delay. However, term newborns infected with CMV after delivery are generally asymptomatic, and
older children and adults often acquire infection with HSV or CMV with either no or mild clinical symptoms. The reasons
for these widely variable clinical presentations are not completely understood, but likely relate to developmental
differences in immune responses.
This review summarizes recent human and animal studies of the immunologic response of the fetus and newborn to these
two infections, in comparison to the responses of older children and adults. The immunologic defense of the newborn
against each virus is considered under the broader categories of (i) the placental barrier to infection, (ii) skin and mucosal
barriers (including antimicrobial peptides), (iii) innate responses, (iv) humoral responses, and (v) cellular responses. A
specific focus is made on recent studies of innate and cellular immunity to HSV and CMV.
Keywords: herpes simplex virus, cytomegalovirus, neonatal immunity, fetal immunity.
and prevalent in the population. All herpesviruses establish
latency in different tissues, and periodic reactivation can lead
to transmission . Although the majority of infections with
herpes simplex virus (HSV) and cytomegalovirus (CMV) are
clinically mild or even asymptomatic, primary infection in
the fetal and perinatal periods can be neurologically
devastating or fatal [2, 3]. The precise reasons for the
increased severity of disease early in life are not clear, and
may involve many aspects of immune defense.
Herpesviruses infections of humans are very common
at mucosal surfaces, they have substantial differences in their
biological characteristics which are relevant to the
Although both HSV and CMV generally initiate infection
*Address correspondence to this author at the Division of Infectious
Diseases, Children's Memorial Hospital, 2300 Children's Plaza, Box 20,
Chicago, Illinois 60614, USA; Tel: 312-503-9783; Fax: 773-880-8226;
understanding of immunity after infection with either agent.
In immune-competent individuals, HSV generally infects a
limited number of cell types, including mucosal and
cutaneous epithelial cells and neurons, and may be clinically
silent or cause ulcerative lesions . Spread of the virus to
other tissues is associated with an inability of the immune
system to limit viral replication to the mucosa, and latent
infection is largely restricted to neurons . Conversely,
CMV often causes a persistent primary infection, even in
immune-competent adults , and remains latent in a variety
of tissues . However, although a mononucleosis-like
syndrome is a recognized clinical presentation of primary
CMV infection, severe disease due to CMV is almost
exclusively restricted to immune-compromised individuals
and 1 in 8000  live births in the United States, though for
unclear reasons the reported incidence is much lower in other
countries [8, 9]. Clinical syndromes of neonatal HSV include
encephalitis (with or without skin or mucosal disease),
HSV causes neonatal infection in between 1 in 2000 
2 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
visceral dissemination (with or without encephalitis), and
isolated skin-eye-mucous membrane disease . Outcomes
of neonatal HSV disease are associated with the clinical
syndrome at presentation, but even with effective antiviral
therapy infection neonatal HSV causes mortality in more
than 15% of all infants and neurologic morbidity in more
than two-thirds of survivors . Despite the availability of
antiviral agents and efforts to prevent HSV transmission
during delivery (such as Caesarean delivery), a recent study
in California noted that rates of neonatal disease and HSV-
associated mortality in newborns have remained stable over
the past ten years . Survivors of neonatal HSV-2
encephalitis appear to be at increased risk of recurrent
disease [12, 13], suggesting a lack of effective control of
acquired in utero, occurring in up to 2.2% of live births in
the United States [5, 14]. CMV is an important cause of fetal
demise and intrauterine growth retardation . About 90%
of congenitally infected infants are asymptomatic .
Congenital CMV infection is the most common acquired
cause of sensorineural hearing loss , which may occur in
patients with either clinically symptomatic [18, 19] or
asymptomatic [20, 21] congenital infection. Congenital
CMV infection is also a major cause of subsequent
developmental and neurologic abnormalities [20, 22].
Fulminant CMV disease in the newborn (cytomegalic
inclusion disease) after intrauterine infection can lead to
severe neurologic morbidity or mortality [3, 22]. Infants born
prematurely who acquire CMV infection postnatally are also
at high risk of symptomatic infection, including after
ingestion of infected breast milk . Term infants infected
postnatally with CMV are generally asymptomatic,
highlighting the importance of immune maturation in control
CMV is the most common known viral infection
newborns have an increased susceptibility to infection with a
variety of different pathogens . The intrauterine
environment is considered to have a general bias favoring
immune tolerance , which may limit the ability of the
fetus to fight infection . During delivery, the newborn
transitions from the normally sterile intrauterine milieu to an
environment harboring numerous potential pathogens.
Mechanical barriers to infection (skin and mucosa) may be
less well developed in newborns relative to older children
and adults . Additionally, innate and adaptive immunity
in the fetus and newborn has quantitative and qualitative
differences from older children and adults, including in the
numbers and function of immune cells, the function and
levels of cytokines, and in the generation and levels of
immune globulins . Herpesviruses have evolved a
variety of strategies for modulating human immune
responses [28-30], which may have greater biological
significance in the immunologically immature fetus and
Relative to older children and adults, human fetuses and
in the context of the important neonatal pathogens HSV and
CMV, highlighting differences in disease caused by these
viruses and in the responses generated. Emphasis is given to
recent studies on the immunopathology of HSV and CMV
infections. Although studies in both humans and mice are
We consider fetal and neonatal immunity in this review
reviewed, we acknowledge that murine immune responses
can differ from corresponding human responses, and data in
mouse models may not directly extrapolate to humans.
PLACENTAL AND AMNIOTIC IMMUNITY
The Fetal-Maternal Interface
contributing to maternal-fetal tolerance, including: (a) the
lack of expression of the classical class I HLA molecules
(HLA-A and HLA-B) by placental tissue , (b) the
expression of non-classical HLA-C  and HLA-G ,
which may serve to inhibit maternal NK cells and induce
regulatory T-cells (Treg) , (c) absence of class II
expression in placental cells , (d) production of
indoleamine 2,3-dioxygenase by placental cells, which may
have direct inhibitory effects on maternal alloreactive T-cells
 and indirect effects on antigen presenting cells and Treg
, and (e) the presence at the placental interface of
specialized maternal immune cells, including maternal Treg
, CD16- NK cells and perhaps other decidual granular
leukocytes . Another important function of the placenta
relevant to fetal immunity is the active transport of maternal
IgG into fetal blood, which is at least partly mediated by the
high expression of the neonatal Fc receptor (FcR, or CD64)
in placental tissue .
Many immune mechanisms have been described as
developmental anatomy of the placenta is useful to
understanding the mechanisms
transplacental infection. The fetal-maternal interface is
formed upon invasion of maternal uterine wall by fetally-
derived placental cells . Cytotrophoblastic progenitor
cells differentiate to form
syncytiotrophoblasts which are bathed in maternal blood in
the floating villi, or invade the decidua to create anchoring
chorionic villi. Thus, depending on the stage of pregnancy,
the most direct route from maternal blood to fetus requires
crossing syncytiotrophoblasts and a variable number of
cytotrophoblasts to reach fetal capillary endothelium and the
Infections acquired in utero may result from ascending or
viral spread. An understanding of
which may limit
pathogens to overcome a variety of anatomic and immune
barriers. The cervical plug, maternal-fetal membranes, and
antimicrobial peptides in these tissues and in the amniotic
fluid may contribute to protection against vertical infection
. The degree to which some of these barriers
(particularly antimicrobial peptides) may protect against
ascending HSV or CMV infection is considered in further
detail in subsequent sections.
Ascending infection of a developing fetus requires
HSV Infection of the Fetus
cases of neonatal HSV are attributed to infection in utero
. Cases of intrauterine HSV infection have been
attributed to ascending infection after either viral reactivation
 or first episode genital infection . Microscopic
placental involvement during intrauterine HSV infection has
been described, but appears to be secondary to amnionitis
HSV rarely causes infection of the fetus; only 5% of
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 3
CMV) may be related to the infrequency with which HSV
causes viremia. Although it was long thought that primary
HSV infection did not commonly lead to viremia, recent
studies have identified HSV DNA in peripheral blood of
24% of patients with primary genital HSV . Viremia has
not been described during recurrent HSV, and the relative
lack of available virus compared to CMV may partly explain
the rarity of transplacental HSV spread. Notably, HSV DNA
has been detected in placental tissue derived from
uncomplicated pregnancies electively terminated at different
times in gestation [45, 46]. Although cellular receptors for
HSV appear to be present in placental tissue [47-50], if virus
manages to infect placental tissue, spread to the fetus appears
generally to be controlled, likely by maternal immune
The lack of transplacental infection due to HSV (unlike
viral spread, another potential important difference between
HSV and CMV is the site of viral latency. HSV is not known
to become latent in immune cells, while CMV (discussed
below) may reactivate in uterine tissue from latently infected
white blood cells . Perhaps reactivation of latent virus at
the fetal-maternal interface also contributes to the ability of
CMV but not HSV to cause transplacental infection.
In addition to differences in transplacental control of
immune responses at the placental interface to resistance to
HSV infection. Even in rare cases of disseminated maternal
HSV disease late in pregnancy, the infant is not always
affected [51-53]. An equally puzzling question is why HSV
does not cause ascending infection more frequently than it
does, since an estimated 2% of women acquire primary
genital infection during pregnancy . Antimicrobial
peptides are discussed further below, but have not been
directly demonstrated to control ascending spread of HSV.
Less is understood about other contributions of maternal
Cytomegalovirus Infection of the Fetus
causes transplacental infection . However, the precise
mechanism for viral transit from mother to fetus is not
known. Tissue tropism of CMV is a complex and active area
of research . CMV is known to infect and establish
persistence within endothelial cells, smooth muscle cells,
and myeloid cells [56, 57]. Circumstantial evidence supports
the concept that CMV may cause fetal infection via an
ascending route, though hematogenous spread to the placenta
is also likely . Guinea pigs have a similar placental
morphology to humans, and guinea pig cytomegalovirus has
been shown to spread hematogenously to infect the placenta
. In this study, virus continued to be detected in the
placenta long after clearance from the maternal blood, but
only about ? of fetuses were infected, suggesting that the
placenta may be both a site of persistent CMV infection and
a barrier to viral transmission. Subsequent studies in human
placentas support a similar route of viral transit from mother
to fetus [60, 61].
In contrast to HSV, there is good evidence that CMV
of the maternal-fetal interface may contribute to reactivation
of latent CMV in cells residing in the uterine wall, analogous
to CMV reactivation in transplant patients . Fetal cells
which invade the uterine wall to contribute to placenta
formation secrete IL-10 , which may have some local
It has been speculated that the immunologic environment
immune-suppressive activity. Latently infected maternal
macrophages and/or dendritic cells (DCs) may migrate to the
uterine wall in response to the presence of other pathogens,
in effect carrying virus to a site at which local immune
suppression may lead to reactivation and subsequent
transmission to the fetus .
may paradoxically facilitiate CMV transmission to the fetus
. In this model, low-avidity maternal anti-CMV
antibodies bind virions via their variable regions and the
neonatal FcR via the constant region, ultimately allowing
FcR to transcytose complexes of virus and antibody across
the syncytiotrophoblast to infect underlying cytotrophoblast
cells, with subsequent viral spread to the fetus.
Dysregulation of cytotrophoblast function in infected cells,
including effects on cell adhesion molecules, may also
contribute to viral dissemination to the fetus .
Conversely, in the presence of strongly neutralizing (high-
avidity) maternal anti-CMV titers, nucleocapsids are retained
within vesicular compartments in syncytiotrophoblast cells
without evidence of viral replication .
A recent study suggested that the neonatal Fc receptor
epidermal growth factor receptor (EGFR) , the integrins
?2?1, ?6?1, and ?V?3 [66, 67], and platelet-derived growth
factor-? receptor (PDGFR-?) . Cytotrophoblasts have
been shown to express ?V?3 and EGFR (but not ?2?1 and
?6?1) , and infection of cytotrophoblasts appears to
depend on the expression of these receptors in a spatially
regulated manner . Decidual cells express PDGFR-?
, but their role in fetal infection has not been studied. It
is tempting to speculate that virus which has successfully
traversed the syncytiotrophoblast (either by an FcR-mediated
process or some other mechanism) is capable of engaging
viral receptors to allow subsequent spread to the fetus;
indeed, prior authors have suggested that resistance to viral
translocation across the placenta might be related to
regulation of different viral receptors .
Putative cell surface receptors for CMV include the
Other Aspects of Fetal-Maternal Immunity
of maternal-fetal immunity to fetal protection against HSV
or CMV infection are not well-described. Both HSV and
CMV can downregulate HLA-C ; it could be speculated
that this removes inhibition from maternal NK cells and
allows for selective NK-mediated killing of virally infected
cells. Indoleamine 2,3-dioxygenase (IDO) produced by
placental cells is thought to contribute to maternal tolerance
by degradation of the essential amino acid tryptophan,
suppressing T-cell responses [35, 36]. In other settings, IDO
is induced by IFN-? production and may have direct anti-
HSV and anti-CMV effects [72, 73]. Further research is
needed to better understand how the maternal-fetal interface
simultaneously allows allogeneic tolerance and protection
The relative contributions of other immunologic aspects
protect the developing fetus from transplacental or ascending
infection (Table 1). Intrauterine infection with HSV is rare,
and appears to be more likely secondary to ascending
infection and amnionitis than transplacental transmission.
Complex and incompletely understood mechanisms
4 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
CMV infection of the fetus is much more common, and
appears to most frequently occur transplacentally. CMV has
several mechanisms which may contribute to its ability to
cause transplacental infection, including direct effects on
muco-epithelial surfaces. Disease localized to the skin, eyes,
and/or mucous membranes is a distinct clinical presentation
of neonatal HSV . HSV encephalitis in the neonate (in
the absence of disseminated disease) is thought to be
initiated by cutaneous or mucosal infection, followed by
viral spread to the supplying sensory nerves and ultimately
to the central nervous system . Immunity at epithelial
surfaces may be less relevant for transplacentally-acquired
congenital CMV infection, but premature infants may
acquire symptomatic infection via mucosal surfaces after
exposure to infected breast milk. In older children and
adults, CMV also generally initiates infection at mucosal
sites, typically either via shedding in saliva or at genital
Both HSV  and CMV  typically initiate infection at
Physical Barriers to HSV and CMV Infection
barrier to infection. Intact skin serves as a barrier to HSV in
the neonate, as shown indirectly by the observation that
invasive monitoring is a risk factor for neonatal HSV .
The skin of a term newborn has similar structure to adult
skin (including epidermis, dermis, and subcutaneous fat), but
the epidermis is thinner . All skin layers are less well-
developed in premature infants than term infants, conferring
even higher risk for skin disruption secondary to trauma
. Even in a term infant, the barrier function of the
stratum corneum differs from that of an adult, indicating
maturation of skin barrier function in the days following
birth . Keratinocytes in the stratum granulosum and
stratum spinosum and underlying dermal cells are the
principal cell type infected by HSV, however DC in the
epithelium (Langerhans cells) are also infected (Puttur FK, et
al., unpublished observations). Disruption of the stratum
corneum may allow virus access to these cells in the
Skin and mucosal epithelial cells can provide a physical
Tissue Distribution of Antimicrobial Peptides
infection, skin has innate antimicrobial functions. Skin and
mucosal keratinocytes produce antimicrobial peptides and
proteins which can be directly protective against infection
[77, 78]. In addition, these peptides and proteins have less
direct influences on immune responses, including promoting
DC development and chemotaxis . These molecules
include lactoferrin, lysozyme, cathelicidin (also known as
human cationic antimicrobial peptide hCAP-18 and as LL-37
for the active 37-amino acid peptide) and the ?-defensins.
Adult keratinocytes constitutively produce human ?-
defensin-1 (hBD-1). Production of hCAP-18 and hBD-2 and
-3 can be induced during an inflammatory response .
Cathelicidins and defensins have also been detected in
mucosal epithelia [81, 82], ocular epithelia [83-85], and
saliva [81, 86].
In addition to serving as a mechanical barrier to
contain antimicrobial peptides. Cathelicidin and hBD-2 are
constitutively expressed in human newborn skin , and
lysozyme and lactoferrin have also been found in the stratum
corneum of term newborns . Lysozyme is present in
newborn stratum corneum at 5-fold higher levels than in
adults , and a murine homologue of cathelicidin is
expressed in the skin of newborn and embryonic mice at 10-
to 100-fold higher levels than found in adult mice . Fetal
and newborn mice also produce cathelicidin in oral mucosal
tissue . The precise roles of antimicrobial peptides in
defense of the newborn against HSV or CMV have not been
studied in detail, but these observations suggest that these
mechanisms are present early in life.
Newborn skin and mucosal epithelia are known to
Cathelicidin and ?-Defensins
Indirect evidence of this comes from studies in patients with
atopic dermatitis (eczema), who have diminished levels of
cathelicidin in skin compared with normal subjects .
Skin of patients with atopic dermatitis may become
secondarily infected with herpes simplex, leading to the
clinical condition of eczema
Immunostaining analysis of skin biopsy samples from
Cathelicidin may have antiviral activity against HSV.
Factors Influencing Fetal HSV or CMV Infection
Generally an ascending infection [42, 43]
Transit may be limited by anatomic barriers (cervical
plug; fetal membranes) and antimicrobial peptides 
Generally a transplacental infection 
Site of latency
Resides in neurons (dorsal root ganglia); may not have
access to uterine structures after reactivation
May reactivate from white blood cells in uterine tissue 
Effect of maternal antibody More relevant to neonatal disease (discussed below)
Neonatal Fc receptor may facilitate transplacental transmission,
especially in presence of low-avidity maternal antibody 
Presence of viral receptors Not known to influence HSV infection of fetus
Spatial regulation of putative CMV receptors may influence
Latency is limited to neurons, which may influence
likelihood of transplacental spread
Infection may influence placental cell structure and function
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 5
individuals with atopic dermatitis and a history of eczema
herpeticum demonstrates lower levels of LL-39 than biopsies
from individuals with atopic dermatitis without this history
. In vitro assays have demonstrated the ability of LL-39
to inhibit viral replication for both HSV-1  and HSV-2
. HSV-2 in explanted skin from mice with a deficiency
in the murine homologue of human cathelicidin replicates to
significantly higher levels than in skin explants from wild-
type mice .
defensins to protect against HSV infection. In vitro studies
fail to show an individual effect of hBD-1 or hBD-2 on
binding, entry, or replication of HSV-2, although hBD-3 and
several human ?-defensins have anti-HSV activity .
Keratinocytes are not known to produce ?-defensins, though
these primarily leukocyte-derived peptides are produced in
the human vaginal mucosa and contribute to the anti-HSV
activity of cervicovaginal secretions . The ability of
combinations of natural human ?-defensins to provide
protection against HSV infection has not been studied in
detail, though there is much active research in the use of
cationic oligomers (including homologues of ?- and ?-
defensins) [92, 94, 95] and non-human defensins  to
inhibit HSV binding and replication .
Data are less available regarding the ability of human ?-
comparatively less attention. For congenital infection, these
molecules may have less relevance overall. Antiviral activity
against CMV has been shown for some ?-defensins ,
which may participate in limiting transplacental spread.
Compared with HSV, the antiviral activity of cathelicidin
the ?-defensins against CMV has received
Other Antimicrobial Peptides
antimicrobial peptides, lactoferrin and its peptic digestion
product lactoferricin have received significant attention for
their antiviral activity. Several in vitro studies testing activity
of lactoferrin and/or lactoferricin against either herpes
simplex or cytomegalovirus suggest inhibitory activity,
possibly by interfering with cell surface binding [98-103].
The clinical significance of this activity is not known. It is
worth noting that human breast milk contains many
antimicrobial peptides, including lactoferrin in high
concentrations , but that this activity does not fully
prevent either HSV [105, 106] or CMV [104, 107]
transmission via breast-feeding.
Among the other skin and mucosa-associated
influence the susceptibility of the newborn to HSV and
perhaps also CMV infection. Antimicrobial peptides may
have activity against HSV, and are present in newborns,
suggesting a possible role in protection against HSV
infection. Lactoferrin in breast milk may help to limit CMV
transmission by this route.
Differences in skin and mucosal epithelial integrity may
innate and adaptive immunity has been among the most
important advances in immunology in the past twenty years.
Reviews addressing the innate response in neonatal HSV
infection published in the mid- to late-1980’s focused on
Increased understanding of the interactions between
cytotoxicity (ADCC), and the monocyte/macrophage lineage
in terms of their effects on immune response to HSV [108-
110]. Many recent studies have added understanding of the
importance of toll-like receptors and the downstream
signaling produced through these molecules to neonatal HSV
and CMV responses.
NK cells, antibody-dependent cellular
Toll-Like Receptor Signaling
(TLR) family expressed in humans, which function to sense
microorganisms through detection of pathogen-associated
molecular patterns . Signals transmitted through TLR3,
TLR2, and TLR9 have been described as contributing to the
antiviral response to herpesviruses, and are considered
There are at least ten members of the toll-like receptor
Toll-Like Receptor 3
which may be produced during viral replication . The
potential importance of TLR3 signaling to immune defense
against HSV has been recently highlighted by the connection
between this pathway and susceptibility to HSV encephalitis
[113, 114]. These reports describe children with HSV
encephalitis found to have polymorphisms in TLR3  or
UNC93B , a protein required for signaling through
TLR3, TLR7, TLR8, and TLR9. This latter group of patients
was found to have diminished IFN-?, IFN-?, and IFN-?
production in response to polyinosine-polycytidylic acid
(poly(I:C)), a TLR3 agonist which mimics the natural TLR3
ligand dsRNA .
Toll-like receptor 3 binds double-stranded RNA ,
overall general attenuation of responses to TLR ligands.
Normally, ligation of TLR3 leads to DC production of type I
interferons (IFN-? and IFN-?), DC maturation (including
expression of MHC class II, adhesion, and costimulatory
molecules), and production of proinflammatory cytokines
such as IL-12 [115, 116]. Upon stimulation with poly(I:C),
myeloid DCs (mDCs) isolated from human cord blood
produce significantly lower levels of bioactive IL-12 and
IFN-? and have diminished
costimulatory molecules CD40 and CD80 when compared
with DCs isolated from adult blood . Diminished ex
vivo production of IFN-? by newborn peripheral blood
mononuclear cells (PBMCs) relative to adults has also been
demonstrated after exposure to viruses , including HSV
. Although TLR3 is expressed in keratinocytes ,
genital mucosa , and the central nervous system
(including fetal astrocytes) [122, 123], the relative responses
of adult and neonatal cells other than DCs to TLR3 agonists
have not been assessed.
Studies of innate immunity in newborns suggest an
upregulation of the
between TLR3 signaling and HSV encephalitis, several
studies have further clarified potential roles for TLR3 in the
immune response to HSV infection. Pretreatment of murine
genital mucosa with the TLR3 ligand poly(I:C) protects
against subsequent genital HSV-2 challenge, with no
detectable mucosal replication of virus [124, 125]. This
effect may be mediated by stimulation of IFN-? production,
but does not appear to be due to production of IFN-?, IFN-?,
or TNF-? . Cultured human female genital epithelial
In accordance with the above-mentioned relationship
6 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
cells demonstrate a similar resistance to HSV-2 infection
after pre-treatment with poly(I:C) . The NT2-N cell
line, which models postmitotic human neurons, also
expresses TLR3 and responds to poly(I:C) with production
of IFN-? . Somewhat surprisingly, infecting NT2-N
cells with HSV-1 does not lead to IFN-? production, though
rabiesvirus infection does . It is unclear whether this is
due to HSV interference with dsRNA-sensing pathways;
HSV is known to inhibit type I IFN production during acute
infection, perhaps in part through expression of the virion
host shutoff (vhs) protein [129, 130]. Also, acute neuronal
infection may cause differing patterns of gene expression
and different innate responses compared with latency or
reactivation. Glial cells may also play a role in TLR3-
mediated innate protection of neurons from HSV infection.
Murine microglia express multiple TLRs, and respond to
TLR agonists with cytokine production and upregulation of
costimulatory molecules . TLR3 stimulation of
astrocytes with poly(I:C) induces production of IDO ,
which as discussed below and in the section on placental
immunity may have direct anti-HSV and anti-CMV activity
CMV infection, at least in some tissues. Poly(I:C) treatment
inhibits CMV replication in cultured human ectocervical
tissue and foreskin fibroblasts in an IFN-?-dependent
manner . Treatment of cultured human fetal astrocytes
with poly(I:C) or IFN-? inhibits CMV replication, an effect
that may be mediated by IDO production  or by the
anti-viral protein viperin . Studies of murine infection
with the murine version of CMV (MCMV) have shown less
anti-viral activity associated with TLR3 stimulation, since
the absence of TLR3 does not increase MCMV replication
 or susceptibility of mice to infection .
TLR3 signaling is thought to be involved in control of
differences in TLR3-mediated responses of newborn humans
confer increased susceptibility to infection or disease after
exposure to HSV or CMV. There are also no published
studies which show increased susceptibility of TLR3 knock-
out mice to experimental HSV infection, nor are there in
vitro studies in which cells expressing TLR3 have been
shown to be less susceptible to infection with HSV or CMV.
Redundancy in innate antiviral responses may in part explain
the lack of any effects.
It is not completely clear whether developmental
Toll-Like Receptor 2
positive bacterial lipopeptides . TLR2 can form
heterodimers with TLR1 or TLR6 to recognize various
microbial components . Although specific viral ligands
for TLR2 have not been identified , recent studies
suggest that TLR2 may be involved in innate responses to
HSV and CMV infection. In contrast to TLR3, however,
evidence suggests that TLR2 signaling may lead to increased
pathology after HSV infection. These studies support the
concept advanced by several investigators that the
inflammatory response may exacerbate pathology in HSV
TLR2 was initially identified as a sensor of Gram-
susceptibility to central nervous system HSV infection. Mice
deficient in TLR2 have a diminished cytokine response and
Like TLR3, TLR2 signaling has been associated with
intraperitoneal HSV-1 infection , with the difference in
mortality more pronounced in newborn (4 day old) mice than
adults. These observations were related to increased cytokine
(IL-6) and chemokine production (MCP-1) in wild-type mice
relative to TLR2 knockout mice; similar observations have
recently been made in a murine model of HSV eye infection
. Kurt-Jones et al. also showed that PBMCs from
newborn humans responded to HSV with increased
production of pro-inflammatory cytokines (IL-6 and IL-8)
compared with adult cells , a finding sometimes
observed in other experimental systems comparing innate
responses of newborn vs adult PBMCs [146-148]. The
authors suggest that unlike the observation of dampened
signaling through TLR3 in newborns relative to adults, there
may be an enhanced response to signaling through TLR2,
explaining the greater susceptibility of newborns to HSV
mortality from neurologic disease after
infection. Polymorphisms in the human gene for TLR2 are
associated with increased recurrences of HSV-2 genital
lesions and increased viral shedding in humans . As
noted for TLR3 signaling, some murine glial cells also
respond to HSV in a TLR2 dependent manner .
Other studies support a role for TLR2 signaling in HSV
infection has been called into question by the in vitro
observation that clinical isolates are rarely detected by
TLR2, and only certain laboratory HSV strains are detected
. This study found that clinical and some laboratory
HSV isolates generally exist as a collection of subspecies of
viral clones, most of which do not activate TLR2, and that
TLR2 and TLR9 are sequentially engaged by HSV clones
recognized by TLR2. A large fraction of this TLR2-
dependent recognition of HSV by DCs requires TLR9.
Subspecies which do not stimulate TLR2 may still stimulate
TLR9. It is also notable that in mice, delivery of TLR-2
ligands (peptidoglycan) to vaginal mucosa is not protective
against subsequent HSV-2 challenge . Together, these
observations highlight the redundancy in innate detection
and suggest the possibility of greater importance for TLR9
relative to TLR2 in detection of HSV. Importantly, control
of murine infection in the brain may require synergistic
activity of both TLR2 and TLR9  (discussed further
The relative importance of TLR2 signaling in HSV
of CMV infection , and signaling of TLR2 in response
to CMV is strongly enhanced by the co-receptor CD14.
Interaction with TLR2, likely in heterodimeric form with
TLR1, involves the CMV envelope glycoproteins gB and gH
. Clinically, a TLR2 polymorphism in liver transplant
patients is associated with elevated CMV replication, and
homozygosity for this polymorphism confers increased risk
of CMV disease . Treatment of cultured human
ectocervical tissue with the TLR2 agonist lipoteichoic acid
leads to inhibition of CMV replication in an IFN-?-
dependent manner, but similar treatment in foreskin
fibroblasts (which do not express TLR2) did not demonstrate
inhibition . In vitro, the TLR2-induced response to
human CMV was recently shown to specifically lead to the
production of inflammatory cytokines, while the type I
interferon response was independent of TLR2 signaling
TLR2 has been demonstrated to play a role in detection
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 7
. A role for TLR2 signaling in fetal infection is
supported by the demonstration of a TLR2-dependent
inflammatory response after exposure to CMV in an in vitro
model of human syncytiotrophoblast,
independent of DNA transcription . The importance of
TLR2 in controlling CMV infection has also been shown for
mice: deficiency of TLR2 leads to elevated MCMV
replication in vivo, which may be related to NK cell
recruitment, proliferation, or sensitivity to apoptosis .
Toll-Like Receptor 9
CpG motifs . The relative importance of TLR9 in
overall human response to HSV or CMV infections is
unclear, though the lack of signaling through TLR9 by itself
does not appear to produce
susceptibility to viral disease . Signaling through
several of the toll-like receptors, including TLR9, involves
the adaptor molecule IL-1R-associated kinase 4 (IRAK-4)
. Humans with IRAK-4 deficiency are at increased risk
for infections with some bacteria [160, 161], but do not
appear to be predisposed to severe viral infection ,
again suggesting redundancy in human innate anti-viral
sensing. Fibroblasts and PBMCs from patients with IRAK-4
deficiency produce identical levels of type I IFNs in
response to HSV (and other viruses) ex vivo compared with
controls . Despite this, PBMCs from these patients
produce no type I IFNs in response to the TLR9 agonist CpG
. The authors note that although this evidence suggests
that IRAK-4 deficiency (and therefore signaling though
TLR9) may not by itself predispose to severe viral infection,
very few patients have been diagnosed with IRAK-4
deficiency, leaving open the possibility that more serious
viral infections may have occurred in undiagnosed cases.
TLR9 recognizes double-stranded DNA unmethylated at
detect both HSV-1 and CMV, presumably through TLR9
. Cord blood pDCs stimulated with these viruses were
found to produce less IFN-? than their adult counterparts,
which was not attributable to lower expression of TLR9 on
cord blood pDCs . In mice, viral DNA from both HSV-
1  and HSV-2 [163, 164] is detected by pDCs and
conventional DCs (myeloid; cDCs) through TLR9. As noted
above, in conventional DCs TLR9 appears to detect
subspecies of HSV which may or may not be detected by
TLR2 ; pDCs do not express TLR2 , and therefore
appear to primarily use TLR9 to sense HSV. Recent studies
suggest that pDCs provide the bulk of the early IFN-?
response to HSV infection via TLR9 detection, while at later
times other cell types produce IFN-? and IFN-? by TLR9-
independent mechanisms . TLR9-deficient mice are
more susceptible than wild-type mice to genital challenge
with HSV-2, with a significant impairment of local mucosal
responses observed in the absence of TLR9 .
Synergistic responses via TLR2 and TLR9 after herpes
simplex infection were recently demonstrated after HSV
infection in mice . In this study, mice lacking both
TLR2 and TLR9 had lower titers of virus in the brain but not
the liver after intraperitoneal infection with HSV-2, relative
to single knockout mice or wild-type mice. Similarly,
TLR2/9 double knockout mice were more susceptible to
intravaginal infection than wild-type mice, and had higher
viral titers in brain but not in vaginal washes or spinal cords.
Circulating human plasmacytoid dendritic cells (pDCs)
Synergy in cytokine production was not associated with the
expression of TLR2 or TLR9 within different cells types,
leading the authors to suggest that both receptors are
necessary and act through multiple cell types for a complete
response to HSV infection .
TLR9 deficiency. As noted above, in vivo recognition of
MCMV depends on TLR9, although multiple pathways, both
TLR-dependent and independent,
establishing adaptive immunity to MCMV . Control of
CMV infection in mice is related to combined signaling
through TLR3 and TLR9, with TLR9-deficient mice more
susceptible to mortality after MCMV infection than TLR3-
deficient or wild-type mice . TLR9-dependent cytokine
production stimulates viral clearance by a specific
population of NK cells expressing a receptor recognizing
MCMV . More recent studies suggest that some of the
redundancy in innate sensing of MCMV may be mediated by
TLR7, which has not previously been implicated in sensing
of DNA viruses .
Susceptibility of mice to MCMV is associated with
are important in
sensing pathways may potentiate susceptibility to severe
infection in individual patients, the above data are consistent
with the possibility that TLR-mediated control of viral
infection has differential effects within different tissues.
Supporting this possibility is a recent study showing that
TLR9 was necessary for IFN-? production in spleens but not
livers of mice infected with MCMV . Absence of TLR9
did not affect MCMV titers in liver compared with control
mice, while MCMV titers in spleen were significantly higher
in TLR9 knockout mice relative to wild-type.
In addition to the observation that redundant antiviral
Other Innate Sensors of Viral Infection
mechanisms capable of recognizing RNA in the antiviral
response. The cytosolic RNA helicases retinoic acid-
inducible gene I (RIG-I) and melanoma-differentiation-
associated gene 5 (MDA5) induce type I IFN expression in
response to RNA, through the mitochondrial antiviral
signaling protein (MAVS) adaptor . Activation of the
MAVS pathway has been suggested to be important in the
type I IFN responses of murine embryonic fibroblasts and
perhaps macrophages after HSV infection , and has
also been shown to affect the expression of the anti-MCMV
protein viperin . Innate sensors of cytosolic DNA have
also been recently described , but their relevance to
HSV and CMV infections remains to be determined.
Increasing evidence implicates other innate sensing
Interaction of HSV Glycoproteins with Immune Receptors
not been well described for HSV or CMV, but recent work
suggests that at least for HSV envelope glycoproteins are
detected by innate sensors. Conventional DCs were
demonstrated to become activated and produce IFN-? and
IL-10 in response to a combination of the four essential HSV
glycoproteins gD, gB, and the heterodimer gH-gL .
Although these proteins are involved in viral entry , this
maturation process was independent of membrane fusion or
the interaction of gD with its known receptors. Previous
work suggested that HSV envelope glycoproteins may
induce type I interferon secretion through interactions with
the chemokine receptors CCR3 and CXCR4 . Further
The viral determinants of innate immune signaling have
8 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
work is needed to understand precisely how herpesvirus
glycoproteins stimulate innate immune responses, and
whether these processes are altered in the newborn.
newborns may be related to lower cytokine production
relative to adults. DCs and other antigen-presenting cells
from cord blood generally produce lower levels of cytokines
than comparable adult cells to various stimuli ex vivo
(reviewed in ). In both premature and term infants,
fewer PBMC produce IFN-? in response to HSV stimulation
than adults, and lower levels of IFN-? are produced on a per
cell basis . However, most investigators report an
increased number of pDCs in cord blood relative to adult
blood samples .
Effective control of viral infection in fetuses and
HSV infection may be inferred by the observation that HSV
inhibits type I IFN signaling at several levels [178, 179].
Signaling through the IFN?/? receptor involves activation of
Tyk2 and JAK1, which leads to phosphorylation of STAT2
and formation of a STAT1-STAT2 heterodimer, which
translocates to the nucleus and associates with additional
proteins to stimulate transcription of interferon-inducible
genes . JAK1 and STAT2 are depleted in cells infected
with HSV-1 in vitro, due partly to the viral vhs protein 
and to increased expression of endogenous inhibitors .
Human deficiency in STAT1 (which is also involved in
response to type II IFN, such as IFN-?) confers susceptibility
to severe HSV infection; a patient with homozygous Stat1
mutation died from disseminated HSV with recurrent
encephalitis . A patient with a homozygous Tyk2
mutation was described as having recurrent skin and oral
mucosal lesions caused by HSV . In mice, the absence
of receptors for type I IFNs  and the lack of Stat1 
leads to increased HSV replication in the nervous system and
The importance of type I IFN signaling to control of
of CMV infection. Like HSV, both human  and murine
 CMV express proteins inhibiting type I IFN
production. Human CMV expresses a protein which
complexes with the STAT1-STAT2 heterodimer to prevent
binding to promoters of IFN-responsive genes , while
MCMV expresses a protein which despite selectively
binding STAT2 interferes with both type I and type II IFN
activity . In vivo, control of viral replication is impaired
in mice lacking the receptor for type I IFN (IFN?/?R-/-)
[186, 187] and in mice lacking Tyk2 , relative to wild-
type mice. Intracranial injection of MCMV into either
newborn or adult mice leads to much higher type I IFN
expression in adult brains than in newborns, and exogenous
IFN-?, IFN-?, or IFN-?, or poly (I:C) protected human brain
tissue against CMV infection and cell death in vitro .
Together, although relative deficiencies in TLR signaling
and type I IFN may contribute to the susceptibility of
newborns and fetuses to HSV and CMV, the complexity and
interrelatedness of these signaling pathways suggests that it
is likely that additional host-virus adaptations and occasional
susceptibility mutations remain to be discovered.
The type I IFN response is also important to the control
effective control of HSV and CMV infections. As alluded to
Numerous other cytokines are thought to be important for
in the previous section, IFN-? is involved in control of acute
neuronal infection, and has also been shown to be critical to
the recall response in murine intravaginal HSV-2 infection
 and for maintaining neuronal latency (reviewed in
). Additional cytokines implicated in immune control of
HSV and CMV infection include TNF-? [192, 193], IL-12
[194-197], IL-18 , IL-23 , and IL-1? . Again,
relative roles for these cytokines in the predisposition of the
fetus and newborn to HSV or CMV infection have not been
clearly delineated. Recently, production of IL-6 and TNF-?
were found to be reduced in newborn murine skin after
infection with HSV (Jones CA, unpublished observations).
Human mutations in genes involved in some cytokine
signaling pathways can predispose to severe disease from
HSV, including mutations in NF-?B essential modulator
(NEMO) . However, patients receiving anti-TNF-?
therapy are not generally thought to be at increased risk for
herpesvirus reactivation , despite case reports of severe
CMV  and HSV  disease. Studies have not been
reported which assess whether patients receiving anti-TNF-?
treatment shed virus more frequently or in higher amounts.
Humans with mutations leading to deficiencies in IL-12 or
IL-23  are also not known to be at increased risk of
severe HSV or CMV disease.
Dendritic Cells (DCs)
been an intense area of research, and recent reviews have
highlighted some of the complex interactions between
certain populations of DCs and HSV [202, 203] or CMV
. HSV can infect immature human cDCs but not pDCs
efficiently in vitro [205, 206], impairing their maturation
[206, 207] and inducing apoptosis [205, 208]. Apoptosis of
murine DCs after HSV infection has also been demonstrated,
and appears to be induced more rapidly by HSV-2 than
HSV-1 . Impairment of maturation in immature
neonatal murine DCs after HSV-2 infection was greater than
in corresponding adult cells . Murine studies have
shown that infected Langerhans cells and dermal cDCs do
not directly stimulate CD4+ and CD8+ T-cell responses after
HSV-1 infection, but carry antigen to draining lymph nodes
where different DC subsets act to cross-present antigen to
promote T-cell activation [210, 211]. Similar mechanisms of
direct DC infection with subsequent apoptosis and cross-
presentation of antigen by uninfected lymph node-resident
DCs have been proposed for CMV . Along with B cells
(and to a lesser extent other APCs), mucosal cDCs are also
important in recall responses to mucosal challenge in mice
The understanding of virus-dendritic cell interactions has
DC take up HSV, perhaps with greater propensity than adult
DCs (Jones CA, unpublished observations). Neonatal DC
maturation is also impaired after HSV infection, and these
cells migrate out of skin to the draining lymph nodes more
slowly than adult DCs
observations). Little is known about the cDC response in
human newborns, particularly after HSV or CMV infection.
Recent experiments in mice have shown that neonatal
(Jones CA, unpublished
infection by producing significant amounts of IFN-? and
developing antigen-presenting function to stimulate antigen-
specific T cell proliferation [165, 212]. Recent work has
Plasmacytoid DCs are known to respond to viral
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 9
shown that human pDCs, which are not normally found in
skin, migrate to dermis in response to recurrent genital HSV
. These cells remain resistant to HSV infection, and
participate in the proliferation of HSV-specific lymphocytes.
A specific role for pDCs in neonatal HSV or CMV infection
has not been as well-studied, though the importance of TLR9
to both pDC responses  and to control of HSV and
CMV infection (discussed above), and the relative deficiency
in IFN-? production by neonatal pDCs , suggests that
attenuated pDC responses may contribute to fetal and
neonatal susceptibility to these viruses. Willems et al. 
have recently reviewed differences in DC function between
neonates and adults, and note the importance of the type I
IFN/Flt3L signaling pathways to neonatal DC activation.
Natural Killer (NK) Cells
proposed to be a major contributor to the severity of neonatal
HSV disease . These deficiencies may either be
intrinsic, or related to the diminished production of type I
IFNs and other NK cell-activating cytokines in newborns
. The activation of NK cells is complex, involving
dendritic cells and cytokines such as type I IFNs, IL-12, and
IL-18 . Studies in mice and case reports in humans
suggest that deficiencies in at least some components of NK
activation may confer susceptibility to herpesvirus infection
Deficiencies in NK cell responses of newborns have been
defects in NK number or function are commonly associated
with susceptibility to herpesvirus infection . A patient
with altered expression of the Fc receptor for IgG type IIIA
(also known as Fc?RIIIA or CD16-II) was reported as
suffering from recurrent infections, particularly with herpes
simplex . This mutation was associated with a marked
reduction in spontaneous NK cell activation. A patient with
apparent isolated NK deficiency had severe interstitial
pneumonia associated with
subsequently required IV antiviral therapy after primary
HSV infection .
Although isolated human NK cell deficiency is rare,
CMV infection, and
infection has been well-described, and has been recently
reviewed . Resistance of different strains of mice to
MCMV infection reflects the effectiveness of their NK response
to infection . Although NK cell-mediated killing of HSV-
and CMV-infected cells is associated with downregulation of
class I MHC molecules on the surface of the infected cell ,
NK cell control of MCMV infection also involves direct
recognition of the viral m157 protein by the NK activation
receptor Ly49H . The expression of Ly49H on NK cells
varies among different mouse strains, in direct relation to the
susceptibility of these strains to MCMV infection . A
human parallel to this observation has not been identified. In
addition to Ly49H, other host genetic factors influencing NK
cells are also involved in resistance to MCMV [226-228].
Although several studies support the concept that neonatal
susceptibility to herpesvirus infections may be related to NK
cell deficits [216, 229-235], the molecular details of these
findings remain to be elucidated. The importance to neonatal
and congenital disease of a subpopulation of NK cells known as
NKT cells in early control of HSV [236-238] and CMV
infection  also remains to be further defined.
The importance of the NK response in murine CMV
influence immunity to HSV and CMV infections, any of
which may contribute to some degree to neonatal
susceptibility to disease (Table 2). Many innate responses
appear to be redundant, making elucidation of their relative
importance challenging. Data in mice and humans suggests
that cytokine production mediated by TLR2 may influence
immunopathology of neonatal HSV infection [143, 145].
TLR2 signaling may be important to congenital CMV
infection as well [152, 156]. A general dampening of
cytokine production in newborns may affect their response to
infection . Neonatal dendritic cell and NK cell function
may differ from adults after HSV (Jones, CA, unpublished
observations) or CMV infection.
Numerous aspects of the innate immune response
and CMV disease in the fetus and newborn is well-described,
and will only receive brief mention here. Pre-existing
maternal humoral immunity to HSV  or CMV  is
partially protective against the development of disease in
utero or in the perinatal period. In addition to serostatus, the
avidity of anti-HSV maternal antibodies is correlated with
neonatal disease . The human fetus can respond to in
utero CMV infection with antibody production , but it
is not clear to what degree (if any) these responses provide
protection against disease.
The importance of passive antibody protection to HSV
dissemination in the newborn. Infants with disseminated
disease were less likely to have detectable neutralizing
antibody titers in the first week of illness than those with
other clinical presentations of HSV disease . Studies in
mice showed that maternal immunization with a replication-
defective virus reduced visceral dissemination in their pups
after oral challenge, supporting the role of maternal IgG in
limiting viral dissemination . Adult mice can be
protected against HSV disease with passive antibody transfer
, but neutralizing activity did not correlate with
protection against HSV disease in a mouse model of
encephalitis . Human vaccine studies have also shown
that high titers of neutralizing antibody are unable to protect
against sexual transmission , though this may have
different pathogenesis than neonatal disease. It is also
noteworthy that antibodies per se are not required for
adequate control of HSV or CMV infections. Patients with
primary antibody deficiencies
agammaglobulinemia) [250, 251], common variable immune
deficiency , or complete IgA deficiency , are not
known to be at risk for severe herpesvirus infections.
Circulating antibodies may provide partial protection
neonatal HSV disease by limiting HSV
was intrinsically biased toward antigenic tolerance [253,
254]. However, responses to antigenic challenge in the
newborn may under certain conditions behave like those of
the adult [255, 256]. Ridge et al. showed that the balance
between the antigen dose and the number of antigen-
Early studies suggested that neonatal cellular immunity
10 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
presenting cells at the site of T-cell activation influences the
TH1-TH2 bias , and Sarzotti et al. demonstrated that
infection with high doses of a murine retrovirus biased
murine newborn T-cells towards a TH2 cytokine pattern
. Neonatal cellular immune responses often show a
strong TH2 bias [257-259], particularly with secondary
stimulation . Selective apoptosis of TH1 cells generated
during the primary response may contribute to this bias
( and Jones CA, unpublished observations).
lymphocyte proliferative responses [244, 262], associated
with decreased IFN-? production . These studies were
done by bulk stimulation with HSV antigen, and responses at
the single cell level have not been measured in detail in
pediatric patients using flow cytometric techniques. More
recently, neonatal mice have been demonstrated to generate a
paucity of both TH1 and TH2 cytokines relative to adult mice
in response to infection with a replication-defective strain of
HSV-2 . Studies of the human newborn T-cell response
to CMV have been conducted on cord blood samples [264-
266], and although these responses can in some cases
resemble those of adults, they do not correlate well with
presence of disease .
Older studies of HSV-specific responses in neonatal HSV
have suggested diminished HSV-specific
newborn response to HSV show diminished proliferation and
cytokine production in response to stimulation with HSV
antigen [244, 262]. Burchett et al. compared responses of
circulating lymphocytes between individuals with primary
HSV infection, including 13 newborn infants, three
parturient women, and nine nonparturient adults .
Lymphocyte proliferation and IFN-? (but not TNF-?)
production were specifically diminished in response to
stimulation with HSV antigen in newborn and parturient
patients compared to nonparturient adults. These responses
became comparable to those of nonparturient adults only
three to six weeks after symptom onset, leading the authors
to suggest that delayed acquisition of specific cellular
Investigations of the role of T-cells in the human
immunity may predispose to more severe clinical disease
Ridge et al. , Evans and Jones found that neonatal mice
could develop TH1-biased CD4+ T-cell responses in draining
lymph nodes at lower levels of HSV challenge .
However, although TH2-biased responses could be generated
in adult mice at high infectious doses of replication-
incompetent or inactivated virus, newborn responses (TH1 or
TH2) were attenuated relative to the adult responses at the
same conditions . Notably, newborn mice infected with
a strain of HSV-1 capable of only a single replicative cycle
were protected against subsequent challenge, and generated
antibodies, CD4+ T-cells, and CD8+ T-cells which responded
to virus and were each separately protective against
challenge with wild-type virus in transfer experiments .
CD4+ T-cell responses to CMV in children differ from
those in adults. Relative to adults, young children have lower
IFN-? and IL-2 production by CD4+ T-cells on a per-cell
basis, as assessed by intracellular cytokine staining in
response to CMV antigen . These cells also express
lower levels of CD154 (CD40 ligand) than adult cells .
The development of this response in young infants was
recently followed in a prospective cohort study in the
Gambia; this study supported the above observations, but
also noted no differences in responses between congenitally
infected infants and those acquiring CMV postnatally .
Despite these observations, none of the infected children in
this study were found to have CMV disease. Further studies
are needed to understand the role cellular immunity may play
in explaining the different clinical presentations of CMV
disease and asymptomatic infection.
In mice, somewhat consistent with the observations of
circulating lymphocytes from HSV-infected newborns with
HSV antigen leads to diminished lymphocyte proliferation
compared to adults were likely measuring primarily CD4+
responses [244, 262]. Information on HSV-specific CD8+ T-
The studies discussed above showing that stimulation of
Influence of Innate Immune Responses on Relative Susceptibility of Newborns to HSV or CMV Infection
Ex vivo production of IFN-? in response to HSV is diminished in
newborn PBMCs relative to adults 
Poly(I:C) stimulation of cord blood mDCs induces lower cytokine responses than adults 
TLR2-/- mice less susceptible than wild-type to mortality after
HSV-1 infection, with difference more pronounced in neonates
than adults 
Inflammatory response to CMV in human placental cells
in vitro depends on TLR2 
TLR9 Cord blood pDCs stimulated with HSV-1 or CMV produce less IFN-? than adults 
IL-6 and IL-8 production increased in newborn PBMCs exposed
to HSV relative to adults , but IL-6 and TNF-? are reduced
in newborn murine skin (Jones, CA, unpublished observations)
IFN-? production by neonatal PBMCs is lower after stimulation
with HSV than adult PBMCs 
Type I IFNs are produced in lower amounts in newborn
mice than adults after intracranial injection 
Maturation of neonatal murine DCs infected with HSV is
impaired more than in adults , and migration to draining
lymph nodes is slower (Jones, CA, unpublished observations)
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 11
cell responses is largely limited to studies in mice. Newborn
mice infected with HSV develop a delayed CD8+ T-cell
response in draining lymph nodes compared with adult mice,
with a lower peak activity . This response is
independent of HSV dose, in contrast with the findings for
HSV-specific CD4+ T-cells . Despite the delayed and
attenuated HSV-specific response, neonatal CD8+ T-cells
were observed to upregulate expression of activation markers
in vivo earlier than adults, but expression of these markers
was not sustained . It is possible that dysregulation of
the early antigen-specific CD8+ T-cell response in newborns
contributes to their relative difficulty in controlling HSV
CD8+ T-cells are present in identical frequencies and have
detectable intracellular IFN-? perforin expression production
at identical levels as adults, despite persisting high
concentrations of virus in urine . CMV infection in
utero leads to detectable CMV-specific CD8+ T-cells as
early as 28 weeks gestation, and CMV-specific CD8+ T-cells
from congenitally infected infants produce cytokines in
response to antigen and can lyse target cells loaded with
CMV peptide . Despite a seemingly functional anti-
CMV CD8+ T-cell response in the 28-week old fetus,
symptomatic CMV disease was apparent , suggesting
that CD8+ T-cell responses alone do not explain the different
presentations of symptomatic CMV disease vs asymptomatic
infection. Notably, the functional responses measured in this
study represent recall responses on secondary antigenic
stimulation, and would not measure relative defects in
primary induction of CD8+ responses in newborns and
fetuses relative to adults.
In CMV infection of young children, CMV-specific
Regulatory T-Cells (Tregs)
Regulatory T-cells (Tregs) are a population of CD25+
CD4+ T-cells involved in establishing and maintaining
immunologic tolerance . During infection, these cells
may function to limit associated tissue damage . This
has been shown in a mouse model of HSV eye infection,
where depletion of Tregs led to significant worsening of
stromal keratitis, both by minimizing induction of HSV-
specific CD4+ T-cells and by limiting the migration of CD4+
T-cells to the site of infection . Tregs have also been
shown to attenuate HSV-specific CD8+ T-cell responses in
the murine footpad model of HSV-1 infection . In
contrast, recent studies in the murine HSV-2 vaginal
challenge model show increased mucosal pathology and
morbidity in mice depleted of Tregs during the acute phase
of infection , suggesting that the influence of Tregs
may depend on the site of initial infection.
same proportions as adults. T-cells with a Treg phenotype
(CD4+CD25+) are detected in the thymus of a human fetus as
early as 13 weeks gestation, and extrathymic CD4+CD25+
cells are detected after 14 weeks gestation . The overall
percentage of Tregs in newborn humans is comparable to
that of adults, and consists of between about 3 and 7% of the
total CD4+ T-cell population . In mice, Tregs comprise
between 5 and 10% of the CD4+ population; unlike humans,
murine Tregs are not detected in the periphery before day 3
of life . Peripheral lymphoid Tregs reach adult levels in
mice by about day 7 of life .
Newborn humans and mice appear to have Tregs in the
phenotype has recently been described which is less
susceptible to CD95L (Fas ligand)-mediated apoptosis .
These cells constitute a minority of the Treg population in
adults and appear to decrease in frequency with increasing
age. In cord blood, almost all Tregs belong to this naïve
possibility that Tregs in newborns may dampen the acute
response to infection more effectively than adults, a
potentially detrimental effect in some infectious settings.
The attenuated HSV-specific CD4+ and CD8+ T-cell
responses observed in neonatal mice may be related to Tregs
. Consistent with prior studies in adult mice ,
HSV-specific IFN-? production by T-cells is enhanced in
both neonatal and adult mice depleted of Tregs before
infection. However, in the absence of Tregs the expansion,
activation, and cytotoxicity of HSV-specific CD8+ T-cells
four days after infection is enhanced only in neonatal mice.
Treg depletion also leads to reduced HSV titers in draining
lymph nodes and brain in neonates, suggesting that Treg-
mediated suppression of the antiviral response may
contribute to the enhanced virulence of this virus in
newborns . However, a separate study in adult mice
showed increased morbidity and mortality in association
with increased viral titers with ablation of Tregs during the
acute phase of genital HSV-2 infection . Although
higher levels of IFN-? and IFN-? were measured in the
draining lymph nodes of Treg-deficient mice, levels of pro-
inflammatory cytokines were lower in the mucosa, and
corresponded to a decrease in the inflammatory infiltrate,
suggesting a role for Tregs in coordinating cell trafficking
during acute infection .
A subpopulation of human Tregs with a naïve surface
This suggests the
has also been described . Depletion of Tregs from adult
human PBMC led to increased IFN-? production by anti-
CMV CD8+ T-cells ex vivo, an effect which was reversed by
adding back the depleted Tregs. Specific relevance of this
finding to newborn or fetal CMV responses has not been
demonstrated, but it may be speculated that the relative
absence of Tregs in early gestation may contribute to
immunopathology associated with congenital infection.
Regulatory T-cell suppression of anti-CMV responses
infection appears to be a complex balance of various effector
cells, antigenic load, and perhaps other factors (Table 3).
Overall, newborns infected with HSV appear to demonstrate
attenuated cellular immune
proliferation and cytokine production affected. CMV
infection may also lead to some attenuation in CD4+
responses in young children, though no obvious differences
in CD8+ T-cell responses have not been found between
newborns, young children, and adults after CMV infection.
The influence of Tregs on newborn responses to either HSV
or CMV infection is only beginning to be understood, but
immunopathology in the fetus and newborn may be
influenced by the presence of Tregs.
The cellular immune response of the newborn to viral
responses, with both
CONCLUSIONS AND FUTURE DIRECTIONS
differences to older children and adult in their immune
The newborn display both quantitative and functional
12 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
response to HSV and CMV. These differences appear in all
arms of the immune response. Some but not all newborn
responses to herpesviruses are attenuated or delayed,
resulting in impaired induction of protective adaptive
responses and memory (e.g. HSV CD8+ T-cell responses).
Other neonatal responses are heightened (e.g. CNS responses
to TLR2, or Treg responses), resulting in greater
immunopathology. Differences between the newborn
response to HSV and CMV to the immunocompetent and
between each virus provide important lessons about the
requirements for protective immunity to both viruses and
about the immunobiology of HSV and CMV.
Sexually Transmitted Infections and Topical Microbicides
(STI-TM) Cooperative Research Center and by a Child
Health Research Career Development Award through the
Department of Pediatrics, Feinberg School of Medicine, and
Children’s Memorial Research Center at Northwestern
University. DMK receives support from National Institutes
of Health Grant AI30731.
WJM is sponsored by grants through the Midwest
 Pellett PE, Roizman B. The Family Herpesviridae: A Brief
Introduction. In: Knipe DM, Howley PM, editors. Fields Virology.
Philadelphia, PA: Lippincott, Williams, & Wilkins; 2007. p. 2479 -
Corey L. Herpes Simplex Virus. In: Mandell G, Bennett J, Dolin R,
editors. Principles and Practice of Infectious Diseases. 6th ed.
Philadelphia, Pennsylvania: Churchill Livingstone; 2005.
Crumpacker CS, Wadhwa S. Cytomegalovirus. In: Mandell GL,
Bennett JE, Dolin R, editors. Principles and Practice of Infectious
Diseases. 6th ed. Philadelphia: Churchill Livingstone; 2005.
Roizman B, Knipe D, Whitley R. Herpes Simplex Viruses. In:
Knipe D, Howley P, Eds. Fields Virology. 5th ed. Philadelphia:
Lippincott Williams & Wilkins; 2007.
Mocarski Jr. ES, Shenk T, Pass RF. Cytomegalovirus. In: Knipe
DM, Howley PM, editors. Fields Virology. 5th ed. Philadelphia:
Lippincott Williams & Wilkins; 2007.
Whitley R, Davis EA, Suppapanya N. Incidence of neonatal herpes
simplex virus infections in a managed-care population. Sex Transm
Dis 2007; 34(9): 704-8.
 Morris S, Bauer H, Samuel M, Gallagher D, Bolan G. Neonatal
herpes morbidity and mortality in California, 1995-2003. Sex
Transm Dis 2008 2007; 35(1): 14-8.
Jones CA, Isaacs D, McIntyre P, Cunningham A, Garland S.
Neonatal herpes simplex virus infection. In: Mahajan D, Zurynski
Y, Peadon E, Elliott EJ, editors. Australian Paediatric Surveillance
Unit Research Report, 2005-6. Sydney2006. p. 24-5.
Kimberlin DW. Neonatal HSV infections: the global picture.
Herpes 2004; 11(2): 31-2.
Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol
Rev 2004 ; 17(1): 1-13.
Kimberlin DW, Lin CY, Jacobs RF, et al. Natural history of
neonatal herpes simplex virus infections in the acyclovir era.
Pediatrics 2001; 108(2): 223-9.
Gutman LT, Wilfert CM, Eppes S. Herpes simplex virus
encephalitis in children: analysis of cerebrospinal fluid and
progressive neurodevelopmental deterioration. J Infect Dis 1986;
Kimura H, Aso K, Kuzushima K, Hanada N, Shibata M,
Morishima T. Relapse of herpes simplex encephalitis in children.
Pediatrics 1992; 89(5 Pt 1): 891-4.
Stagno S, Pass RF, Dworsky ME, Alford CA. Congenital and
perinatal cytomegalovirus infections. Semin Perinatol 1983; 7(1):
Istas AS, Demmler GJ, Dobbins JG, Stewart JA. Surveillance for
congenital cytomegalovirus disease: a report from the National
Congenital Cytomegalovirus Disease Registry. Clin Infect Dis
1995; 20(3): 665-70.
Demmler GJ. Infectious Diseases Society of America and Centers
for Disease Control. Summary of a workshop on surveillance for
congenital cytomegalovirus disease. Rev Infect Dis 1991; 13(2):
Nance WE, Lim BG, Dodson KM. Importance of congenital
cytomegalovirus infections as a cause for pre-lingual hearing loss. J
Clin Virol 2006; 35(2): 221-5.
Williamson WD, Desmond MM, LaFevers N, Taber LH, Catlin FI,
Weaver TG. Symptomatic congenital cytomegalovirus. Disorders
of language, learning, and hearing. Am J Dis Child 1982; 136(10):
Pass RF, Stagno S, Myers GJ, Alford CA. Outcome of
symptomatic congenital cytomegalovirus infection: results of long-
term longitudinal follow-up. Pediatrics 1980; 66(5): 758-62.
Williamson WD, Percy AK, Yow MD, et al. Asymptomatic
congenital cytomegalovirus infection. Audiologic, neuroradiologic,
and neurodevelopmental abnormalities during the first year. Am J
Dis Child 1990; 144(12): 1365-8.
Williamson WD, Demmler GJ, Percy AK, Catlin FI. Progressive
hearing loss in infants with
cytomegalovirus infection. Pediatrics 1992; 90(6): 862-6.
Influence of Adaptive Immune Responses on Relative Susceptibility of Newborns to HSV or CMV Infection
Humoral immunity Circulating antibodies may limit viral dissemination [244, 245]
Overall diminished proliferation and IFN-? production of
newborn PBMCs relative to adults in response to HSV antigen
Cord blood PBMCs after congenital infection can function
comparably to adult cells [264-266]
Paucity of TH1 and TH2 cytokines after HSV infection in
neonatal mice relative to adults 
Lower IFN-? and IL-2 production by CD4+ T-cells in
response to CMV antigen in young children relative to
Lower expression of CD154 (CD40 ligand) in CMV-
specific CD4+ T-cells from young children compared with
adult cells 
CD8+ T-cell response in draining lymph nodes is delayed in
newborn mice infected with HSV compared with adults, with a
lower peak activity 
Young children have identical frequencies of CMV-specific
CD8+ T-cells and detection of intracellular IFN-? perforin as
Expansion, activation, and cytotoxicity of HSV-specific CD8+
T-cells in the absence of Tregs is enhanced in neonatal but not
adult mice .
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 13
 Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA.
Symptomatic congenital cytomegalovirus infection: neonatal
morbidity and mortality. Pediatr Infect Dis J 1992; 11(2): 93-9.
Hamprecht K, Maschmann J, Jahn G, Poets CF, Goelz R.
Cytomegalovirus transmission to preterm infants during lactation. J
Clin Virol 2008; 41(3): 198-205.
Lewis DB, Wilson CB. Developmental immunology and role of
host defenses in fetal and neonatal susceptibility to infection. In:
Remington JS, Klein JO, Wilson CB, Baker CJ, editors. Infectious
Diseases of the Fetus and Newborn. 6th ed. Philadelphia: Elsevier
Saunders; 2006. p. 87-210.
Trowsdale J, Betz AG. Mother's little helpers: mechanisms of
maternal-fetal tolerance. Nat Immunol 2006; 7(3): 241-6.
Morein B, Blomqvist G, Hu K. Immune responsiveness in the
neonatal period. J Comp Pathol 2007; 137 (Suppl 1): S27-31.
Yosipovitch G, Maayan-Metzger A, Merlob P, Sirota L. Skin
barrier properties in different body areas in neonates. Pediatrics
2000; 106(1 Pt 1): 105-8.
Lorenzo M, Ploegh H, Tirabassi R. Viral immune evasion
strategies and the underlying cell biology. Semin Immunol 2001;
Tortorella D, Gewurz B, Furman M, Schust D, Ploegh H. Viral
subversion of the immune system. Annu Rev Immunol 2000; 18:
Alcami A, Koszinowski U. Viral mechanisms of immune evasion.
Trends Microbiol 2000; 8(9): 410-8.
Parham P. NK cells and trophoblasts: partners in pregnancy. J Exp
Med 2004 18; 200(8): 951-5.
Pazmany L, Mandelboim O, Vales-Gomez M, Davis DM, Reyburn
HT, Strominger JL. Protection from natural killer cell-mediated
lysis by HLA-G expression on target cells. Science 1996;
LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED. HLA-
G1-expressing antigen-presenting cells induce immunosuppressive
CD4+ T cells. Proc Natl Acad Sci USA 2004; 101(18): 7064-9.
Murphy SP, Choi JC, Holtz R. Regulation of major
histocompatibility complex class II gene expression in trophoblast
cells. Reprod Biol Endocrinol 2004; 2: 52.
Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic
fetal rejection by tryptophan catabolism. Science 1998; 281(5380):
Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance
and tryptophan catabolism. Nat Rev Immunol 2004; 4(10): 762-74.
Tilburgs T, Roelen DL, van der Mast BJ, et al. Evidence for a
selective migration of fetus-specific CD4+CD25bright regulatory T
cells from the peripheral blood to the decidua in human pregnancy.
J Immunol 2008; 180(8): 5737-45.
Drake PM, Gunn MD, Charo IF, et al. Human placental
cytotrophoblasts attract monocytes and CD56(bright) natural killer
cells via the actions of monocyte inflammatory protein 1alpha. J
Exp Med 2001; 193(10): 1199-212.
Simister NE, Story CM, Chen HL, Hunt JS. An IgG-transporting
Fc receptor expressed in the syncytiotrophoblast of human
placenta. Eur J Immunol 1996 ; 26(7): 1527-31.
Burton GJ, Sibley CP, Jauniaux ERM. Placental Anatomy and
Physiology. In: Gabbe SG, Niebyl JR, Simpson JL, editors.
Obstetrics: Normal and Problem Pregnancies. 5th ed. Philadelphia:
Churchill Livingstone; 2007.
Levy O. Innate immunity of the newborn: basic mechanisms and
clinical correlates. Nat Rev Immunol 2007; 7(5): 379-90.
Chatterjee A, Chartrand SA, Harrison CJ, Felty-Duckworth A,
Bewtra C. Severe intrauterine herpes simplex disease with
placentitis in a newborn of a mother with recurrent genital infection
at delivery. J Perinatol 2001; 21(8): 559-64.
Vasileiadis GT, Roukema HW, Romano W, Walton JC, Gagnon R.
Intrauterine herpes simplex infection. Am J Perinatol 2003; 20(2):
Johnston C, Magaret A, Selke S, Remington M, Corey L, Wald A.
Herpes Simplex Virus Viremia during Primary Genital Infection. J
Infect Dis 2008.
Pereira L, Maidji E, McDonagh S, Genbacev O, Fisher S. Human
cytomegalovirus transmission from the uterus to the placenta
correlates with the presence of pathogenic bacteria and maternal
immunity. J Virol 2003; 77(24): 13301-14.
 McDonagh S, Maidji E, Ma W, Chang HT, Fisher S, Pereira L.
Viral and bacterial pathogens at the maternal-fetal interface. J
Infect Dis 2004; 190(4): 826-34.
Montgomery RI, Warner MS, Lum BJ, Spear PG. Herpes simplex
virus-1 entry into cells mediated by a novel member of the
TNF/NGF receptor family. Cell 1996; 87(3): 427-36.
Lopez M, Eberle F, Mattei MG, et al. Complementary DNA
characterization and chromosomal localization of a human gene
related to the poliovirus receptor-encoding gene. Gene 1995;
Gill RM, Ni J, Hunt JS. Differential expression of LIGHT and its
receptors in human placental villi and amniochorion membranes.
Am J Pathol 2002 ; 161(6): 2011-7.
Gill RM, Coleman NM, Hunt JS. Differential cellular expression of
LIGHT and its receptors in early gestation human placentas. J
Reprod Immunol 2007; 74(1-2): 1-6.
Allen RH, Tuomala RE. Herpes simplex virus hepatitis causing
acute liver dysfunction and thrombocytopenia in pregnancy. Obstet
Gynecol 2005; 106(5 Pt 2): 1187-9.
Yaziji H, Hill T, Pitman TC, Cook CR, Schrodt GR. Gestational
herpes simplex virus hepatitis. South Med J 1997; 90(3): 347-51.
Kang AH, Graves CR. Herpes simplex hepatitis in pregnancy: a
case report and review of the literature. Obstet Gynecol Surv 1999;
Brown Z, Selke S, Zeh J, et al. The acquisition of herpes simplex
virus during pregnancy. N Engl J Med 1997; 337(8): 509-15.
Mostoufi-zadeh M, Driscoll SG, Biano SA, Kundsin RB. Placental
evidence of cytomegalovirus infection of the fetus and neonate.
Arch Pathol Lab Med 1984; 108(5): 403-6.
Jarvis MA, Nelson JA. Human cytomegalovirus persistence and
latency in endothelial cells and macrophages. Curr Opin Microbiol
2002; 5(4): 403-7.
Jarvis MA, Nelson JA. Human cytomegalovirus tropism for
endothelial cells: not all endothelial cells are created equal. J Virol
2007; 81(5): 2095-101.
Pereira L, Maidji E, McDonagh S, Tabata T. Insights into viral
transmission at the uterine-placental interface. Trends Microbiol
2005; 13(4): 164-74.
Griffith BP, McCormick SR, Fong CK, Lavallee JT, Lucia HL,
Goff E. The placenta as a site of cytomegalovirus infection in
guinea pigs. J Virol 1985; 55(2): 402-9.
Fisher S, Genbacev O, Maidji E, Pereira L. Human
cytomegalovirus infection of placental cytotrophoblasts in vitro and
in utero: implications for transmission and pathogenesis. J Virol
2000; 74(15): 6808-20.
Trincado DE, Munro SC, Camaris C, Rawlinson WD. Highly
sensitive detection and localization of maternally acquired human
cytomegalovirus in placental tissue by in situ polymerase chain
reaction. J Infect Dis 2005; 192(4): 650-7.
Roth I, Corry DB, Locksley RM, Abrams JS, Litton MJ, Fisher SJ.
Human placental cytotrophoblasts produce the immunosuppressive
cytokine interleukin 10. J Exp Med 1996; 184(2): 539-48.
Maidji E, McDonagh S, Genbacev O, Tabata T, Pereira L.
Maternal antibodies enhance or prevent cytomegalovirus infection
in the placenta by neonatal Fc receptor-mediated transcytosis. Am J
Pathol 2006; 168(4): 1210-26.
Tabata T, McDonagh S, Kawakatsu H, Pereira L. Cytotrophoblasts
infected with a pathogenic human cytomegalovirus strain
dysregulate cell-matrix and cell-cell adhesion molecules: a
quantitative analysis. Placenta 2007; 28(5-6): 527-37.
Wang X, Huong SM, Chiu ML, Raab-Traub N, Huang ES.
Epidermal growth factor receptor is a cellular receptor for human
cytomegalovirus. Nature 2003 24; 424(6947): 456-61.
Wang X, Huang DY, Huong SM, Huang ES. Integrin alphavbeta3
is a coreceptor for human cytomegalovirus. Nat Med 2005; 11(5):
Feire AL, Koss H, Compton T. Cellular integrins function as entry
receptors for human cytomegalovirus via a highly conserved
disintegrin-like domain. Proc Natl Acad Sci USA 2004; 101(43):
Soroceanu L, Akhavan A, Cobbs C. Platelet-derived growth factor-
alpha receptor activation is required for human cytomegalovirus
infection. Nature 2008 ; 455(7211): 391-5.
Maidji E, Genbacev O, Chang HT, Pereira L. Developmental
regulation of human cytomegalovirus receptors in cytotrophoblasts
14 Current Immunology Reviews, 2010, Vol. 6, No. 1 Muller et al.
correlates with distinct replication sites in the placenta. J Virol
2007; 81(9): 4701-12.
Saji M, Taga M, Matsui H, Suyama K, Kurogi K, Minaguchi H.
Gene expression and specific binding of platelet-derived growth
factor and its effect on DNA synthesis in human decidual cells.
Mol Cell Endocrinol 1997; 132(1-2): 73-80.
Huard B, Fruh K. A role for MHC class I down-regulation in NK
cell lysis of herpes virus-infected cells. Eur J Immunol 2000; 30(2):
Adams O, Besken K, Oberdorfer C, MacKenzie CR, Takikawa O,
Daubener W. Role of indoleamine-2,3-dioxygenase in alpha/beta
and gamma interferon-mediated antiviral effects against herpes
simplex virus infections. J Virol. 2004; 78(5): 2632-6.
Bodaghi B, Goureau O, Zipeto D, Laurent L, Virelizier JL,
Michelson S. Role of IFN-gamma-induced indoleamine 2,3
dioxygenase and inducible nitric oxide synthase in the replication
of human cytomegalovirus in retinal pigment epithelial cells. J
Immunol 1999; 162(2): 957-64.
Brown Z, Wald A, Morrow R, Selke S, Zeh J, Corey L. Effect of
serologic status and cesarean delivery on transmission rates of
herpes simplex virus from mother to infant. JAMA 2003; 289(2):
Cartlidge P. The epidermal barrier. Semin Neonatol 2000; 5(4):
Eichenfield LF, Hardaway CA. Neonatal dermatology. Curr Opin
Pediatr 1999 ; 11(5): 471-4.
Nizet V, Ohtake T, Lauth X, et al. Innate antimicrobial peptide
protects the skin from invasive bacterial infection 2001; 414: 454-
Howell MD, Wollenberg A, Gallo RL, et al. Cathelicidin
deficiency predisposes to eczema herpeticum. J Allergy Clin
Immunol. 2006; 117(4): 836-41.
Jenssen H, Hamill P, Hancock RE. Peptide antimicrobial agents.
Clin Microbiol Rev 2006; 19(3): 491-511.
Braff MH, Gallo RL. Antimicrobial peptides: an essential
component of the skin defensive barrier. Curr Top Microbiol
Immunol 2006; 306: 91-110.
Mathews M, Jia HP, Guthmiller JM, et al. Production of beta-
defensin antimicrobial peptides by the oral mucosa and salivary
glands. Infect Immun 1999 ; 67(6): 2740-5.
Frohm Nilsson M, Sandstedt B, Sorensen O, Weber G, Borregaard
N, Stahle-Backdahl M. The human cationic antimicrobial protein
(hCAP18), a peptide antibiotic, is widely expressed in human
squamous epithelia and colocalizes with interleukin-6. Infect
Immun 1999; 67(5): 2561-6.
Gordon YJ, Huang LC, Romanowski EG, Yates KA, Proske RJ,
McDermott AM. Human cathelicidin (LL-37), a multifunctional
peptide, is expressed by ocular surface epithelia and has potent
antibacterial and antiviral activity. Curr Eye Res. 2005; 30(5): 385-
McNamara NA, Van R, Tuchin OS, Fleiszig SM. Ocular surface
epithelia express mRNA for human beta defensin-2. Exp Eye Res
1999; 69(5): 483-90.
Narayanan S, Miller WL, McDermott AM. Expression of human
beta-defensins in conjunctival epithelium: relevance to dry eye
disease. Invest Ophthalmol Vis Sci 2003; 44(9): 3795-801.
Woo JS, Jeong JY, Hwang YJ, Chae SW, Hwang SJ, Lee HM.
Expression of cathelicidin in human salivary glands. Arch
Otolaryngol Head Neck Surg 2003 129(2): 211-4.
Dorschner RA, Lin KH, Murakami M, Gallo RL. Neonatal skin in
mice and humans expresses increased levels of antimicrobial
peptides: innate immunity during development of the adaptive
response. Pediatr Res 2003; 53(4): 566-72.
Walker VP, Akinbi HT, Meinzen-Derr J, Narendran V, Visscher
M, Hoath SB. Host defense proteins on the surface of neonatal
skin: implications for innate immunity. J Pediatr 2008; 152(6): 777-
Murakami M, Ohtake T, Dorschner RA, Gallo RL. Cathelicidin
antimicrobial peptides are expressed in salivary glands and saliva. J
Dent Res 2002; 81(12): 845-50.
Ong PY, Ohtake T, Brandt C, et al. Endogenous antimicrobial
peptides and skin infections in atopic dermatitis. N Engl J Med
2002; 347(15): 1151-60.
Wollenberg A, Wetzel S, Burgdorf W, Haas J. Viral infections in
atopic dermatitis: pathogenic aspects and clinical management. J
Allergy Clin Immunol 2003 ; 112(4): 667-74.
 Hazrati E, Galen B, Lu W, et al. Human alpha- and beta-defensins
block multiple steps in herpes simplex virus infection. J Immunol
2006; 177(12): 8658-66.
John M, Keller MJ, Fam EH, et al. Cervicovaginal secretions
contribute to innate resistance to herpes simplex virus infection. J
Infect Dis 2005; 192(10): 1731-40.
Akkarawongsa R, Potocky TB, English E, Gellman SH, Brandt CR.
Inhibition of Herpes Simplex Virus Type 1 Infection by Cationic ?-
Peptides. Antimicrob Agents Chemother 2008; 52(6): 2120-9.
Sinha S, Cheshenko N, Lehrer RI, Herold BC. NP-1, a rabbit alpha-
defensin, prevents the entry and intercellular spread of herpes
simplex virus type 2. Antimicrob Agents Chemother 2003; 47(2):
Yasin B, Wang W, Pang M, et al. Theta defensins protect cells
from infection by herpes simplex virus by inhibiting viral adhesion
and entry. J Virol 2004 ; 78(10): 5147-56.
Daher KA, Selsted ME, Lehrer RI. Direct inactivation of viruses by
human granulocyte defensins. J Virol 1986; 60(3): 1068-74.
van der Strate BW, Beljaars L, Molema G, Harmsen MC, Meijer
DK. Antiviral activities of lactoferrin. Antiviral Res 2001; 52(3):
Andersen JH, Osbakk SA, Vorland LH, Traavik T, Gutteberg TJ.
Lactoferrin and cyclic lactoferricin inhibit the entry of human
cytomegalovirus into human fibroblasts. Antiviral Res 2001; 51(2):
Andersen JH, Jenssen H, Gutteberg TJ. Lactoferrin and
lactoferricin inhibit Herpes simplex 1 and 2 infection and exhibit
synergy when combined with acyclovir. Antiviral Res 2003; 58(3):
Andersen JH, Jenssen H, Sandvik K, Gutteberg TJ. Anti-HSV
activity of lactoferrin and lactoferricin is dependent on the presence
of heparan sulphate at the cell surface. J Med Virol 2004; 74(2):
Marchetti M, Trybala E, Superti F, Johansson M, Bergstrom T.
Inhibition of herpes simplex virus infection by lactoferrin is
dependent on interference with
glycosaminoglycans. Virology 2004; 318(1): 405-13.
Jenssen H, Andersen JH, Uhlin-Hansen L, Gutteberg TJ, Rekdal O.
Anti-HSV activity of lactoferricin analogues is only partly related
to their affinity for heparan sulfate. Antiviral Res 2004; 61(2): 101-
van der Strate BW, Harmsen MC, Schafer P, et al. Viral load in
breast milk correlates with transmission of human cytomegalovirus
to preterm neonates, but lactoferrin concentrations do not. Clin
Diagn Lab Immunol 2001; 8(4): 818-21.
Dunkle LM, Schmidt RR, O'Connor DM. Neonatal herpes simplex
infection possibly acquired via maternal breast milk. Pediatrics
1979; 63(2): 250-1.
Sullivan-Bolyai JZ, Fife KH, Jacobs RF, Miller Z, Corey L.
Disseminated neonatal herpes simplex virus type 1 from a maternal
breast lesion. Pediatrics 1983 ; 71(3): 455-7.
Stagno S, Cloud GA. Working parents: the impact of day care and
breast-feeding on cytomegalovirus infections in offspring. Proc
Natl Acad Sci USA. 1994 29; 91(7): 2384-9.
Kohl S. The neonatal human's immune response to herpes simplex
virus infection: a critical review. Pediatr Infect Dis J 1989; 8(2):
Kohl S. The immune response of the neonate to herpes simplex
virus infection. In: Rouse BT, Lopez C, editors. Immunobiology of
herpes simplex virus infection. Boca Raton, FL: CRC Press, Inc.;
1984. p. 121-9.
Wilson CB. Immunologic basis for increased susceptibility of the
neonate to infection. J Pediatr 1986; 108(1): 1-12.
Kawai T, Akira S. Pathogen recognition with Toll-like receptors.
Curr Opin Immunol 2005; 17(4): 338-44.
Jin MS, Lee JO. Structures of the toll-like receptor family and its
ligand complexes. Immunity 2008; 29(2): 182-91.
Casrouge A, Zhang SY, Eidenschenk C, et al. Herpes simplex virus
encephalitis in human UNC-93B deficiency. Science 2006;
Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in
patients with herpes simplex encephalitis. Science 2007;
Cella M, Salio M, Sakakibara Y, Langen H, Julkunen I,
Lanzavecchia A. Maturation, activation, and protection of dendritic
the virus binding to
Immunobiology of Herpes Simplex Virus and Cytomegalovirus Infections Current Immunology Reviews, 2010, Vol. 6, No. 1 15 Download full-text
cells induced by double-stranded RNA. J Exp Med 1999; 189(5):
Manetti R, Annunziato F, Tomasevic L, et al. Polyinosinic acid:
polycytidylic acid promotes T helper type 1-specific immune
responses by stimulating macrophage production of interferon-
alpha and interleukin-12. Eur J Immunol 1995 ; 25(9): 2656-60.
De Wit D, Tonon S, Olislagers V, et al. Impaired responses to toll-
like receptor 4 and toll-like receptor 3 ligands in human cord blood.
J Autoimmun 2003 ; 21(3): 277-81.
Neustock P, Kruse A, Bock S, St Pierre B, Kirchner H. Deficient
interferon-alpha response of newborns in comparison to adults.
Lymphokine Cytokine Res 1993 ; 12(2): 109-14.
Cederblad B, Riesenfeld T, Alm GV. Deficient herpes simplex
virus-induced interferon-alpha production by blood leukocytes of
preterm and term newborn infants. Pediatr Res 1990; 27(1): 7-10.
Kollisch G, Kalali BN, Voelcker V, et al. Various members of the
Toll-like receptor family contribute to the innate immune response
of human epidermal keratinocytes. Immunology 2005; 114(4): 531-
Fazeli A, Bruce C, Anumba DO. Characterization of Toll-like
receptors in the female reproductive tract in humans. Hum Reprod
2005; 20(5): 1372-8.
Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E.
Preferential expression and function of Toll-like receptor 3 in
human astrocytes. J Neuroimmunol 2005; 159(1-2): 12-9.
Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of
Toll-like receptors in the human central nervous system. J
Neuropathol Exp Neurol 2002; 61(11): 1013-21.
Ashkar A, Yao X, Gill N, Sajic D, Patrick A, Rosenthal K. Toll-
like receptor (TLR)-3, but not TLR4, agonist protects against
genital herpes infection in the absence of inflammation seen with
CpG DNA. J Infect Dis 2004; 190(10): 1841-9.
Herbst-Kralovetz MM, Pyles RB. Quantification of poly(I: C)-
mediated protection against genital herpes simplex virus type 2
infection. J Virol 2006; 80(20): 9988-97.
Gill N, Deacon PM, Lichty B, Mossman KL, Ashkar AA.
Induction of innate immunity against herpes simplex virus type 2
infection via local delivery of Toll-like receptor ligands correlates
with beta interferon production. J Virol 2006 ; 80(20): 9943-50.
MacDonald EM, Savoy A, Gillgrass A, et al. Susceptibility of
human female primary genital epithelial cells to herpes simplex
virus, type-2 and the effect of TLR3 ligand and sex hormones on
infection. Biol Reprod 2007; 77(6): 1049-59.
Prehaud C, Megret F, Lafage M, Lafon M. Virus infection switches
TLR-3-positive human neurons to become strong producers of beta
interferon. J Virol 2005 ; 79(20): 12893-904.
Duerst RJ, Morrison LA. Herpes simplex virus 2 virion host shutoff
protein interferes with type I interferon production and
responsiveness. Virology 2004; 322(1): 158-67.
Melroe GT, DeLuca NA, Knipe DM. Herpes simplex virus 1 has
multiple mechanisms for blocking virus-induced interferon
production. J Virol 2004 ; 78(16): 8411-20.
Olson J, Miller S. Microglia initiate central nervous system innate
and adaptive immune responses through multiple TLRs. J Immunol
2004; 173(6): 3916-24.
Suh HS, Zhao ML, Rivieccio M, et al. Astrocyte indoleamine 2,3-
dioxygenase is induced by the TLR3 ligand poly(I: C): mechanism
of induction and role in antiviral response. J Virol 2007; 81(18):
Harwani SC, Lurain NS, Zariffard MR, Spear GT. Differential
inhibition of human cytomegalovirus (HCMV) by toll-like receptor
ligands mediated by interferon-beta in human foreskin fibroblasts
and cervical tissue. Virol J 2007; 4: 133.
Rivieccio MA, Suh HS, Zhao Y, et al. TLR3 ligation activates an
antiviral response in human fetal astrocytes: a role for viperin/cig5.
J Immunol 2006; 177(7): 4735-41.
Delale T, Paquin A, Asselin-Paturel C, et al. MyD88-dependent
and -independent murine cytomegalovirus sensing for IFN-alpha
release and initiation of immune responses in vivo. J Immunol
2005; 175(10): 6723-32.
Edelmann KH, Richardson-Burns S, Alexopoulou L, Tyler KL,
Flavell RA, Oldstone MB. Does Toll-like receptor 3 play a
biological role in virus infections? Virology 2004; 322(2): 231-8.
Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R,
Golenbock D. Cutting edge: recognition of Gram-positive bacterial
cell wall components by the innate immune system occurs via Toll-
like receptor 2. J Immunol 1999; 163(1): 1-5.
Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate
immunity. Cell 2006; 124(4): 783-801.
Sato A, Linehan MM, Iwasaki A. Dual recognition of herpes
simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl
Acad Sci USA 2006 14; 103(46): 17343-8.
Lundberg P, Ramakrishna C, Brown J, et al. The immune response
to herpes simplex virus type 1 infection in susceptible mice is a
major cause of central nervous system pathology resulting in fatal
encephalitis. J Virol 2008; 82(14): 7078-88.
Sergerie Y, Boivin G, Gosselin D, Rivest S. Delayed but not early
glucocorticoid treatment protects the host during experimental
herpes simplex virus encephalitis in mice. J Infect Dis 2007;
Fitch M, van de Beek D. Drug Insight: steroids in CNS infectious
diseases--new indications for an old therapy. Nat Clin Pract Neurol
2008; 4(2): 97-104.
Kurt-Jones EA, Chan M, Zhou S, et al. Herpes simplex virus 1
interaction with Toll-like receptor 2 contributes to lethal
encephalitis. Proc Natl Acad Sci USA 2004; 101(5): 1315-20.
Sarangi PP, Kim B, Kurt-Jones E, Rouse BT. Innate recognition
network driving herpes simplex
immunopathology: role of the toll pathway in early inflammatory
events in stromal keratitis. J Virol 2007; 81(20): 11128-38.
Kurt-Jones EA, Belko J, Yu C, et al. The role of toll-like receptors
in herpes simplex infection in neonates. J Infect Dis 2005; 191(5):
Karlsson H, Hessle C, Rudin A. Innate immune responses of
human neonatal cells to bacteria from the normal gastrointestinal
flora. Infect Immun 2002; 70(12): 6688-96.
Schultz C, Rott C, Temming P, Schlenke P, Moller JC, Bucsky P.
Enhanced interleukin-6 and interleukin-8 synthesis in term and
preterm infants. Pediatr Res 2002; 51(3): 317-22.
Mohamed MA, Cunningham-Rundles S, Dean CR, Hammad TA,
Nesin M. Levels of pro-inflammatory cytokines produced from
cord blood in-vitro are pathogen dependent and increased in
comparison to adult controls. Cytokine 2007 ; 39(3): 171-7.
Bochud P, Magaret A, Koelle D, Aderem A, Wald A.
Polymorphisms in TLR2 are associated with increased viral
shedding and lesional rate in patients with genital herpes simplex
virus type 2 infection. J Infect Dis 2007; 196(4): 505-9.
Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR.
Cutting edge: TLR2-mediated proinflammatory cytokine and
chemokine production by microglial cells in response to herpes
simplex virus. J Immunol 2005; 175(7): 4189-93.
Sørensen L, Reinert L, Malmgaard L, Bartholdy C, Thomsen A,
Paludan S. TLR2 and TLR9 synergistically control herpes simplex
virus infection in the brain. J Immunol 2008; 181(12): 8604-12.
Compton T, Kurt-Jones EA, Boehme KW, et al. Human
cytomegalovirus activates inflammatory cytokine responses via
CD14 and Toll-like receptor 2. J Virol 2003 ; 77(8): 4588-96.
Boehme KW, Guerrero M, Compton T. Human cytomegalovirus
envelope glycoproteins B and H are necessary for TLR2 activation
in permissive cells. J Immunol 2006; 177(10): 7094-102.
Kijpittayarit S, Eid AJ, Brown RA, Paya CV, Razonable RR.
Relationship between Toll-like receptor 2 polymorphism and
cytomegalovirus disease after liver transplantation. Clin Infect Dis
2007; 44(10): 1315-20.
Juckem LK, Boehme KW, Feire AL, Compton T. Differential
initiation of innate immune responses induced by human
cytomegalovirus entry into fibroblast cells. J Immunol 2008;
Chan G, Guilbert LJ.
cytomegalovirus induces placental syncytiotrophoblast apoptosis in
a Toll-like receptor-2 and tumour necrosis factor-alpha dependent
manner. J Pathol 2006; 210(1): 111-20.
Szomolanyi-Tsuda E, Liang X, Welsh RM, Kurt-Jones EA, Finberg
RW. Role for TLR2 in NK cell-mediated control of murine
cytomegalovirus in vivo. J Virol 2006; 80(9): 4286-91.
Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor
recognizes bacterial DNA. Nature 2000; 408(6813): 740-5.
Yang K, Puel A, Zhang S, et al. Human TLR-7-, -8-, and -9-
mediated induction of IFN-alpha/beta and -lambda Is IRAK-4
dependent and redundant for protective immunity to viruses.
Immunity 2005; 23(5): 465-78.
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