published: 03 June 2011
Immune control of Legionella infection: an in vivo
Ralf Schuelein1, Desmond K.Y.Ang2, Ian R. van Driel2and Elizabeth L. Hartland1*
1Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia
2Department of Biochemistry and Molecular Biology and the Bio21 Institute, University of Melbourne, Parkville, Victoria, Australia
Carmen Buchrieser, Pasteur Institute,
Dario S. Zamboni, Universidade de
São Paulo, Brazil
Hubert Hilbi, Max von
Elizabeth L. Hartland, Department of
Microbiology and Immunology,
University of Melbourne, Parkville,
VIC 3010, Australia.
Legionella pneumophila is an intracellular pathogen that replicates within alveolar
macrophages. Through its ability to activate multiple host innate immune components,
L. pneumophila has emerged as a useful tool to dissect inflammatory signaling pathways
in macrophages. However the resolution of L. pneumophila infection in the lung requires
ined the coordination of events that lead to effective immune control of the pathogen. Here
we discuss L. pneumophila interactions with macrophages and dendritic cell subsets and
highlight the paucity of knowledge around how these interactions recruit and activate other
immune effector cells in the lung.
Keywords: Legionnaire’s disease, inflammation, macrophages, plasmacytoid dendritic cells, cytokines
Members of the genus Legionella are Gram-negative, facultative
intracellular bacteria of amoebae, including free-living, freshwa-
ter, or soil amoebae (Rowbotham, 1980; Tyndall and Domingue,
1982; Fields, 1996). Legionella pneumophila was the first species
described and is the known causative agent of an acute form
of pneumonia termed Legionnaires’ disease (Fraser et al., 1977;
McDade et al., 1977). Humans become secondarily infected after
mission to the human lung, L. pneumophila enters and replicates
in alveolar macrophages, leading to inflammation and disease
(Horwitz and Silverstein, 1980; Horwitz, 1983a). Replication in
macrophages is thus a hallmark of L. pneumophila infection.
Within macrophages, the bacteria block phagolysosome fusion
and intercept vesicles trafficking in the secretory pathway (Hor-
witz, 1983b; Kagan and Roy, 2002). The resulting Legionella-
containing vacuole (LCV), ultimately takes on properties of the
rough endoplasmic reticulum (Roy and Tilney,2002; Isberg et al.,
2009). The formation of the LCV is dependent on a functional
effectors into the host cell cytosol (Segal and Shuman,1997; Segal
et al., 1998; Vogel et al., 1998). At least 275 effectors have been
identified (Zhu et al., 2011), that target multiple and overlapping
host cell functions including host cell GTPase activity, phos-
phoinositide metabolism,protein secretion,apoptosis,eukaryotic
protein translation, ubiquitination, NF-κB activation and mito-
chondrial function, reviewed in (Franco et al., 2009; Isberg et al.,
2009; Weber et al., 2009; Hubber and Roy, 2010; Newton et al.,
REPLICATION OF L. PNEUMOPHILA IN MACROPHAGES
Macrophages and dendritic cells (DC) are important sen-
tinels of the immune system detecting infectious agents by
highly conserved microbial motifs, so-called pathogen-associated
molecular patterns (PAMPs; Janeway Jr., 1992). Pattern recog-
nition is mediated by a set of invariant pattern-recognition
receptors (PRRs) of which four families have been identi-
fied: toll-like receptors (TLRs), retinoic acid-inducible gene-I
(RIG-I) like receptors (RLRs), C-type lectin receptors (CLRs),
and nucleotide-binding and oligomerization domain (NOD)-like
receptors (NLRs; Takeuchi and Akira, 2010). NLRs comprise a
large family of cytoplasmic PRRs of which only a few members
have been characterized in detail. Some NLRs form multiprotein
complexes called inflammasomes (Schroder and Tschopp, 2010)
and activation of these complexes leads to the cleavage of the cen-
of cell death known as pyroptosis which is accompanied by the
release of pyrogenic IL-1ß,IL-18,and IL-33 (Davis et al., 2011).
The flagellin sensing Nlrc4 inflammasome plays a central role
strains of mice are resistant to L. pneumophila infection. The dis-
covery of the Nlrc4 inflammasome began with the observation
that macrophages derived from most mouse strains restrict bac-
terial replication with the notable exception of the A strain (often
called A/J, although this terminology refers only to mice derived
directly from the Jackson or Janvier laboratories;Yamamoto et al.,
1988). Crosses between A mice and non-permissive C57BL/6
mice showed that the susceptibility of the A strain is controlled
by a single locus on mouse chromosome 13, designated Lgn1
(Beckers et al., 1995; Dietrich et al., 1995). Genetic studies then
identified the new NLR gene, Naip5, within this locus as respon-
sible for the increased susceptibility of A mice to infection (Diez
et al., 2003; Wright et al., 2003). Subsequent work showed that
Naip5-dependent restriction of L. pneumophila relies on a func-
tional copy of Naip5 as well as Nlrc4 and activation of caspase-1
(Zamboni et al., 2006). Restriction results from the presence of
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Schuelein et al.Immunity to Legionella
bacterial flagellin in the host cytosol, and recognition of the
C-terminus of flagellin is sufficient for activation of the Nlrc4
inflammasome (Molofsky et al., 2006; Ren et al., 2006; Lightfield
et al., 2008). Interestingly, the cytosolic localization of flagellin
and/or restriction of replication depends on a functional Dot/Icm
type 4 secretion system (Amer et al., 2006; Molofsky et al., 2006;
Ren et al., 2006; Zamboni et al., 2006; Lamkanfi et al., 2007).
However, it is not known how the Dot/Icm system contributes
to the translocation of flagellin into the host cytosol and whether
the detection of flagellin by the inflammasome occurs directly or
indirectly with the help of cofactors.
While formation of the inflammasome leads to the activation
of caspase-1, as well as maturation and secretion of IL-1ß and IL-
18,neither cytokine makes a major contribution to the restriction
of L. pneumophila in vitro or in vivo (Amer et al., 2006; Zamboni
et al., 2006; Coers et al., 2007; Akhter et al., 2009; Miao et al.,
2010). Nevertheless, caspase-1 knockout macrophages are more
permissive for L. pneumophila replication and caspase1-deficient
2006; Zamboni et al., 2006). Caspase-1 activation upon bacterial
infection may also result from an alternative Nlrc4-independent
(Asc), yet Asc is dispensable for restriction (Zamboni et al., 2006;
Case et al., 2009). Although depletion or inhibition of caspase-
1 activity leads to decreased targeting of bacteria to lysosomes
(Amer et al., 2006; Zamboni et al., 2006), the mechanism of
caspase-1-dependent restriction of L. pneumophila replication in
macrophages and in vivo is yet to be fully resolved. Activation
of the Nlrc4 inflammasome can lead to macrophage cell death
et al., 2009; Silveira and Zamboni, 2010). Downstream molecules
such as caspase-7, interferon regulatory factor (IRF) 1 and IRF8
also play a significant role in caspase-1 signaling and in the case
of caspase-7, this activation leads to increased macrophage apop-
tosis (Akhter et al., 2009; Fortier et al., 2009). caspase7-deficient
et al., 2009). However, the ability of L. pneumophila to replicate
within macrophages in vitro does not necessarily equate with vir-
ulence in whole animals. For example, type I interferon (IFN-I)
receptor-deficient macrophages, support enhanced replication of
L. pneumophila yet IFN-I receptor-deficient mice are no more
susceptible to infection in vivo (Monroe et al., 2009; Ang et al.,
In contrast to macrophages derived from restrictive mouse
strains, human macrophages or monocytes allow robust replica-
tion of L. pneumophila despite the presence of Naip and Nlrc4
L. pneumophila replication when overexpressed (Vinzing et al.,
2008) suggesting that the level of inflammasome activity may
is downregulated during L. pneumophila infection of monocytic
THP-1 cells (Abdelaziz et al., 2011). More studies in human cells,
ideally in primary macrophages,will provide a useful comparison
to the results derived from using mouse infection models.
are likely to play an important role in generating a protective
immune response and warrant further analysis. In mouse and
human macrophages, infection with live L. pneumophila induces
2009; Monroe et al., 2009; Plumlee et al., 2009; McCoy-Simandle
et al., 2011), whereas other cytokines such as IL-12 and IFN-γ
appear to be produced at only very low levels,if at all (Matsunaga
et al., 2001, 2003). In whole animals, increased susceptibility to
pulmonary L. pneumophila results from cytokine and/or cytokine
receptor deficiencies in IL-12, IFN-γ, and TNF (Brieland et al.,
1998; Shinozawa et al., 2002; Fujita et al., 2008). This suggests
that cytokine production by cell types other than macrophages
is important for controlling infection. At this stage a thorough
understanding of the role of distinct cytokines and immune cells
in combating L. pneumophila lung infection is lacking.
LEGIONELLA PNEUMOPHILA INTERACTIONS WITH DC
Dendritic cells represent a heterogeneous group of cells with spe-
cialized functional properties. DC play a critical role in eliciting
adaptive immune responses through their role as primary anti-
gen presentation cells (Heath and Carbone,2009). Several subsets
of DC are now recognized in the mouse, which began with the
identification of CD8−and CD8+DC in the spleen (Heath and
Carbone, 2009). Further examination of precursor-product rela-
tionships led to the identification of distinct end stage subsets of
DC, including CD4−CD8−(double-negative) DC, CD103+, and
CD11b+migratory DC and Langerhans cells, as well as plasma-
cytoid DC (pDC) which are set apart from the other conventional
DC by their gene expression profile. The role of pDC in generat-
ing adaptive immunity is unclear although evidence for a role in
antigen presentation is emerging (Heath and Carbone, 2009).
to the restriction of L. pneumophila infection in vivo (Ang et al.,
2010). pDC are known for their ability to combat viral infection
Bocarsly et al., 2008). However, a role for pDC in resistance to
mophila infection, pDC are rapidly recruited to the lungs of mice
and depletion of pDC significantly increases bacterial burden in
the lung (Ang et al., 2010). Currently, the mechanism by which
pDC restrict L. pneumophila infection is not known. However,
it is clear that IFN-I is not necessary as IFN-I-receptor-deficient
(IFNAR−/−) mice are not more severely infected by L. pneu-
mophila compared to wild type mice (Monroe et al., 2009; Ang
et al., 2010). Moreover, depletion of pDC in IFNAR−/− mice
I signaling is dispensable for the anti-bacterial activity of pDC
(Ang et al., 2010). Although L. pneumophila can infect pDC (Ang
et al., 2010), the number of bacteria per host cell is significantly
lower compared to macrophages, suggesting that, similar to con-
ventional DC,bacteria do not replicate intracellularly within pDC
(Neild and Roy, 2003). The mechanisms that recruit pDC to the
lung are not yet known but as the primary site of L. pneumophila
replication, macrophages are a likely source of chemoattractant
Frontiers in Microbiology | Cellular and Infection Microbiology
June 2011 | Volume 2 | Article 126 | 2
Schuelein et al. Immunity to Legionella
tion by producing cytokines that activate neutrophils, NK cells,
and/or macrophages to kill intracellular bacteria (Figure 1). Fur-
ther investigation is needed to determine the mechanisms by
which pDC restrict L. pneumophila infection and importantly
whether these mechanisms are utilized to combat other bacterial
In contrast to macrophages, conventional DC do not allow
replication of L. pneumophila (Neild and Roy, 2003), even if
Roy, 2003). Restriction of replication by mouse DC is the result
of activation of both caspase-1-dependent pyroptosis and classi-
cal cell death pathways through Bcl-2-associated X (Bax) and Bcl2
The initiation of the intrinsic (mitochondrial) apoptotic pathway
by Bax/Bak leads to early activation of caspase-3 in DC that is
delayed in macrophages (Nogueira et al., 2009). L. pneumophila
is known to induce the intrinsic pathway in macrophages (Hagele
et al., 1998; Gao and Abu Kwaik, 1999; Molmeret et al., 2004;
Abu-Zant et al., 2005; Furugen et al., 2008; Nogueira et al., 2009)
but counteracts the pro-apoptotic stimuli, in part by triggering
NF-κB dependent up-regulation of anti-apoptotic genes (Losick
and Isberg, 2006; Abu-Zant et al., 2007; Bartfeld et al., 2009) as
well as delivering anti-apoptotic Dot/Icm effectors such as SdhA
and SidF (Laguna et al.,2006;Banga et al.,2007). In fact,SidF acts
directly on pro-apoptotic Bcl2 family members Bcl-rambo and
BNIP3 while the anti-apoptotic mechanism of SdhA seems inde-
pendent of central components of the apoptosis pathway (Laguna
et al., 2006; Banga et al., 2007; Nogueira et al., 2009). It is unclear
the same impact in conventional DC, despite the fact that SdhA
appears to be at least partially functional (Nogueira et al., 2009).
Nevertheless, rapid apoptosis is key to the difference between L.
pneumophila replication in macrophages and conventional DC
because adding the anti-apoptotic Dot/Icm effector, AnkG, from
the evolutionarily related pathogen, Coxiella burnetii, inhibits L.
pneumophila inducedapoptosisof DCandreversestherestriction
on bacterial replication (Luhrmann et al., 2010). The importance
is not known.While DC presumably play a role in antigen presen-
for conventional DC in controlling L. pneumophila lung infection
has been proven. It has been proposed that DC may act as a dead
FIGURE 1 | Model for the role of pDC in combating L. pneumophila lung
infection. Infected macrophages produce cytokines and chemokines that
recruit pDC to the lung. Bacteria activate pDC viaTLR/NLR interactions or
cytokines from infected macrophages stimulate pDC cytokine production that
then activates neutrophils, NK cells and macrophages to kill bacteria directly
June 2011 | Volume 2 | Article 126 | 3
Schuelein et al.Immunity to Legionella
end for L. pneumophila replication thereby restricting bacterial
infection but this hypothesis has not been tested directly in vivo,
for example by depletion of conventional DC (Nogueira et al.,
Biopsies from patients with Legionnaire’s disease show bac-
teria contained within multi-organism vacuoles in alveolar
macrophages (Chandler et al., 1977; Glavin et al., 1979; Hernan-
dez et al., 1980). In guinea pig and mouse lung infection models,
alveolar macrophages are the first cells infected by L. pneumophila
(Winn Jr., 1988; LeibundGut-Landmann et al., 2011). As the ini-
tial niche for bacterial replication, macrophages play a pivotal
role in initiating the host response to L. pneumophila. Indeed
recently, IL-1β production by mouse alveolar macrophages was
shown to activate cytokine responses in airway epithelial cells
(LeibundGut-Landmann et al., 2011). As such, this initial inter-
action with macrophages is likely to be crucial for the recruit-
ment of immune effector cells including neutrophils and NK
cells. In both intravenous and respiratory infection models, IL-
18 is required for IFN-γ production by NK cells (Sporri et al.,
of L. pneumophila infection suggested increased susceptibility of
terial load; Sporri et al., 2008), this result was not validated in
the respiratory infection model (Archer et al., 2009). Therefore it
appears that the role of cytokines and immune cells during lung
infection differs from interactions during systemic responses. T-
and B-cells also ultimately contribute to clear the organism (Susa
ment and mechanism of activation has not been closely examined
in the context of L. pneumophila infection in vivo. Given that the
resolutionof L.pneumophila infectionrequiresmultiplecelltypes
and abundant cross talk between immune cells, the role of other
cell types such as DC as well as the mechanism of action of pro-
tective cytokines should be examined. The coordinated functions
of these immune components during L. pneumophila infection
defense mechanisms in the lung.
This work was supported by grants to Elizabeth L. Hartland and
Ian R. van Driel from theAustralian National Health and Medical
Research Council (NHMRC). Elizabeth L. Hartland is supported
by an Australian Research Council Future Fellowship.
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