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Typhoid fever

Tamding Wangdi , Sebastian E. Winter & Andreas J. Bumler


Department of Medical Microbiology and Immunology; School of Medicine; University of

California at Davis; Davis, CA USA
Published online: 01 Mar 2012.

To cite this article: Tamding Wangdi, Sebastian E. Winter & Andreas J. Bumler (2012) Typhoid fever, Gut Microbes, 3:2,
88-92, DOI: 10.4161/gmic.18602
To link to this article:


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Gut Microbes 3:2, 8892; March/April 2012;

2012 Landes Bioscience

Typhoid fever

You cant hit what you cant see

Tamding Wangdi, Sebastian E. Winter and Andreas J. Bumler*
Department of Medical Microbiology and Immunology; School of Medicine; University of California at Davis; Davis, CA USA

Downloaded by [] at 07:14 31 May 2015

Keywords: gastroenteritis, inflammation, salmonella, typhoid fever, diarrhea

The host restricts dissemination of invasive enteric pathogens,
such as non-typhoidal Salmonella serovars, by mounting acute
inflammatory responses characterized by the recruitment
of neutrophils. However, some enteric pathogens, such as
Salmonella enterica serovar Typhi (S. typhi), can bypass these
defenses and cause an invasive bloodstream infection known
as typhoid fever. Recent studies on virulence mechanisms of
S. typhi suggest that tight regulation of virulence gene
expression during the transition from the intestinal lumen
into the intestinal mucosa enables this pathogen to evade
detection by the innate immune system, thereby penetrating
defenses that prevent bacterial dissemination. This example
illustrates how the outcome of host pathogen interaction
at the intestinal mucosal interface can alter the clinical
presentation and dictate the disease outcome.

The detection of conserved molecular patterns and pathogeninduced processes by the innate immune system induces proinflammatory responses that culminate in the recruitment of
neutrophils, the pathological hallmark of gastroenteritis (reviewed
in ref. 13). Macrophages are the preferred intracellular niche of
non-typhoidal Salmonella serovars and might serve as a vehicle for
their dissemination. Intracellular survival in macrophages shelters
non-typhoidal Salmonella serovars from neutrophil attack.
However, macrophages can detect the vacuolar pathogen through
NLRC4 and react by releasing non-typhoidal Salmonella serovars
through pyroptosis (reviewed in ref. 14), a process that exposes
the microbe to neutrophils.15 Clearance of bacteria from systemic
sites makes neutrophils an effective defense against disseminated
bacterial infection as illustrated by the fact that neutropenia is a
risk factor for developing bloodstream infections with nontyphoidal Salmonella serovars.16,17
Similar to non-typhoidal Salmonella serovars, S. typhi employs
its flagella and T3SS-1 to invade the intestinal epithelium,18,19
followed by T3SS-2-mediated survival inside macrophages.20 Akin
to non-typhoidal Salmonella serovars, purified S. typhi flagellin
signals through TLR5,21 the lipid A moiety of purified S. typhi
LPS is a potent TLR4/MD2/CD14 agonist,22 the O-antigen of
purified S. typhi LPS activates complement23 and macrophages
detect the deployment of the S. typhi T3SS-1 as pathogen-induced
process in vitro24 (Fig. 1). However, in humans S. typhi is
associated with typhoid fever, which differs dramatically in its
clinical presentation from gastroenteritis caused by non-typhoidal
Salmonella serovars (reviewed in ref. 25). While rapid recruitment
of neutrophils leads to symptoms of gastroenteritis within 24 h
after ingestion of non-typhoidal Salmonella serovars,26 S. typhi
does not evoke overt responses during the initial invasion of the
intestinal mucosa, as indicated by an average incubation period of
two weeks.27 Although S. typhi causes intestinal inflammation, the
inflammatory infiltrates are dominated by mononuclear cells and
neutrophils are scarce.28-32 Finally, S. typhi causes a disseminated
bloodstream infection in immunocompetent individuals, while
non-typhoidal Salmonella serovars are associated with a localized
gastroenteritis. These clinical observations raise the question of
how pathogens that are so similar in their basic repertoire of
virulence factors can cause so different host responses and disease
manifestations in humans. Surprisingly, inconspicuous changes in
the control of virulence gene expression in S. typhi might hold the
answer to this question.
A first clue on how gene regulation in S. typhi differs from
that in non-typhoidal Salmonella serovars came from studies by

2012 Landes Bioscience.

Do not distribute.

In immunocompetent individuals non-typhoidal Salmonella

serovars are associated with gastroenteritis, a localized infection
of the terminal ileum, colon and mesenteric lymph nodes.1 Upon
ingestion, non-typhoidal Salmonella serovars use flagella-mediated
motility and the invasion-associated type III secretion system
(T3SS-1) to enter the ileal and colonic mucosa.2,3 Subsequently, a
second type III secretion system (T3SS-2) is deployed to mediate
survival in tissue macrophages.4 The presence of bacteria in tissue
can be sensed by the host innate immune surveillance system
through detection of conserved molecular patterns.5 For example,
bacterial flagellin is a conserved molecular pattern recognized
by Toll-like receptor 5 (TLR5)6 the lipid A moiety of lipopolysaccharide (LPS) is recognized by the TLR4/MD2/CD14 receptor
complex7 and the O-antigen moiety of LPS is recognized by
complement (Fig. 1), which involves covalent attachment of
complement component 3 fragment b (C3b) by an ester bond
formed with free hydroxyl-groups in LPS sugar moieties.8 In
addition, the host can gauge the pathogenic potential of microbes
by detecting pathogen-induced processes.9 A pathogen-induced
process that marks non-typhoidal Salmonella serovars for
detection by the host is the deployment of T3SS-1, sensed
through NLRC4 (nucleotide-binding oligomerization domainlike receptor family caspase-associated recruitment domaincontaining protein 4).10-12
*Correspondence to: Andreas J. Bumler; Email:
Submitted: 09/05/11; Revised: 10/19/11; Accepted: 10/31/11


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Furthermore, TviA in conjunction with RcsB represses

expression of the flhDC genes (Fig. 2).40,43 FlhDC is the
master regulator of flagellin gene expression.44 One FlhDCregulated gene, fliZ, encodes a regulatory protein that induces
expression of the hilD gene, encoding an activator of the hilA
gene.45,46 Finally, HilA positively regulates T3SS-1 gene
expression.47,48 Through this mechanism, TviA suppresses
invasion and flagella production, while activating Vi-antigen
expression at low-osmolarity conditions (Fig. 2).40 But how
can this unassuming change in virulence gene expression alter
the outcome of host pathogen interaction?
Full suppression of tviA expression occurs at conditions that
resemble the osmolarity encountered in the intestinal lumen.49
This regulation ensures that S. typhi is motile and invasive as it
approaches the mucosal surface. However, upon invasion of
the intestinal epithelium, S. typhi is exposed to conditions of
lower osmolarity, which results in a rapid induction of TviA
expression.49 In turn, TviA in conjunction with RcsB induces
expression of the Vi-antigen, while repressing flagella and
T3SS-1 expression as the pathogen transits through the
epithelium (Fig. 2).49,50 Once S. typhi emerges in the lamina
propria, several pathogen-induced processes and conserved
molecular patterns are no longer detectable by the innate
immune surveillance system.
Specifically, TviA/RcsB turns off expression of flagella, a
conserved molecular pattern whose detection by TLR5
expressed on the basolateral surface of epithelial cells serves
as an indicator of microbial translocation from the gut.43 When
TviA expression in S. typhi is induced in vitro by inactivating
rpoS, a gene encoding a negative regulator of tviA,51 macrophages
exhibit a reduced ability to release intracellular bacteria through
pyroptosis.52 These data suggest that the ability of macrophages
to detect a pathogen-induced process of S. typhi is impaired,
presumably because TviA-regulation suppresses T3SS-1 expression. Finally, expression of the Vi-antigen by S. typhi prevents
complement activation through the alternative pathway,53,54 most
likely because this capsular polysaccharide does not contain free
hydroxyl groups that could form ester bonds with C3b,55 a process
necessary for formation of C3 convertase on the bacterial surface.
Complement activation leads to the generation of the anaphylatoxins C3a and C5a, two potent enhancers of cytokine responses
elicited by endotoxin (lipid A) (reviewed in ref. 56). Thus,
reduced complement activation might explain the apparent
inhibition of TLR4/CD14/MD2 signaling by the Vi-antigen.57-60
In summary, when S. typhi enters the intestinal mucosa, TviAregulation helps the microbe to conceal pathogen-induced
processes and conserved molecular patterns (Fig. 1) from its host.
Through this stealth mechanism, S. typhi eludes detection by
the innate immune system, a you cant hit what you cant
see*-strategy that makes it difficult for the host to contain the
dissemination of the intruding microbe.
By evading detection by the innate immune system, the viaB
locus impairs neutrophil recruitment in the intestinal mucosa,61,62

2012 Landes Bioscience.

Figure 1. Detection of S. typhimurium by the innate immune system results

in neutrophil recruitment. Complement, TLR5 and TLR4/MD2/CD14 detect
conserved molecular patterns of S. typhimurium, including LPS and flagella.
A pathogen-induced process detected by the host innate immune system
is the deployment of T3SS-1, which is sensed through NLRC4. Signals
generated by activation of complement, TLR5, TLR4/MD2/CD14 and NLRC4
cooperate in orchestrating neutrophil recruitment.

Do not distribute.

Eleanor Metcalf and coworkers on invasion of epithelial cell lines.

This work revealed that, unlike non-typhoidal Salmonella
serovars, S. typhi needs to be grown under conditions of highosmolarity (300 mM NaCl) for optimal invasion33 and maximum
expression of T3SS-1 genes.34 The second clue was provided by
the observation that S. typhi grown at low-osmolarity is poorly
invasive, but entry into epithelial cells is markedly increased
in strains lacking expression of the virulence (Vi) capsular
polysaccharide, also known as Vi-antigen.35 Production of the
Vi-antigen is encoded by the viaB (Vi-antigen B) locus, a 14 kb
DNA region on the S. typhi chromosome that is absent from the
genomes of non-typhoidal Salmonella serovars associated with
human gastroenteritis.36,37 Expression of the Vi-antigen at lowosmolarity correlates with reduced secretion of flagellin and
impaired invasiveness. In contrast, growth of S. typhi at highosmolarity conditions suppresses Vi-antigen expression, which is
accompanied by increased invasiveness and elevated flagellin
secretion.38,39 It turns out that the first gene within the viaB
locus, tviA, encodes the regulatory protein responsible for these
phenotypic changes.40
The tviA gene is not expressed under high-osmolarity conditions, but the EnvZ/OmpR two-component regulatory system
induces tviA expression under conditions of low-osmolarity.40,41
TviA forms heterodimers with RcsB, the response regulator of the
RcsBCD phosphorelay system, to activate expression of genes in
the viaB locus, which encode proteins involved in the Vi-antigen
biosynthesis (tviBCDE) and Vi-antigen export (vexABCDE).37,42

Walter Johnson

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which helps explain the scarcity of neutrophils in intestinal

infiltrates28-32 and the long incubation period of typhoid
fever.27 A viaB-mediated inhibition of pyroptosis might
also reduce exposure of S. typhi to neutrophil attack.52
Furthermore, inhibition of C3b deposition on the bacterial
surface prevents phagocytosis of S. typhi through complement
receptor (CR) 3,53,54 a process coupled to a respiratory burst
in neutrophils.8 Through this mechanism, S. typhi prevents
phagocytosis and the generation of a respiratory burst when it
encounters neutrophils,63-65 a cell type crucial for preventing
dissemination of non-typhoidal Salmonella serovars in
humans, as indicated by the increased risk of neutropenic
individuals to develop bloodstream infections.16,17 Finally,
TviA-mediated repression of flagella expression increases
bacterial dissemination in an animal model, presumably
because detection of this conserved molecular pattern by the
innate immune system helps to orchestrate host responses that
enhance bacterial clearance from systemic sites and/or prevent
bacterial dissemination49 (Fig. 1). Collectively, these mechanisms help explain why S. typhi slips past the hosts defenses to
cause an invasive bloodstream infection, even in immunocompetent individuals.
The picture emerging from these studies is that subtle
changes in the regulation of virulence gene expression can
influence the outcome of host pathogen interaction in the
intestinal mucosa. Common approaches for studying innate
immunity, such as stimulating host cells with purified
conserved molecular patterns, cannot model such interactions
accurately, which is one of the reasons why TviA-mediated
innate immune evasion has eluded us until recently.
Furthermore, studies on the interaction of S. typhi with tissue
culture cells can be misleading, unless care is taken that
bacteria are cultured under conditions that mimic gene
expression in vivo. Although TviA-mediated innate immune
evasion is easily overlooked, its influence on the outcome
of host pathogen interaction is profound, as vividly illustrated
by the different clinical presentations of typhoid fever and

2012 Landes Bioscience.

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Figure 2. TviA-mediated gene regulation conceals conserved molecular
patterns and pathogen-induced processes during S. typhi infection.
Expression of TviA is induced at tissue osmolarity by the OmpR/EnvZ
two-component system. TviA in conjunction with RcsB activates expression
of the tviBCDEvexABCDE operon and represses expression of the flhDC
operon. As a result, S. typhi expresses the Vi-antigen while suppressing
flagella and T3SS-1 expression when entering the intestinal mucosa.
The Vi-antigen interferes with the detection of LPS as a conserved molecular
pattern. Thus, TviA-mediated gene regulation prevents detection of a
pathogen-induced process (i.e., the deployment of T3SS-1) and detection
of conserved molecular patterns (i.e., LPS and flagella) by the innate immune
surveillance system in the intestinal mucosa.





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Work in A.J.B.s laboratory is supported by Public Health

Service Grants AI040124, AI044170, AI076246, AI088122
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Volume 3 Issue 2