Interferon interplay helps tissue cells to cope with SARS-coronavirus infection.
ABSTRACT SARS coronavirus (SARS-CoV), the causative agent of severe acute respiratory syndrome, is a versatile pathogen armed with a host of factors countering the antiviral type I interferon (IFN) system. Hence, tissue cells infected with SARS-CoV are unable to launch an IFN response. Plasmacytoid dendritic cells, however, produce high levels of IFN after infection. We recently demonstrated that minute amounts of IFN applied before infection (IFN priming) can ameliorate the IFN response of tissue cells to SARS-CoV. IFN priming of SARS-CoV-infected cells activated genes for IFN transcription, IFN signaling, antiviral effector proteins, ubiquitinylation and ISGylation, antigen presentation, and other cytokines and chemokines, whereas IFN treatment or infection alone had no major effect. Thus, the IFN which is produced by plasmacytoid dendritic cells could enable tissue cells to at least partially overturn the SARS-CoV-induced block in innate immune activation.
[show abstract] [hide abstract]
ABSTRACT: An outbreak of severe acute respiratory syndrome (SARS) has been reported in Hong Kong. We investigated the viral cause and clinical presentation among 50 patients. We analysed case notes and microbiological findings for 50 patients with SARS, representing more than five separate epidemiologically linked transmission clusters. We defined the clinical presentation and risk factors associated with severe disease and investigated the causal agents by chest radiography and laboratory testing of nasopharyngeal aspirates and sera samples. We compared the laboratory findings with those submitted for microbiological investigation of other diseases from patients whose identity was masked. Patients' age ranged from 23 to 74 years. Fever, chills, myalgia, and cough were the most frequent complaints. When compared with chest radiographic changes, respiratory symptoms and auscultatory findings were disproportionally mild. Patients who were household contacts of other infected people and had older age, lymphopenia, and liver dysfunction were associated with severe disease. A virus belonging to the family Coronaviridae was isolated from two patients. By use of serological and reverse-transcriptase PCR specific for this virus, 45 of 50 patients with SARS, but no controls, had evidence of infection with this virus. A coronavirus was isolated from patients with SARS that might be the primary agent associated with this disease. Serological and molecular tests specific for the virus permitted a definitive laboratory diagnosis to be made and allowed further investigation to define whether other cofactors play a part in disease progression.The Lancet 05/2003; 361(9366):1319-25. · 38.28 Impact Factor
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ABSTRACT: Plasmacytoid dendritic cells (pDC) have emerged as a principal subset of dendritic cells in both human and mouse. PDC morphology, surface markers, their migration in vivo and the ability to rapidly produce large amounts of type I interferons (IFN-alpha/beta) in response to toll like receptor (TLR) triggering sets them apart from other dendritic cell subsets. This review highlights the features that make pDC uniquely able to sense and respond to viral infection.Seminars in Immunology 09/2005; 17(4):253-61. · 6.39 Impact Factor
Article: Innate immunity to virus infection.[show abstract] [hide abstract]
ABSTRACT: The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Three classes of receptors, designated retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), Toll-like receptors (TLRs), and nucleotide oligomerization domain (NOD)-like receptors (NLRs), sense viral components, such as double-stranded RNA (dsRNA), single-stranded RNA, and DNA. RLRs and TLRs play essential roles in the production of type I interferons (IFNs) and proinflammatory cytokines in cell type-specific manners. While the RLRs play essential roles in the recognition of RNA viruses in various cells, plasmacytoid dendritic cells utilize TLRs for detecting virus invasion. NLRs play a role in the production of mature interleukin-1 beta to dsRNA stimulation. Activation of innate immune cells is critical for mounting adaptive immune responses. In this review, we discuss recent advances in our understanding of the mechanisms of viral RNA recognition by these different types of receptors and its relation to acquired immune responses.Immunological Reviews 02/2009; 227(1):75-86. · 11.15 Impact Factor
www.landesbioscience.com Virulence 273
Virulence 1:4, 273-275; July/August 2010; © 2010 Landes Bioscience
Addendum to: Kuri T, Zhang X, Habjan M,
Martínez-Sobrido L, García-Sastre A, Yuan Z,
Weber F. Interferon priming enables cells to
partially overturn the SARS-Coronavirus-induced
block in innate immune activation. J Gen Virol
2009; 90:2686–94; PMID: 19625461; DOI: 10.1099/
Key words: SARS, interferon antago-
nism, plasmacytoid dendritic cells, inter-
feron priming, interferon induction
Previously published online:
*Correspondence to: Friedemann Weber;
ratory syndrome, is a versatile pathogen
armed with a host of factors countering
the antiviral type I interferon (IFN) sys-
tem. Hence, tissue cells infected with
SARS-CoV are unable to launch an IFN
response. Plasmacytoid dendritic cells,
however, produce high levels of IFN after
infection. We recently demonstrated that
minute amounts of IFN applied before
infection (IFN priming) can amelio-
rate the IFN response of tissue cells to
SARS-CoV. IFN priming of SARS-CoV-
infected cells activated genes for IFN
transcription, IFN signaling, antiviral
effector proteins, ubiquitinylation and
ISGylation, antigen presentation, and
other cytokines and chemokines, whereas
IFN treatment or infection alone had no
major effect. Thus, the IFN which is
produced by plasmacytoid dendritic cells
could enable tissue cells to at least par-
tially overturn the SARS-CoV-induced
block in innate immune activation.
ARS coronavirus (SARS-CoV), the
causative agent of severe acute respi-
In 2002, the first epidemic of the new
millenium was provoked by an emerging
virus which caused severe acute respiratory
syndrome (SARS). The outbreak quickly
spread in 28 countries around the globe and
resulted in 8,000 infected people of which
approximately 10% had a fatal course.1
The causative agent was found to be a coro-
navirus subsequently named SARS-CoV.2-5
There is evidence that bats are the reser-
voir host of this virus, since sequences of
closely related viruses were found in these
animals.6-8 Most probably, SARS-CoV ini-
tially spilled over from bats to humans via
an intermediate host like palm civets.
Interferon interplay helps tissue cells
to cope with SARS-coronavirus infection
Thomas Kuri and Friedemann Weber*
Abteilung Virologie; Institut für Medizinische Mikrobiologie und Hygiene; Universität Freiburg; Freiburg, Germany
In order to establish infection and
accomplish spread from one subject or
even species to another, viruses have to
cope with a range of antiviral mechanisms.
The type I interferon (IFNα/β) system
marks the first line of defence with potent
antiviral activity and therefore represents
a powerful part of the innate immune
system of vertebrates.9,10 Depending on
the cell type and on the pathogen, the
IFN system can be activated by different
pathways. IFN production in tissue cells
is preferentially induced after an infection
was recognized by cytoplasmic pattern
recognition receptors (PRRs) which sense
so-called pathogen associated molecu-
lar patterns (PAMP). Prominent virus
PAMPs are double-stranded RNA and
5'triphosphorylated RNA.11,12 Activated
PRRs trigger a signaling cascade which
leads to the induction and secretion of
IFNs, finally resulting in the upregulation
of IFN-stimulated genes (ISG) and in the
establishment of an antiviral state in unin-
fected neighbouring cells. Crucial tran-
scription factors involved in the induction
of IFN are members of the IFN-regulatory
factor (IRF) family. The activation of
IRF-3 represents a pivotal step of IFN
induction in cells of non-lymphoid origin,
like tissue cells.13
SARS-CoV displays a certain IFN
sensitivity. Pre-treatment of cell culture
or animals with ectopic IFN decreases
virus titers and relieves pathogenesis.14-17
However, SARS-CoV employs several
strategies to prevent the activation of
the IFN system.18,19 Firstly, SARS-CoV
replicates in cytoplasmic compartments
surrounded by a double-layer of mem-
branes. This intracellular hiding most
274 Virulence Volume 1 issue 4
immune response can be restored by IFN
priming to some extent.
SARS-CoV massively remodels the
endoplasmatic reticulum (ER)—Golgi
compartment in order to establish sites
for viral replication and budding.20,21,36
Surprisingly, these rearrangements had
no influence on protein secretion, since
primed cells secreted exactly the amounts
of IFN which were expected from the
measured IFNβ mRNA levels. However,
despite the clear transcriptional response
after IFN priming and SARS-CoV infec-
tion, neither IRF-3 nor IRF-7 were visibly
activated. This may indicate that IRF-3
and IRF-7 can be active at sub-detectable
levels which are sufficient to launch an
In a patient study which examined 40
clinically well-defined human SARS cases,
high levels of IFN were found in pre-
crisis patients, but not in crisis patients,
and early production of IFN correlated
with a beneficial outcome for the infected
individuals.37 In line with this, SARS-
CoV-infected macaques launch an IFN
response early after infection.38 Several
IFN-producing cells were found which
were not identified, but it is likely that this
might have been pDCs. Collectively these
data indicate that SARS-CoV infected
pDCs produce IFN which spreads via
the bloodstream and primes tissue cells
to prepare them for infection. It is likely
that such an interplay between profes-
sional IFN producing cells and tissue cells
is a common mechanism that allows an
improved response against viruses.
1. WHO. Summary table of SARS cases by coun-
try, 1 November 2002–26 September 2003. http://
2. Drosten C, Gunther S, Preiser W, van der Werf S,
Brodt HR, Becker S, et al. Identification of a novel
coronavirus in patients with severe acute respiratory
syndrome. N Engl J Med 2003; 348:1967-76.
3. Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR,
Peret T, Emery S, et al. A novel coronavirus associ-
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J Med 2003; 348:1953-66.
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GF, van Amerongen G, van Riel D, et al. Newly dis-
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to produce large amounts of IFN after
infection with SARS-CoV (Fig. 1).31
It is long known that cells which
came in contact with small amounts of
IFN (‘priming’), are able to enhance
their response to virus infection.32-34
This set-up resembles the assumed in
vivo situation in which IFN produced
by SARS-CoV-infected pDCs may
be influencing the surrounding tissue
cells. Therefore, in our recent study we
investigated how IFN priming alters the
transcriptional response of tissue cells
to SARS-CoV infection.35 Global gene
expression profiles and specific analysis of
selected genes revealed that IFN-primed
cells infected with SARS-CoV not only
upregulated the genes for IFNβ itself,
but also those for IFN transcription fac-
tors, IFN signalling components, anti-
viral effector proteins, ubiquitinylation
and ISGylation machineries, antigen
presentation, and other cytokines and
chemokines. Thus, despite the presence
of several anti-IFN strategies employed
by SARS-CoV, activation of the innate
likely results in a spatial separation of the
viral PAMPs and the cellular PRRs.20-22
Furthermore, SARS-CoV actively inhib-
its the activation of IRF-3.23 To date, five
different proteins of this particular virus
have been shown to target IRF-3, in order
to prevent the activation of the IFN sys-
tem.24-26 Moreover, unspecific degradation
of host mRNA can also affect IFN induc-
tion.27,28 As a consequence, tissue cells
are not able to launch an antiviral IFN
response after being infected with SARS-
CoV (Fig. 1).23
Plasmacytoid dendritic cells (pDCs)
are so-called ‘professional’
producing cells. These cells utilize Toll-
like receptors (TLRs) and IRF-7 to
recognize pathogen structures and induce
IFN transcription, respectively.29 The
TLRs of pDCs are located in endosomes
and are pre-associated with adaptor and
signaling molecules in order to launch
an antiviral response quickly after an
invading pathogen has been detected.30
In contrast to tissue cells, pDC are able
Figure 1. iFn production after infection with SArS-coV in cells of different origin. (A) non-lym-
phatic tissue cells are not able to produce iFn after infection with SArS-coV. (B) pdcs can respond
to SArS-coV and secrete robust amounts of iFn. (c) After being sensitized by low amounts of iFn,
tissue cells are able to respond to an infection with SArS-coV.
www.landesbioscience.com Virulence 275
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