Gunn, John S.

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John S Gunn

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Frontiers in Cellular and Infection Microbiology

Salmonella Host- Pathogen Interactions: A Special Topic

John S. Gunn

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Salmonella host–pathogen interactions: a special topic
John S. Gunn*
Department of Microbial Infection and Immunity, Center for Microbial Interface Biology, The Ohio State University, Columbus, OH, USA
*Correspondence: gunn.43@osu.edu
Salmonellae are Enterobacteriaceae that 
cause a spectrum of diseases in humans 
and animals, including enteric (typhoid) 
fever and gastroenteritis (Coburn et al., 
2007; Andrews-Polymenis et al., 2010). 
Most human Salmonella infections result 
in gastroenteritis and are caused by 
Salmonella enterica serovar Typhimurium 
(S. Typhimurium) or Salmonella enterica 
serovar Enteritidis acquired from contami-
nated food. Non-typhoidal Salmonella sero-
types, such as S. Typhimurium, have a broad 
host range and infect a variety of animals. 
Interestingly, while these serotypes cause 
gastroenteritis in humans, they cause a sys-
temic illness similar to typhoid fever in the 
mouse and cow (Andrews-Polymenis et al., 
2010). In contrast, S. Typhi, the etiologic 
agent of typhoid (enteric) fever, infects only 
humans. Typhoid fever is a human systemic 
disease that is responsible for an estimated 
21 million new infections annually result-
ing in approximately 600,000 deaths world-
wide (Crump et al., 2004). It is an important 
health problem in developing countries and 
poses a significant risk to travelers. This 
illness has a mortality rate of 2–3% even 
with adequate antibiotic therapy, as anti-
biotic resistance of S. Typhi is a significant 
problem (Bhutta et al., 1991). Since the host 
range of S. Typhi is restricted to humans, 
the murine model system (S. Typhimurium 
infection of susceptible inbred mice) has 
been widely used to study typhoid fever 
pathogenesis and immunity in the labora-
tory. Examining the progression of natu-
rally acquired infection, the bacterium 
passes through the stomach and into the 
small intestine, preferentially invading, 
as do many other intestinal pathogens, 
through M-cells located in Peyer’s patches 
in the distal ileum. After passage through 
the epithelium, the bacterium encounters, 
infects, replicates within, and disseminates 
(for systemic infections) primarily within 
macrophages. In this special topic, we 
explore the details of this infectious process 
through comprehensive reviews and sum-
maries of key, recent publications.
that find themselves within intestinal epi-
thelial cells. In some instances, bacteria 
were surprisingly shown to escape the 
vacuole, replicate in the cytoplasm, and 
induce pyroptosis, which caused selective 
extrusion of these cells from the monolayer. 
This impacts both host clearance mecha-
nisms and bacterial dissemination. Key to 
this inflammatory event is the activation of 
caspase-1, a topic that is reviewed by Miao 
and Rajan (2011). Upon bacterial sensing 
via membrane-bound toll-like receptors 
(TLRs) and intracellular NOD-like recep-
tors (NLRs), pro-inflammatory pathways 
are activated which aid in clearance. Two 
of the NLR-containing complexes, NLRC4 
and NLRP3 inflammasomes, and the acti-
vation of caspase-1 by these complexes, 
are key to this process, but Salmonella has 
also evolved mechanisms to subvert this 
response.
Increased details of Salmonella SPI-1 
and SPI-2 function and how the factors 
that are secreted by these systems aid 
Salmonella in developing an intracel-
lular niche are discussed by Malik-Kale 
et al. (2011). While the effectors for each 
pathogen are unique, the SPI-1 and SPI-2 
type III secretion system translocated fac-
tors truly establish the intracellular niche 
for Salmonella, and their further under-
standing is key to a complete comprehen-
sion of host–pathogen interactions. They 
focus on the development of the unique 
Salmonella-containing vacuole and the 
role Salmonella plays in shaping its intra-
cellular environment.
After progression of the bacterium 
through the epithelial barrier, Salmonellae 
encounter professional phagocytes. In the 
gut as well as following uptake/phagocytosis, 
Salmonellae are exposed to reactive oxygen 
(ROS) and nitrogen (RNS) intermediates. 
Henard and Vazquez-Torres (2011) describe 
the molecular targets of RNS (e.g., nitric 
oxide) as well as the ability of the bacterium 
to respond to this environment with mecha-
nisms to both detoxify ROS and to repair 
damage- one of the important mechanisms 
One of the first contacts Salmonellae 
make in the intestine, particularly the 
colon, is with other bacteria or normal 
flora. Ahmer and Gunn (2011) describe the 
factors involved in overcoming “coloniza-
tion resistance,” mediated by normal flora 
and the gut innate immunity. In addition 
to mechanisms of innate immune defense 
subversion, they discuss various models and 
techniques that have been utilized to exam-
ine the S. Typhimurium-intestinal micro-
biota interplay. A key concept brought forth 
is that S. Typhimurium has been shown to 
be unable to colonize the mouse intestine 
in the absence of inflammation, as the nor-
mal flora in the non-inflamed state is able to 
effectively outcompete an avirulent (lacking 
inflammatory capacity) Salmonella intruder.
In addition to the normal flora, 
Salmonella must overcome numerous 
other gut barriers to infection, and must 
utilize its own weapons to enter through 
the non-phagocytic intestinal epithelial 
layer. Hallstrom and McCormick (2011) 
describe how Salmonella overcomes these 
hurdles and exploits the host defenses for 
their own purposes. They walk the reader 
through intestinal entry, the mucus layer, 
the intestinal epithelium [with focused dis-
cussion of M-cells as well as a paracellular 
pathway of entry (area between adjacent 
epithelial cells; tight junctions)], and into 
phagocytes where they are trafficked to the 
mesenteric lymph nodes.
Type III secretion systems are key to the 
virulence of several Gram-negative and 
enteric pathogens. The accepted dogma is 
that proteins are secreted by these systems 
directly from the cytoplasm of the bacte-
rium to the cytosol of the host cell. However, 
the review of a manuscript by Akopyan et al. 
(2011) by Perrett and Zhou (2011) discusses 
data showing that this process may also 
occur by two steps – secretion to the bacte-
rial surface followed by Type III secretion 
systems transport.
A manuscript by Knodler et al. (2010) 
reviewed here by Winter and Baumler (2011) 
describe the fate of some S. Typhimurium 
www.frontiersin.org September 2011 | Volume 2 | Article 191 | 1
Editorial
published: 19 September 2011
doi: 10.3389/fmicb.2011.00191
Knodler, L. A., Vallance, B. A., Celli, J., Winfree, S., Hansen, 
B., Montero, M., and Steele-Mortimer, O. (2010). 
Dissemination of invasive Salmonella via bacterial-
induced extrusion of mucosal epithelia. Proc. Natl. 
Acad. Sci. U.S.A. 107, 17733–17738.
Malik-Kale, P., Jolly, C. E., Lathrop, S., Winfree, S., 
Luterbach, C., and Steele-Mortimer, O. (2011). 
Salmonella – at home in the host cell. Front. Microbiol. 
2:125. doi: 10.3389/fmicb.2011.00125
McDermott, J. E., Yoon, H., Nakayasu, E. S., Metz, T. O., 
Hyduke, D. R., Kidwai, A. S., Palsson, B. O., Adkins, J. 
N., and Heffron, F. (2011). Technologies and approaches 
to elucidate and model the virulence program of 
Salmonella. Front. Microbiol. 2:121. doi: 10.3389/
fmicb.2011.00121
Miao, E. A., and Rajan, J. V. (2011). Salmonella and cas-
pase-1: a complex interplay of detection and evasion. 
Front. Microbiol. 2:85. doi: 10.3389/fmicb.2011.00085
Perrett, C. A., and Zhou, D. (2011). Type three secretion 
system effector translocation: one step or two? Front. 
Microbiol. 2:50. doi: 10.3389/fmicb.2011.00050
Winter, S. E., and Baumler, A. J. (2011). Salmonella 
exploits suicidal behavior of epithelial cells. Front. 
Microbiol. 2:48. doi: 10.3389/fmicb.2011.00048
Received: 29 August 2011; accepted: 29 August 2011; pub-
lished online: 19 September 2011.
Citation: Gunn JS (2011) Salmonella host–pathogen inter-
actions: a special topic. Front. Microbio. 2:191. doi: 10.3389/
fmicb.2011.00191
This article was submitted to Frontiers in Cellular 
and Infection Microbiology, a specialty of Frontiers in 
Microbiology.
Copyright © 2011 Gunn. 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.
Acknowledgments
This work was supported by The National 
Institutes of Health grants AI066208 and 
AI043521.
RefeRences
Ahmer, B. M., and Gunn, J. S. (2011). Interaction of 
Salmonella spp. with the intestinal microbiota. Front. 
Microbiol. 2:101. doi: 10.3389/fmicb.2011.00101
Akopyan, K., Edgren, T., Wang-Edgren, H., Rosqvist, R., 
Fahlgren, A., Wolf-Watz, H., and Fallman, M. (2011). 
Translocation of surface-localized effectors in type III 
secretion. Proc. Natl. Acad. Sci. U.S.A. 108, 1639–1644.
Andrews-Polymenis, H. L., Baumler, A. J., McCormick, 
B. A., and Fang, F. C. (2010). Taming the elephant: 
Salmonella biology, pathogenesis, and prevention. 
Infect. Immun. 78, 2356–2369.
Bhutta, Z. A., Naqvi, S. H., Razzaq, R. A., and Farooqui, B. J. 
(1991). Multidrug-resistant typhoid in children: presen-
tation and clinical features. Rev. Infect. Dis. 13, 832–836.
Coburn, B., Grassl, G. A., and Finlay, B. B. (2007). 
Salmonella, the host and disease: a brief review. 
Immunol. Cell Biol. 85, 112–118.
Crump, J. A., Luby, S. P., and Mintz, E. D. (2004). The 
global burden of typhoid fever. Bull. World Health 
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Guiney, D. G., and Fierer, J. (2011). The role of the spv 
genes in Salmonella pathogenesis. Front. Microbiol. 
2:129. doi: 10.3389/fmicb.2011.00129
Hallstrom, K., and McCormick, B. A. (2011). Salmonella 
interaction with and passage through the intestinal 
mucosa: through the lens of the organism. Front. 
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of intracellular survival. They also discuss 
the interesting finding that Salmonella can 
exploit ROS to enhance virulence.
The review from Guiney and Fierer 
(2011) discusses SpvR, SpvB, and SpvC – 
a positive transcriptional regulator and 
two SPI-2 secreted proteins, respectively. 
Interestingly, these loci are not found in 
S. Typhi but are strongly associated with 
non-typhoidal bacteremia causing strains. 
Though unclear concerning their role in 
virulence, they are an example of the spe-
cies-specific virulence traits common in the 
Salmonellae.
All of the pathogenic events discussed 
in this Salmonella special topic rely upon 
effective environmental sensing and gene 
regulation. Salmonella possesses a complex 
regulatory network that has been studied 
in pieces, but not in toto where these regu-
latory network interconnections would be 
defined. Using high throughput genomic 
and proteomic assays and newly developed 
computational approaches for data integra-
tion, McDermott et al. (2011) show how 
these complex networks and inter-system 
regulatory pathways are being defined on a 
genome wide scale. This allows for a never 
before seen “30,000 foot view” of the inter-
workings of the virulence regulatory net-
work in Salmonella.
Gunn Salmonella host–pathogen interactions
Frontiers in Microbiology | Cellular and Infection Microbiology  September 2011 | Volume 2 | Article 191 | 2


Salmonella Host–Pathogen Interactions: A Special Topic

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