mecanismos moleculares utilizados por salmonella

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RESUMEN
Las Células Dendríticas (DCs) son células presentadoras de
antígeno profesionales, capaces de reconocer y degradar antíge-
nos bacterianos que son presentados a linfocitos T vírgenes para
así iniciar la respuesta inmune específica contra los antígenos deri-
vados de patógenos. Por esta razón, algunos microorganismos
patógenos han adquirido mecanismos de virulencia que interfie-
ren con la función de la DC y evitan la activación de la respues-
ta inmune específica. Salmonella enterica serovar Typhimurium, el
agente causal en el ratón de una enfermedad similar a fiebre tifoi-
dea, es capaz de escapar de la presentación de antígenos media-
da por la DC al evitar su degradación lisosomal. Esta capacidad
virulenta de Salmonella requiere la expresión funcional de un Sis-
tema de Secreción de Tipo III (TTSS) y de otras proteínas de viru-
lencia codificadas por la Isla de Patogenicidad 2 (SPI-2). En esta
revisión discutimos estudios recientes que han demostrado que
el impedimento de la función de la DC, debido a la actividad de
los productos génicos de la SPI-2 y a la evasión de la fusión fago-
soma-lisosoma, es crucial para la patogénesis de Salmonella.
PALABRAS CLAVE: Células Dendríticas/ Salmonella enterica sero-
var Typhimurium/ Activación de Linfocitos T/ Islas de Patoge-
nicidad de Salmonella/ Inmunidad Adaptativa/ Sistema de Secre-
ción de Tipo III.
ABSTRACT
Dendritic cells (DCs) are professional antigen presenting cells
with the ability to recognize and degrade bacterial antigens, which
are presented to naïve T cells to initiate the adaptive immune res-
ponse against pathogen-derived antigens. For this reason, some
bacterial pathogens have acquired virulence mechanisms that
interfere with DC function and avoid the adaptive immune res-
ponse activation. Salmonella enterica serovar Typhimurium, the
causative agent of typhoid-like disease in the mouse, is able to
escape from DC-mediated antigen presentation by avoiding lyso-
somal degradation. This feature of virulent Salmonella requires
the functional expression of the Type Three Secretion System
(TTSS) and other virulence proteins encoded within the Salmone-
lla Pathogenicity Island 2 (SPI-2). In this review we discuss recent
studies showing that impairment of DC function by the activity
of SPI-2 gene products and the avoidance of phagosome-lysoso-
me fusion in these cells are crucial for Salmonella pathogenesis.
KEY WORDS: Dendritic Cells/Salmonella enterica serovar Typ-
himurium/ T cell activation/ Salmonella Pathogenicity Island/
adaptive immunity/ Type Three secretion system.
355
RReevviissiióónn
Inmunología
Vol. 24 / Núm 4/ Octubre-Diciembre 2005: 355-361
MMoolleeccuullaarr mmeecchhaanniissmmss uusseedd bbyy SSaallmmoonneellllaa ttoo iinntteerrffeerree
wwiitthh DDeennddrriittiicc CCeellll ffuunnccttiioonn
S.M. Bueno, A.A. Herrada, A.M. Kalergis
Departamento de Genética Molecular y Microbiología,
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile.
MMEECCAANNIISSMMOOSS MMOOLLEECCUULLAARREESS UUTTIILLIIZZAADDOOSS PPOORR SSAALLMMOONNEELLLLAA PPAARRAA IINNTTEERRFFEERRIIRR 
CCOONN LLAA FFUUNNCCIIÓÓNN DDEE LLAA CCÉÉLLUULLAA DDEENNDDRRÍÍTTIICCAA 
Recibido: 5 de Mayo 2005
Aceptado: 28 Julio 2005
Inmunol 24/4 -68p 21/3/06 14:50 Página 355
MOLECULAR MECHANISMS USED BY SALMONELLA TO INTERFERE WITH DENDRITIC CELL FUNCTION VOL. 24 NUM. 4/ 2005
356
IINNTTRROODDUUCCTTIIOONN
Among specialized antigen presenting cells (APCs),
dendritic cells (DC) play a critical role in the initiation
and activation of the adaptive immune response against
microbial pathogens(1, 2). These cells are the link between
innate and adaptive immunity, because they capture
pathogens at the site of infection and degrade their antigens
into peptides, which are presented to T cells bound on MHC
class I and II molecules(3). Furthermore, DCs can migrate
from peripheral tissue to lymph nodes to prime pathogen-
specific T cells(4). Thus, DCs activate specific T cells that
eventually control the proliferation of microbes in host
tissues by means of elicitation of cellular and humoral
adaptive immunity, which in turn can enhance innate
immunity efficiency(5).
DCs are ubiquitous in peripheral tissues that are constantly
exposed to infection by pathogens. In these tissues DCs are
found in an immature state, characterized by a high phagocytic
capacity and a low expression of co-stimulatory molecules
such as CD80, CD86 and CD40. On their surface, immature
DCs also express specific chemokine receptors, which
determine their location in peripheral tissues(6). In this state,
DCs act as sentinel cells by actively detecting microbes and
their derivatives, known as danger signals or Pathogen
Associated Molecular Patterns (PAMPs)(7), which bind to
specific receptors expressed on the DC surface. To accomplish
this function, Toll-like receptor (TLRs) and DC-SIGN
molecules expressed in the surface of DCs play an essential
role in the recognition of PAMPs(7, 8). TLR signalling triggers
phenotypic and metabolic changes on DCs, known as
maturation. This phenomenon is characterized by a decrease
on the phagocytic ability of DCs and an increased surface
expression of molecules such as MHC-I, MHC-II and co-
stimulatory molecules(9-11), all of which are required for an
efficient activation of antigen-specific naïve T cells(3). As a
consequence of maturation, DCs acquire the capacity to
migrate from peripheral tissues to secondary lymphoid
organs by means of either up- and down-regulation of
specific subsets of chemokine receptors(12). The capacity to
migrate to lymph nodes, were naïve T cells reside, is critical
for the initiation of adaptive immunity against pathogenic
bacteria infecting peripheral tissues(13-15).
Several studies have shown that bacterial pathogens
have evolved molecular mechanisms aimed to interfere
with the activity of DCs(16). This evasive capacity seems to
be specially significant for those pathogens that cause
systemic infections, because they must avoid the activation
of the immune response to access internal tissues(16, 17). One
of the best studied microbial pathogen is the intracellular
bacterium Salmonella enterica serovar Typhimurium (herein
S. Typhimurium), the etiological agent for thyphoid-like
disease in mice and the model of study for typhoid fever,
a serious health problem in developing countries caused
by S. Typhimurium(18, 19). Recent studies have shown that
the lethal and systemic infection caused by S. Typhimurium
in mice is characterized by a poor activation of the adaptive
immune response(17, 20).
Considering the fundamental role that DCs play in
the initiation and activation of the adaptive immune response,
subverting DC function is probably one of the key steps for
Salmonella in causing systemic illness. In S. Typhimurium,
several virulence proteins have been described that are
important for intracellular survival and systemic dissemination
in the host(21-23). Some of these virulence factors are proteins
that alter cellular trafficking and allow S. Typhimurium to
avoid lysosomal degradation(24). Recently, it has been shown
that these pathogenic mechanisms are used by S. Typhimurium
to interfere with DC function, specifically with antigen
presentation. In this review we discuss some of the most
recent evidence for the molecular mechanisms used by S.
Typhimurium to interfere with the function of DCs and the
implication for the ability of this pathogen to spread
systemically in the host.
SSAALLMMOONNEELLLLAA VVIIRRUULLEENNCCEE FFAACCTTOORRSS AANNDD
PPAATTHHOOGGEENNEESSIISS OOFF TTYYPPHHOOIIDD--LLIIKKEE DDIISSEEAASSEE
During natural infections, S. Typhimurium enters the
host by the oral route after ingestion of contaminated food
or water. Once bacteria have reached the terminal ileum,
epithelial and M cells are invaded and/or destroyedby S.
Typhimurium, which in turn facilitates bacterial access to
other tissues, like Peyer Patches (PP)(25). From this location,
S. Typhimurium reaches mesenteric lymph nodes and other
internal organs, such as spleen and liver(26, 27), where bacteria
reside in intracellular compartments(28).
Since the capacity of S. Typhimurium to survive in the
intracellular environment is fundamental to cause a successful
systemic disease(28), members of the genus Salmonella
have acquired specialized virulence mechanisms aimed to
survive inside eukaryotic cells. In particular, Type Three
Secretion Systems (TTSS) are one of the most important
virulence factors of S. Typhimurium. TTSSs are molecular
machines that translocate virulence proteins from the bacterial
cytoplasm into the eukaryotic host cells. These bacterial
proteins alter the normal function of host cells and favour
S. Typhimurium invasion and intracellular replication(29).
Components of TTSSs are encoded on Salmonella Pathogenicity
Islands (SPI), which are chromosomal loci harbouring clusters
of virulence genes(30, 31). S. Typhimurium possesses two
Inmunol 24/4 -68p 21/3/06 14:50 Página 356
TTSSs, which are encoded by two separate pathogenicity
islands, SPI-1 and SPI-2. Each of these loci consists of more
than 40 genes involved in virulence(23) and their expression
is tightly and coordinately regulated according to the capacity
of bacteria to sense specific molecular features of the
environment(32). Genes located in the SPI-1 are preferentially
expressed when bacteria locate at the extracellular environment
(33), and the virulence proteins expressed by this chromosomal
region are needed for bacterial-induced internalization
inside non-phagocytic cells in the intestinal epithelium(34).
In contrast, SPI-2 genes are expressed when bacteria
sense the intracellular environment and the virulence proteins
they encode are needed for the survival inside host cells(35,
36). Deletion of genes codifying either for TTSS components
or effector proteins render Salmonella non-virulent, impairing
its ability to cause a systemic illness in the mouse(37, 38).
DDCCSS MMAATTUURRAATTIIOONN AANNDD MMIIGGRRAATTIIOONN TTOO LLYYMMPPHHOOIIDD
TTIISSSSUUEESS AAFFTTEERR SSAALLMMOONNEELLLLAA EENNCCOOUUNNTTEERR
Although for many years macrophages have been
considered the first cells to capture Salmonella in orally
infected mice, recent in vitro and in vivo evidence suggests
that DCs could play a role in the capture of invading
Salmonella(17, 39-41). In vivo studies show that after orogastric
inoculation, S. Typhimurium is associated with DCs that
reside at the PPs and can survive for several days inside
these cells(42). Recent evidence has shown that intestinal
DCs, which express the chemokine receptor CX3CR1, are
able to extend dendrites through the epithelium. This feature
allows DCs to sample bacteria directly from the intestinal
lumen(6, 43, 44). When intestinal DCs encounter S. Typhimurium,
they migrate from the subepithelial dome to the parafollicular
T cell zones(12). Studies performed on polarized cell cultures
have shown that S. Typhimurium flagellin elicits the secretion
of the cytokine CCL20 by follicle-associated epithelium,
which overlays with Peyer’s Patches. This cytokine would
be recognized specifically by CCR6, a receptor present in
the surface of DCs(45), and promote their migration to lymph
nodes. These observations suggest that in vivo, intestinal
DCs could readily detect the presence of invading S.
Typhimurium (Fig. 1).
Once DC encounters Gram-negative bacteria, TLRs
present on DCs surfaces directly recognize PAMPs, inducing
357
INMUNOLOGÍA S.M. BUENO, A.A. HERRADA, A.M. KALERGIS
FFiigguurree 11.. Model for Salmonella infection at the intestinal epithelium. Once Salmonella reaches the intestinal epithelium, bacteria invade host’s cells and can cause
death of M cells and macrophages and reach sub-epithelial dome. In addition, Salmonella can be uptaken at the intestine lumen by resident DCs by means of
cytoplasmatic extensions that protrude through the epithelium. Whether Salmonella induces phagocytosis remains unknown. Recognition of Salmonella PAMPs
would lead to maturation of intestinal DCs and to changes on the pattern of expression of chemokine receptors. As a result, Salmonella loaded-DCs would start
migrating to lymph nodes in response to specific cytokine gradients.
Inmunol 24/4 -68p 21/3/06 14:50 Página 357
358
DC maturation(46). TLR4 would be the main TLR involved
in this process, by direct recognition of Salmonella LPS. In
addition, activation of TLR4 is involved in phagocytosis
and the production of pro-inflammatory cytokines(47). DC
maturation caused by Salmonella is characterized by an
increased surface expression of MHC class II molecules and
co-stimulatory molecules, such as CD40, CD80, CD86 and
CD54 (40, 48, 49). Infected DCs also increase the production of
pro-inflammatory cytokines, such as IL-12(40, 50). Recent
studies using RNA differential display, have shown that
Salmonella-infected DCs upregulate the expression of several
genes, including the macrophage-derived chemokine, which
is a chemoattractive for T cells(51). Once DCs mature as a
result of the contact with bacterial derivatives, for instance
LPS, there is a down-regulation of several chemokine
receptors, including CCR1, CCR4 and CCR5. Simultaneously,
there is an enhancement in the expression of CCR7, which
binds to cytokines CCL19/ MIP-3β and CCL21 that are
secreted by secondary lymphoid organs. All these changes
allow mature DCs to migrate from peripheral tissues to
lymphoid organs(52-54) (Fig. 1).
IINNTTRRAACCEELLLLUULLAARR SSUURRVVIIVVAALL OOFF SSAALLMMOONNEELLLLAA
AANNDD IITTSS IIMMPPAACCTT OONN DDCC FFUUNNCCTTIIOONN
Virulence proteins secreted through Salmonella TTSSs
interfere directly with the host’s cellular processes, such as
actin polymerization(34) and vesicular trafficking(55). The TTSS
encoded on SPI-2 and the proteins delivered by this secretion
system are required to allow Salmonella to avoid phagosome-
lysosome fusion inside both macrophages and DCs (35,
Tobar et al., submitted). Inside eukaryotic cells, Salmonella
reside in specialized compartments called Salmonella containing
vacuoles (SCV)(56) (Fig. 2). Thus, S. Typhimurium is able to
bypass the normal endocytic route and reside inside vacuoles
that are inaccessible to fluid endocytic tracers(49). This feature
requires the activity of several effector proteins secreted by
SPI-2-encoded TTSS, which have been identified as essential
components for the survival of Salmonella inside eukaryotic
cells. Among those effectors proteins are SseF, SseG, SseB
and SpiC, all of which interfere with the normal endocytic
route of host cells(57). It is still a matter of controversy whether
SpiC is also necessary for the secretion of other effectors
secreted by TTSS(58, 59). In addition, studies in macrophages
suggest that SpiC would bind directly to the cellular protein
Hook3, which has been implicated in cellular trafficking(55).
The capacity of Salmonella to interfere with the normal
progression of phagosome into the phagolysosome is not
only crucial for bacterial survival, but also to avoid antigen
presentation. Therefore, activation of the adaptive immune
response would also be impaired by the activity of SPI-2-
encoded TTSS components and effector proteins (Fig. 2).
As a consequence, virulent strains of Salmonella residing
inside DCs are capable of avoiding antigen presentation
and prevent activation of T cells specific for bacterial antigens
(17, 20, 59, Tobar et al., submitted). Similar observations
have been made using T cells derived from different sources
and expressing TCRs specific for a variety of antigens. For
example, some studies have used SM1 transgenic T cells,
which express a TCR that is specific for a MHC-II molecule
(I-Ab)loaded with a peptide derived from S. Typhimurium
flagellin(60, 61). Others have taken advantage of OT-I and OT-
II transgenic T cells, which recognize MHC-I and II molecules
respectively, loaded with peptides derived from the model
antigen Ovalbumin (OVA) (62, 63, Tobar et al., submitted).
Taking advantage of the OVA system by producing
recombinant strains of S. Typhimurium that express OVA
as a neoantigen, it has been shown that DCs infected with
a virulent strain fail to activate CD8+ (OT-I) or CD4+ (OT-
II) transgenic T cells in vitro (Tobar et al., unpublished results).
MOLECULAR MECHANISMS USED BY SALMONELLA TO INTERFERE WITH DENDRITIC CELL FUNCTION VOL. 24 NUM. 4/ 2005
FFiigguurree 22.. The capacity of Salmonella to avoid phagosome-lysosome fusion and
antigen presentation depends on proteins encoded on SPI-2. Virulent strains
of Salmonella invade DCs and avoid phagosome-lysosome fusion by the secretion
of virulence proteins by a TTSS encoded on SPI-2. Avoidance of lysosomal
degradation prevents presentation of bacterial-derived antigens on MHC-I
and MHC-II molecules by infected DCs. On the contrary, Salmonella mutants
carrying deficient SPI-2 or genes encoding for the TTSS are unable to avoid
of phagosome-lysosome fusion. As a result, bacteria are degraded and antigens
are presented on MHC-I and MHC-II molecules to CD4+ and CD8+ T cells,
respectively.
Inmunol 24/4 -68p 21/3/06 14:50 Página 358
In vivo studies have shown that infection with virulent S.
Typhimurium fail to induce the proliferation of adoptively-
transferred OT-I, OT-II or SM1 transgenic T cells (17, 20,
Tobar et al., submitted). Recent studies indicate that genes
encoded on SPI-2 are required to avoid antigen presentation
by DCs on MHC-I and MHC-II molecules, probably due to
impairment on bacterial intracellular survival and lysosome
avoidance (Fig. 2). The impact of SPI-2 deletion on antigen
presentation is probably due to the inability of Salmonella
to avoid phagosome-lysosome fusion. Failure to avoid
lysosomal targeting would in turn lead to bacterial degradation
and presentation of their antigens on MHC molecules.
However, the specific mechanisms or genes responsible for
the interference of MHC-I and MHC-II antigen presentation
by DCs due to S. Typhimurium infection have not been
described yet.
DDCCSS AASS VVEEHHIICCLLEESS FFOORR SSAALLMMOONNEELLLLAA
DDIISSSSEEMMIINNAATTIIOONN
Taken together, the studies described above support the
notion that DCs could be used as a vehicle for systemic
dissemination for this pathogen. DCs are cells able to sample
bacteria present in the intestinal lumen and migrate from
this peripheral zone to deeper organs such as lymph nodes
and spleen, where they prime antigen-specific naïve T cells(43).
Due to the migratory capacity of DCs and the ability of S.
Typhimurium to survive inside these cells and avoid antigen
presentation, DCs could be used as a silent dissemination
vehicle for S. Typhimurium. Evidence supporting the
exploitation of DCs as a mean for systemic spread of S.
Typhimurium derives from the observation that these bacteria
rapidly associate with CD18+ cells upon oral infection, which
mediate the dissemination of the bacteria towards internal
tissues(64). Additional in vivo studies have demonstrated that
DCs at Peyer Patches are the first cell type from the sub-
epithelial dome to be infected by S. Typhimurium after an
orogastric infection in mice(42). Furthermore, recent studies
have shown that upon an intravenous infection of S.
Typhimurium, more that 50% of bacteria that reach the
spleen are found inside DCs(41, 65). Therefore, the capacity of
S. Typhimurium to avoid antigen presentation by DCs could
be directly correlated with the bacterium’s ability to spread
systemically into the host, without the activation of specific
T cell immunity.
CCOONNCCLLUUDDIINNGG RREEMMAARRKKSS
The ability of virulent strains of Salmonella to interfere
with DC function finds support in several recent independent
studies. These observations provide a new model for Salmonella
pathogenicity, based on its capacity to impair the function
of an immune cell required to prime adaptive immunity:
Virulence factors involved in the mechanisms used by
Salmonella to avoid presentation of bacterial antigens to T
cells by DCs are required for systemic infection. These
findings could contribute to the characterization of the
molecular processes responsible for the ability of Salmonella
to produce a systemic disease in the host, avoiding activation
of an adaptive immune response, and to the design of
new and improved vaccines against this intracellular pathogen.
AACCKKNNOOWWLLEEDDGGMMEENNTTSS
We are grateful of Drs. M. Iruretagoyena and R. Cabrera
and J. Jalocha for critical reading of the manuscript. The
authors are supported by grants FONDECYT #1030557,
#1050979 and #3060041, DIPUC #2002/11E, IFS #A/3639-
1 and #B/3764-1 and Millennium Nucleus on Immunology
and Immunotherapy. . 
CORRESPONDENCE TO: 
Alexis M. Kalergis
Facultad de Ciencias Biológicas
Pontificia Universidad Católica de Chile. 
Alameda #340, Santiago, Chile. 
Phone: 56-2-686-2842, Fax: 56-2-222-5515
e-mail: akalergis@bio.puc.cl
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