International audiencePathogens that are able to enter and multi- ply within human cells are responsible for multiple diseases and millions of deaths worldwide. Thus, the challenge is to elu- cidate these pathogen-specific and cell biological mechanisms involved in intra- cellular growth and spread. Bacteria from the genus Legionella belong to this group of pathogens. They are environmental bac- teria and ubiquitous in nature, where they parasitize protozoa

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Legionella: From protozoa to humans

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Legionella: from protozoa to humans

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Carmen Buchrieser

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Legionella: from protozoa to humans
Carmen Buchrieser*
Institut Pasteur, Biologie des Bactéries Intracellulaires and CNRS URA 2171, Paris, France
*Correspondence: cbuch@pasteur.fr
Pathogens that are able to enter and multi-
ply within human cells are responsible for 
multiple diseases and millions of deaths 
worldwide. Thus, the challenge is to elu-
cidate these pathogen-specific and cell 
biological mechanisms involved in intra-
cellular growth and spread. Bacteria from 
the genus Legionella belong to this group 
of pathogens. They are environmental bac-
teria and ubiquitous in nature, where they 
parasitize protozoa. Strikingly, the capac-
ity to grow intracellularly in protozoa like 
Acanthamoeba castellanii, Hartmannella sp., 
or Naegleria sp., has generated a pool of vir-
ulence traits during evolution, which allow 
Legionella to infect also human cells. Thus 
important human pathogens are present 
within the genus Legionella, the most prom-
inent are L. pneumophila (Fraser et al., 1977; 
Mcdade et al., 1977) and L. longbeachae 
(Mckinney et al., 1981). These bacteria are 
the causative agents of Legionnaires’ dis-
ease, a severe pneumonia diagnosed mainly 
in people whose immune defenses are weak-
ened. Legionella is transmitted through 
breathing infected aerosols present in many 
artificial water systems like air condition-
ing systems, cooling towers, showers, and 
other aerosolizing devices. When reaching 
the alveolar parts of the lungs Legionella is 
engulfed by macrophages where it is able 
to multiply resulting in a severe, often 
fatal pneumonia. Intracellular infection is 
a consequence of the bacterium’s capacity 
to manipulate host cellular processes using 
bacterial proteins that are delivered into 
the host cell by specialized secretion sys-
tems (Isberg et al., 2009; Hubber and Roy, 
2010). In this Research Topic, we present a 
collection of Review, Opinion, Perspective, 
and Primary research articles that present 
both the well-established and the newly 
discovered strategies used by Legionella 
to achieve this intracellular lifestyle while 
escaping from the host immune response.
Recent advance in genome sequencing 
has had a tremendous impact on our under-
standing of the pathogenesis,  evolution and 
diversity of L. pneumophila and L. long-
Central to the pathogenesis of L. pneu-
mophila and L. longbeachae is its Type IV 
secretion system (T4SS) called Dot/Icm. It 
is predicted to translocate over 270 effector 
proteins into the host cell which allow this 
bacterium to manipulate host cell functions 
to its advantage and to assure intracellular 
survival and replication. Nagai and Kubori 
(2011) recapitulate our present understand-
ing of the T4SS apparatus and its compo-
nents by taking advantage of genomic 
and structural information. Finally, using 
comparative genomics information of 
several bacteria and plasmids carrying 
similar systems a comparative analysis of 
T4SS components is presented. The fol-
lowing five reviews, research, and opin-
ion articles discuss some of the secreted 
effectors of this T4SS and their divers 
roles in pathogenesis of L. pneumophila. 
Hilbi et al. (2011) present evidence that L. 
pneumophila subverts phosphoinositide 
(PI) lipids by anchoring specific effectors 
through distinct PIs to the cytosolic face of 
the Legionella containing vacuole (LCV) to 
promote the interaction with host vesicles 
and organelles, catalyze guanine nucleo-
tide exchange of small GTPases, or bind to 
PI-metabolizing enzymes. Interestingly, L. 
pneumophila secretes also three glycosyl-
transferases through its T4SS. Belyi et al. 
(2011) report on this novel family of effec-
tor proteins that are structurally similar to 
clostridial glycosylating toxins. However, 
in L. pneumophila they do not produce 
toxic effects but modify the eukaryotic 
elongation factor EF1A to inhibit protein 
synthesis and subsequently to induce cell 
death. Another exciting strategy employed 
by L. pneumophila by secreting proteins 
encoding a eukaryotic F-box domain is the 
exploitation of the host’s polyubiquitina-
tion and farnesylation machineries. In an 
original research article Al-Quadan and 
Kwaik (2011) discuss in detail how one of 
the L. pneumophila encoded F-box proteins 
uses these conserved eukaryotic signaling 
pathways to proliferate in Dictyostelium dis-
coideum, a model ameba used as  infection 
beachae and the knowledge of the genome 
sequence has guided and facilitated the 
research on Legionella in many laborato-
ries. Starting this issue, Gomez Valero et al. 
(2011) present a comprehensive review on 
what we have learned from the sequenc-
ing and analyses of six L. pneumophila 
and five L. longbeachae genomes published 
since 2004. In particular, genome sequence 
analysis revealed the presence of proteins 
with high similarity to eukaryotic proteins 
or proteins with domains preferentially or 
only present in eukaryotic genomes that 
are mimicking host functions helping 
the pathogen to replicate intracellularly 
(Cazalet et al., 2004, 2010). Further insight 
in the genetic basis of host differences and 
the evolution of the eukaryotic like proteins 
in these two pathogens are given.
The bacterial cell wall is at the forefront 
of the interaction with the host and is essen-
tial for cellular integrity and the resistance 
to external stress and aggressions. Shevchuk 
et al. (2011) provide an update on the struc-
ture, molecular composition, and virulence 
properties of the L. pneumophila cell enve-
lope. In their review they show convincingly 
that lipopolysaccharide and several outer 
membrane proteins like Mip, a peptidyl-
prolyl-cis/trans isomerase, a phospholipase 
A are essential virulence factors. It becomes 
clear that promising new fields of research 
will be the analyses of proteins, carbohy-
drates, and lipids of the cell envelope as 
they serve for both, structural and signal-
ing roles. In the following review article 
Garduno et al. (2011) present us the current 
knowledge on the many functions that one 
of these outer membrane proteins, Hsp60 
or HtpB plays in the L. pneumophila biology. 
This chaperonin is an unusual multifunc-
tional protein which was discovered already 
as early as 1986 as an antigen that promi-
nently reacted with patients diagnosed with 
Legionnaires’ disease. Over 20 years later it 
has been shown to have protein folding as 
well as protein folding independent roles 
and that it is associated with virulence and 
survival of L. pneumophila.
www.frontiersin.org October 2011 | Volume 2 | Article 182 | 1
Editorial
published: 12 October 2011
doi: 10.3389/fmicb.2011.00182
model. Excitingly, this same effector also 
has another eukaryotic motif, which is 
used by the host’s prenylation machinery 
for anchoring it in the outer leaflet of the 
LCV (Ivanov et al., 2010; Price et al., 2010). 
In another primary research article Price 
et al. (2010) show, that L. pneumophila con-
tain several other proteins with this motif, 
that are also used by the host prenylation 
machinery to anchor proteins into cellular 
membranes contributing in this way to the 
evasion of lysosomal fusion by the LCV.
A further strategy of L. pneumophila 
to establish an environment beneficial to 
replication is to specifically targets and 
exploit the host phosphorylation system 
through T4SS effectors that act directly on 
phosphorylation cascades. Haenssler and 
Isberg (2011) present a comprehensive 
and exciting review on the different host 
kinases and phosphatases that are targeted 
during L. pneumophila infection and show 
how L. pneumophila modulates host cell 
signal transduction by phosphorylation 
at multiple levels. The part discussing the 
different strategies of L. pneumophila to 
modulate host functions through T4SS 
effectors of L. pneumophila finishes with 
an opinion article by Luo (2011b) that 
discusses a recent, stimulating finding. 
L. pneumophila has evolved an effector 
protein, which specifically target another 
bacterial effector protein for degradation 
to shutdown its action within the host cells 
at later stages of infection. This demon-
strates a sophisticated level of coevolution 
between eukaryotic cells and L. pneumoph-
ila involving an effector that functions as a 
key regulator to temporally coordinate the 
function of a cognate effector protein and 
opens now the way for additional research 
into possible interaction of bacterial effec-
tors among them and not only with host 
proteins.
To timely secret this large repertoire of 
different effectors and to adapt the metabo-
lism and the physiology of L. pneumophila 
to the changing host environment, a tight 
regulation of the expression of the differ-
ent genes coding these proteins is necessary. 
Thus L. pneumophila has evolved a com-
plex regulatory system and many different 
regulatory elements governing its life cycle. 
One of the master regulators is CsrA that 
is regulated by binding to two small regu-
latory RNAs (Rasis and Segal, 2009; Sahr 
et al., 2009). Faucher and Shuman (2011) 
give an overview of what is known about 
small regulatory RNAs in L. pneumophila 
and present in a second article the first tran-
scriptome analysis of L. pneumophila infect-
ing human macrophages (Faucher et al., 
2011). A model of the regulatory networks 
involving small RNA mediated control of 
virulence gene regulation in L. pneumophila 
is presented.
In the following part of this Research 
Topic Joshi and Swanson stress important 
aspects of Legionella–host interactions, by 
providing a critical view on the Legionella 
response to autophagy, a host defense against 
invading microbes (Joshi and Swanson, 
2011). They propose that L. pneumophila 
is able to halt the autophagosome matura-
tion by secreting different effector proteins. 
Once L. pneumophila adapted to an acidic 
environment another effector, LepB releases 
this blockage and the now acid resistant L. 
pneumophila are able to continue replicat-
ing in these autophagolysosomes. In the fol-
lowing article, Luo discusses recent progress 
in understanding the mechanisms L. pneu-
mophila employs to interfere with apoptosis 
and how this modulation also contributes to 
the intracellular life cycle of this bacterium 
(Luo, 2011a).
Finally, infection by a pathogen and its 
outcome is always an interplay between 
the pathogen and the host. Thus, the host 
response to infection with L. pneumophila 
is a very important research question. This 
topic is the focus of a review by Massis 
and Zamboni (2011) that summarizes the 
current knowledge of the innate immune 
response to L. pneumophila infection. The 
implication of the different families of 
pattern recognition receptors (PRR) like 
TLRs, NLRs, and RLRs are discussed and a 
comprehensive analyses of the events trig-
gered by the recognition of intracellular L 
pneumophila by these PRRs is presented. 
Schuelein et al. (2011) close this research 
topic by providing a thoughtful opin-
ion article about the immune control of 
Legionella infection. The authors stress that 
macrophages play a pivotal role in initiating 
the host response to L. pneumophila infec-
tion, however, given the fact that the reso-
lution of L. pneumophila infection needs 
multiple cell types and abundant cross talk 
between immune cells they propose that the 
role of other cell types such as dendritic cells 
and the mechanism of action of protective 
cytokines should be examined in the future.
The field of microbiology and the study 
of host pathogen interactions is moving fast 
ahead and, in conjunction with the ava-
lanche of data provided by the application 
of new, powerful “omics” methods, the tre-
mendous advances in imaging techniques 
allowing in vivo, and single cell analyses 
and improvements in analytical methods, 
will lead to many exciting new discoveries 
in the future.
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Received: 15 August 2011; accepted: 18 August 2011; pub-
lished online: 12 October 2011.
Citation: Buchrieser, C (2011) Legionella: from proto-
zoa to humans. Front. Microbio. 2:182. doi: 10.3389/
fmicb.2011.00182
This article was submitted to Frontiers in Cellular 
and Infection Microbiology, a specialty of Frontiers in 
Microbiology.
Copyright © 2011 Buchrieser. This is an open-access article 
subject to a non-exclusive license between the authors and 
Frontiers Media SA, which permits use, distribution and 
reproduction in other forums, provided the original authors 
and source are credited and other Frontiers conditions are 
complied with.
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Buchrieser Legionella and legionellosis
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Legionella: From Protozoa to Humans

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