Microbes and Infection, 3, 2001, 1335−1344

© 2001 Éditions scientifiques et médicales Elsevier SAS. All rights reserved

S1286457901014952/REV

Animal models of Salmonella infections:

enteritis versus typhoid fever
Renato L. Santosa, Shuping Zhanga, Renée M. Tsolisa, Robert A. Kingsleyb,
L. Garry Adamsa, Andreas J. Bäumlerb*
a
Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4467, USA
b
Department of Medical Microbiology and Immunology, College of Medicine, Texas A&M University System Health Science Center,
407 Reynolds Medical Building, College Station, TX 77843-1114, USA

ABSTRACT – The most common disease syndromes caused by Salmonella serotypes in humans,
typhoid fever and enteritis, can be modeled using Salmonella enterica serotype Typhimurium infections in
mice and calves, respectively. This article reviews murine typhoid and bovine enteritis and discusses
strengths, limitations and distinctive features of these animal models. © 2001 Éditions scientifiques et
médicales Elsevier SAS
murine typhoid / bovine enteritis / Salmonella pathogenesis

1. Introduction travel. In human volunteers, fever is the first symptom and

From the standpoint of human disease, Salmonella
serotypes can be divided into three groups that cause
distinctive clinical syndromes, typhoid fever, bacteremia
and enteritis. Animal models are frequently used to study
the virulence mechanisms of Salmonella serotypes that are
important for two of these human disease syndromes,
typhoid fever and enteritis. This article will review the
strengths and limitations of using different animal species
to model infections caused by Salmonella serotypes in
man. The symptoms in human patients or volunteers
closely resemble signs of disease observed in primate
models. However, the high cost and scarcity of these
animals has prevented the widespread use of this model.
Emphasis will therefore be placed on two animal models
that are used most successfully for elucidating virulence
mechanisms, the mouse and the calf. To give the reader
background information on how closely the animal model
approximates the human disease the characteristic fea-
tures of typhoid fever, bacteremia and enteritis are sum-
marized briefly in the following paragraphs.
Typhoid (enteric) fever is a systemic infection in man
that is caused by Salmonella serotypes which are strictly
adapted to humans or higher primates, including Salmo-
nella enterica serotypes Typhi, Paratyphi A, Paratyphi B,
and Paratyphi C. The disease is currently rare in the United
States [1] and Europe but endemic in Asia, Africa and
South America from where it can be imported by foreign
manifests after a median incubation period of 5–9 days,
depending on the challenge dose [2]. Typhoid fever
patients are often constipated during the early stages of
infection but about one third develop diarrhea subsequent
to the onset of fever [3]. Biopsies taken from the upper
small intestine as early as three days post experimental
infection of volunteers with serotype Typhi reveal diffuse
enteritis caused predominantly by a mononuclear leuko-
cyte infiltrate [4]. Similarly, mucosal thickening of the
ileum due to a polymorphonuclear-poor, mononuclear-
rich infiltrate is characteristic in typhoid fever patients [5].
Tissue colonization of serotype Typhi may produce capil-
lary thrombosis in Peyer’s patches of the terminal ileum
which can result in hemorrhage, necrosis (usually observed
in the second week of infection), ulceration and intestinal
perforation (usually observed in the third week) [6].
Enlargement of mesenteric lymph nodes, liver and spleen
is accompanied by granulomatous lesions. The low-level
bacteremia detected in most patients is important for the
systemic spread of bacteria but endotoxin appears not to
play a major role in the pathogenesis of typhoid fever [7,
8]. While rhesus monkeys are resistant to infection, typhoid
fever can be induced by oral infection of chimpanzees
with serotype Typhi [9]. In this animal model, mucosal
thickening of the ileum and enlargement of Peyer’s patches
is due to a diffuse enteritis characterized by infiltration of
predominantly mononuclear leukocytes [10]. Further-
more, a reactive follicular hyperplasia of lymphoid fol-
licles of Peyer’s patches is noted [11].

*Correspondence and reprints. Enteritis is caused by any of more than 2 500 Salmo-
E-mail address: abaumler@tamu.edu (A.J. Bäumler). nella serotypes, however, S. enterica serotypes Typhimu

Microbes and Infection 1335

2001, 1335-0
Forum in Immunology
rium and Enteritidis are encountered most frequently [12].
Salmonella enteritis represents the second most common
cause of bacterial food-borne disease of known etiology in
the United States [1]. The most common vehicles of trans-
mission are meat, meat products, dairy products, eggs or
egg products containing Salmonella serotypes either
because animals are infected or because fecal contamina-
tion occurs during processing [13]. The infection is local-
ized to the ileum, colon and mesenteric lymph nodes and
commonly manifests within 12–72 h after ingestion of
contaminated food with diarrhea, vomiting and abdomi-
nal pain. Rectal biopsies reveal an acute enteritis charac-
terized by mucosal edema and acute inflammation with
polymorphonuclear leukocytes [14, 15]. Bacteremia is
uncommon and transient in this syndrome [16]. Enteritis
can be modeled by oral infection of rhesus monkeys with
serotype Typhimurium [17, 18]. In this model, lesions due
to infiltration of the mucosa with polymorphonuclear leu-
kocytes are first observed in the colon and subsequently
involve the ileum. Blood cultures of rhesus monkeys are
negative and no significant lesions are observed in liver,
spleen or bone marrow.
Bacteremia (septicemia) is the least common clinical
syndrome in man. It is caused by the porcine-adapted
S. enterica serotype Choleraesuis and the bovine-adapted
S. enterica serotype Dublin which may enter the food
chain through undercooked pork products or unpasteur-
ized milk, respectively [19–21]. The syndrome clinically
differs from enteritis in that bacteria are frequently isolated
from blood while diarrhea is observed in only about one
third of the patients infected with serotypes Dublin or
Choleraesuis [19, 20, 22]. Bacteremia is often accompa-
nied by a high spiking fever that distinguishes the syn-
drome from typhoid fever in which a more continuous
fever is observed [19]. Furthermore, bacteremia caused by
serotypes Dublin or Choleraesuis often occurs without
local manifestations (enteric pathology is encountered
rarely), a clinical feature that distinguishes this syndrome
from both, typhoid fever and enteritis [19]. Finally, among
patients recovering from infection with serotype Choler-
aesuis, healthy carriers are encountered less frequently
than typically described for serotypes causing enteritis or
typhoid fever. Thus a rapid clearance of the organism from
intestinal sites distinguishes the bacteremic syndrome from
both enteritis and typhoid fever [19].
2. The mouse model of typhoid fever
In 1892 Loeffler described the causative agent of murine
typhoid, an epidemic typhoid fever-like disease in mice.
The lesions in internal organs of mice closely resembled
those observed in typhoid fever victims. Since the mouse
isolate displayed similar growth characteristics as bacteria
isolated from typhoid fever patients (then known as Bacil-
lus typhi) it was termed B. typhimurium (now S. enterica
serotype Typhimurium) [23]. Initial studies revealed that
the distribution of bacteria in tissue of mice infected with
serotype Typhimurium [24, 25] is similar to that in typhoid
fever patients [26]. These early reports therefore estab-
lished murine typhoid as an animal model for the study of
1336
Santos et al.
typhoid fever. Serotype Typhimurium is a natural pathogen
for rodents as shown by its frequent association with
disease in this animal reservoir [27]. The interaction of
serotype Typhimurium with one of its natural hosts is
considered by many to be a better model for studying
typhoid fever than more recently developed artificial sys-
tems (e.g., serotype Typhi infection of mice treated with
iron) [28].
Today, susceptible mouse lineages (e.g., Balb/c) are
widely used to study the pathogenesis of serotype Typh-
imurium infections. These animals show signs of disease
(i.e. elevated temperature as indicated by ruffled fur)
between 4–8 days post oral infection, however, diarrhea
does not develop. Gross pathology of the intestine com-
monly reveals enlarged Peyer’s patches and a thickening
of the ileal mucosa. A diffuse enteritis is present in the
small intestine characterized by a predominantly mono-
nuclear leukocyte infiltrate as well as edematous villi
which become shortened in height (figure 1) [29]. Follicu-
lar hyperplasia of the lymphoid tissue, capillary thrombo-
sis, hemorrhage, and ulcerations may be present in the
terminal ileum at areas of Peyer’s patches. The intestinal
epithelium in other areas of the intestine remains largely
intact (figure 1). The intestinal pathology and inflamma-
tory reaction in mice is hence more similar to that of
typhoid fever patients [4–6] than it is to that caused by
serotype Typhimurium in human intestines [14, 15].
Furthermore, unlike the localized infection serotype
Typhimurium causes in man, susceptible mice develop a
systemic disease characterized by rapid bacterial multipli-
cation in the liver and spleen at a net growth rate of
0.5–1.5 log/day [30, 31] which results in hepatomegaly
and splenomegaly. Growth of bacteria in the mesenteric
lymph node, the liver and the spleen triggers the formation
of acute abscesses containing predominantly polymor-
phonuclear leukocytes. These microscopic lesions become
enlarged and are gradually transformed into granulomata
with central necrosis and peripheral mononuclear leuko-
cytes [32]. In these lesions, serotype Typhimurium resides
intracellularly inside macrophages [33]. The granulomata
observed in mice are similar to those present in tissues of
chimpanzees infected with serotype Typhi [11]. Death of
animals likely results from the lesions in hepatic tissues
triggered by pro-inflammatory cytokine and/or inducible
nitric oxide synthase responses elicited by lipid A [34].
One obvious limitation of the mouse model of typhoid
fever is that serotype Typhimurium causes enteritis rather
than typhoid fever in humans. Thus, humans and mice
exhibit strikingly different host responses to serotype Typh-
imurium infections. Furthermore, serotype Typhi genes
which are required for causing typhoid fever but which are
absent from or functionally altered in serotype Typhimu-
rium cannot be studied in the mouse model. In addition,
not all information obtained using the mouse model can
be directly applied to improving our understanding of
typhoid fever since some virulence factors of serotype
Typhimurium are absent from the serovar Typhi genome.
For instance, the Salmonella plasmid virulence (spv)
operon is required for full mouse virulence of serotype
Typhimurium [35] but is not present in serotype Typhi
[36]. Finally, some genes that are present in serotype Typhi
Microbes and Infection
2001, 1335-0
Animal models of Salmonella infections
Figure 1. Hematoxylin and eosin stained histological sections of
the murine ileum (bar = 100 µm). Upper half: uninfected con-
trol. Lower half: ileum of Balb/c mouse 5 days post infection with
a lethal dose of serotype Typhimurium strain ATCC14028. Note
a diffuse enteritis associated with edema which is caused by
infiltration of predominantly mononuclear leukocytes.
and required for serotype Typhimurium infection in mice
are not essential for the pathogenesis of typhoid fever. For
example, a mutation in galE renders serotype Typhimu-
rium avirulent for mice [37, 38] but a serotype Typhi galE
mutant is not avirulent for human volunteers [39].
Although it is important to be aware of possible limita-
tions when extrapolating results from murine typhoid to
typhoid fever, it is clear that the strengths of the mouse
model outweigh its shortcomings. The mouse model has
been extremely useful in identifying virulence mecha-
nisms of serotype Typhimurium. The type III secretion
system encoded by Salmonella pathogenicity island (SPI)
2 and the spv operon, two major virulence determinants of
serotype Typhimurium, were identified during in vivo
screens performed in the mouse model [40, 41]. Further-
more, the mouse model was used to establish the role
during infection of major virulence factors identified in
tissue culture assays, such as the type III secretion system
encoded on SPI1 [42] and many others. The use of knock-
out mice has revealed new insights into host factors
required for innate resistance and acquired immunity to
Salmonella infections [43–51]. In addition, the mouse
model has been used successfully for identifying live
Microbes and Infection
2001, 1335-0
Forum in Immunology
attenuated typhoid fever vaccine candidates. That is muta-
tions in aroA [52], cya and crp [53], phoP [54] and htrA
[55] cause optimal attenuation of serotype Typhimurium
in mice while retaining immunogenicity of the vaccine
strain. The information generated in the mouse model was
used for the design of new live attenuated serotype Typhi
vaccine strains carrying deletions in aroC and aroD [56],
aroC, aroD and htrA [57], aroA, aroC and htrA [58], cya
and crp [59] or phoPQ [60]. These data illustrate the
usefulness of the mouse model for studying the pathogen-
esis of typhoid fever.
3. The bovine model of human enteritis
Since mice infected with serotype Typhimurium do not
develop diarrhea, murine typhoid is not suited to study the
pathogenesis of enteritis in humans. In contrast, natural or
experimental infection of calves with serotype Typhimu-
rium results in an enteric disease with clinical and patho-
logical features that parallel the disease in man. Recent
studies have thus focused on the calf as a model for
Salmonella-induced enteritis.
Although cattle may be infected with many Salmonella
serotypes [61, 62], the two serotypes most frequently
associated with disease are Dublin and Typhimurium
[63–65]. In humans these serotypes are associated with
different disease syndromes, namely bacteremia and
enteritis, respectively [20, 21]. Similarly, the disease caused
by serotype Dublin in cattle differs in several aspects from
that caused by serotype Typhimurium. Unlike serotype
Typhimurium, serotype Dublin may cause abortion in
pregnant cows and heifers with no other clinical signs of
infection [66, 67]. Infections with serotype Dublin may
result in chronic carriage as opposed to only transient
carriage observed in cattle infected with serotype Typh-
imurium [68, 69]. Eventually these carriers may have
activation of the infection associated with clinical signs
[63]. Like serotype Typhimurium infections, the most
important clinical manifestation of serotype Dublin infec-
tion in young calves is diarrhea [70, 71]. However, sero-
type Typhimurium induces greater secretory and inflam-
matory responses than serotype Dublin in bovine ligated
ileal loops [72]. Furthermore, serotype Dublin causes a
more invasive infection in calves which can manifest as
meningoencephalitis, polyarthritis, osteomyelitis, and
pneumonia that eventually occurs in the absence of a
diarrheal disease [67]. The spv operon, which is required
during the systemic phase of infection in mice, is essential
for full virulence of serotype Dublin in calves [73, 74] but
plays little role during the localized infection caused by
serotype Typhimurium calves [75]. Considering the inva-
sive character of serotype Dublin infections in both cattle
and humans, the enteric disease caused by serotype Typh-
imurium in calves appears to be better suited to for mod-
eling Salmonella-induced enteritis in man.
Upon oral infection with serotype Typhimurium calves
develop clinical signs within 12–48 h [75], which is simi-
lar to the short incubation period observed in rhesus
monkeys [17] or human volunteer studies [76]. Clinical
signs of disease during experimental infection include
1337
Forum in Immunology Santos et al.

diarrhea, anorexia, fever, dehydration and prostration [75,

77, 78]. Usually oral inoculations with 104–107 colony-
forming units (CFU) causes transient diarrhea which per-
sists for 2–8 days, whereas lethality may be caused at
doses between 108 and 1011 CFU [75, 77–79]. Morbidity
and mortality are inversely proportional to age [78] and
approximately 75% of natural serotype Typhimurium infec-
tions occur in calves less than 2 months of age, before the
animals are weaned [65]. Similarly, the incidence of
Salmonella-induced enteritis in the US is highest among
children aged less than 1 year with 111 cases per 100 000
population [80].
Calves infected with serotype Typhimurium tend to
have a more severe dehydration than in other neonatal
diarrheal diseases, resulting in an average weight loss of
18.7% [81]. The most marked hematological change in
infected calves is a transient leukopenia with neutropenia
at the early stages, reflecting the initial influx of polymor-
phonuclear leukocytes into the intestinal mucosa, while
neutrophilia develops at later stages of the infection [78,
82]. The levels of plasma sodium and calcium are
decreased possibly as a result of the electrolyte loss during
serotype Typhimurium-induced diarrhea [83]. Calves with
Salmonella-induced diarrhea frequently develop meta-
bolic acidosis with blood pH measurements of 7.0 or less
[67]. Fluid and electrolyte imbalances associated with
acidosis have also been reported for Salmonella-induced
enteritis in man [84].
The most severe pathological changes in calves infected
with serotype Typhimurium are restricted to the intestine Figure 2. Gross pathology of the bovine ileum. Upper half:
[75, 77]. Grossly, the mesenteric lymph nodes are often uninfected control. Lower half: 12 h post infection with a lethal
enlarged and the caudal portion of the small intestine dose of serotype Typhimurium strain ATCC14028. Note the
(caudal jejunum and ileum) is congested and distended severe acute fibrinopurulent necrotizing enteritis with
with fluid. A fibrino-purulent enteritis is commonly seen pseudomembrane formation.
although the aspect of the exudate may vary from mucoid
to fibrino-necrotic. A distinct fibrino-necrotic pseudomem- nuclear leukocytes are proposed to play a decisive role in
brane is sometimes attached to the surface of Peyer’s the pathogenesis of serotype Typhimurium-induced diar-
patches and, in severe cases, may cover the mucosa of the rhea.
terminal 5 m of the ileum and the cranial 1–2 m of the The ileal ligated loop model, adapted from other spe-
colon (figure 2) [75, 77]. Microscopically, marked lym- cies to calves [87] can be used for studying the early
phoid depletion is evident in the lymphoid nodules at the pathologic changes occurring during infection [88] and
Peyer’s patches [75]. However, lymphoid depletion is not for characterizing virulence factors [89]. A drawback of
restricted to the intestinal wall and may be observed in the ligated intestinal loop model is that it is only suited for
other lymphoid organs such as mesenteric lymph nodes, studying early steps during infection. As a result, data
thymus and spleen [85]. Furthermore, experimentally obtained using ileal loop experiments may not be predic-
infected animals develop a fibrino-purulent necrotizing tive of the degree of attenuation observed during an oral
enteritis characterized by a severe diffuse infiltration of infection. For instance, a sopB (sigD) mutant of serotype
polymorphonuclear leukocytes associated with necrosis Typhimurium causes significantly less fluid accumulation
of the upper mucosa [75, 77]. Similar lesions occur in and polymorphonuclear leukocyte influx in bovine ileal
naturally infected calves [86]. The intestinal pathology loops, suggestive of a role in diarrheal disease (Santos, R.L.
and the pattern of inflammatory reaction (influx of pre- et al., Infect. Immun. 69 (2001) 4610–4617). However, a
dominantly polymorphonuclear leukocytes) observed in serotype Typhimurium sopB mutant causes diarrhea, intes-
calves is thus strikingly similar to that of serotype tinal lesions and lethal morbidity in calves infected orally
Typhimurium-induced enteritis in non-human primates [75]. These data suggest that the onset of fluid accumula-
[17, 18] and in humans [14, 15]. In sharp contrast, mice tion and polymorphonuclear leukocyte influx is merely
infected with serotype Typhimurium develop a diffuse delayed in a sopB mutant. Despite this shortcoming, the
enteritis in the small intestine characterized by localized bovine ligated ileal loop model clearly is a valuable tool to
erosion of intestinal epithelium and a predominantly study early steps of enteric disease in cattle.
mononuclear leukocyte infiltrate that is not associated Ultrastructural studies of infected ileal ligated loops
with diarrhea (figure 1) [29]. Therefore, polymorpho- demonstrate that serotype Typhimurium induces ruffling of
1338 Microbes and Infection
2001, 1335-0
Animal models of Salmonella infections
the plasma membrane at the apical side of intestinal
epithelial cells [88], invading either M cells or absorptive
enterocytes (figure 3) [90]. In ligated ileal loops, bacteria
can be detected inside epithelial cells as early as 20 min
post infection, and in macrophages in the lamina propria
containing bacteria were detected at 60 min after infec-
tion [88]. A blunting of villi is observed soon after infection
of loops with serotype Typhimurium (figure 4). Although
the mechanism of Salmonella-induced diarrhea is still not
clear, some previous reports indicate that it is distinct from
a secretory diarrhea such as that caused by cholera toxin
[18, 84, 91]. As discussed in the following section, viru-
lence factors essential for serotype Typhimurium to cause
disease in calves are implicated in inducing influx of
polymorphonuclear leukocytes. Infiltration with polymor-
phonuclear leukocytes is evident within 1 h after infection
in ligated ileal loops and this inflammatory response pre-
Figure 3. Transmission electron micrographs of serotype Typh-
imurium strain ATCC14028 invading epithelial cells in bovine
ligated ileal loops (bar = 2 µm). Upper half: bacterial invasion of
enterocytes associated with ruffling of the membrane at the apical
surface. Lower half: bacterial invasion of M cells.
Microbes and Infection
2001, 1335-0
Forum in Immunology
cedes fluid secretion (Santos, R.L. et al., Infect. Immun. 69
(2001) 4610–4617). Within 12 h post infection the intes-
tinal epithelium is largely destroyed and a fibrinopurulent
exudate forms in the intestinal lumen (figure 5). Since
polymorphonuclear leukocyte influx and damage to the
intestinal epithelium precede fluid accumulation in intes-
tinal loops it can be speculated that serotype Typhimurium
causes a predominantly exudative diarrhea.
In summary, the calf is an excellent model for studying
Salmonella-induced enteritis since serotype Typhimurium
is a natural pathogen of cattle in which it causes similar
signs of disease and pathology as observed in humans.
4. The relative importance of serotype
Typhimurium virulence factors during
infection of mice and calves
As outlined above, serotype Typhimurium is used both
in the mouse model of typhoid fever and the bovine model
Figure 4. Scanning electron micrographs of bovine ligated ileal
loops (bar = 50 µm). Upper half: uninfected control. Lower half:
3 h post infection with serotype Typhimurium strain
ATCC14028. Note the marked blunting of intestinal villi.
1339
Forum in Immunology
Figure 5. Hematoxylin and eosin stained histological sections of
bovine ligated ileal loops (bar = 100 µm). Upper half: uninfected
control. Lower half: 12 h post infection with serotype Typhimu-
rium strain ATCC14028. Note diffuse infiltration with predomi-
nantly polymorphonuclear leukocytes, destruction of intestinal
epithelium (with the exception of epithelial cells in the crypts),
and fibrinopurulent exudate in the intestinal lumen.
of human enteritis. The analysis of serotype Typhimurium
mutant phenotypes in mice and calves reveals that major
virulence determinants do not contribute equally to murine
typhoid and bovine enteritis.
A number of virulence determinants required for growth
at systemic sites of infection in mice are less important
during the localized infection caused by serotype Typh-
imurium in calves. For instance, LPS core biosynthesis
genes, the spv operon and SPI2 are required for growth of
serotype Typhimurium at systemic sites of infection in
mice [92–94]. A serotype Typhimurium galE mutant is
avirulent in the murine typhoid model [37, 38] but causes
mortality when administered orally to calves at a dose of
1010 CFU/animal [95]. The spv operon is required for full
mouse virulence [35] but serotype Typhimurium spv
mutants cause severe intestinal lesions and mortality at
wild-type level in calves infected orally at a dose of
1010 CFU/animal [75]. A mutation in SPI2 renders sero-
type Typhimurium avirulent (> 10 000-fold attenuated) for
mice [41] because bacteria have a reduced ability to
1340
Santos et al.
replicate in macrophages [96]. In calves, on the other
hand, inactivation of SPI2 results in a reduced severity of
intestinal lesions but only in a modest attenuation (< 15-
fold) of serotype typhimurium during an oral infection
[75].
While mutations in galE, spv and SPI2 lead to a greater
attenuation of serotype Typhimurium in the mouse than in
the calf model, the opposite is true for mutations in genes
required during the intestinal phase of infection. For
example, the invasion associated type III secretion system
encoded by SPI1 is required for serotype Typhimurium
colonization of murine Peyer’s patches [42] and the bovine
small intestine [83, 97]. Mutations that prevent type III
secretion (prgH) or translocation (sipB, sipC, sipD) of
effector proteins into the host cell cytosol result in aviru-
lence and the absence of diarrhea in the calf model [75,
83]. A mutation in hilA, encoding a positive regulator of
SPI1 [98], renders serotype Typhimurium avirulent during
oral infection of calves [75] and results in strongly reduced
fluid accumulation and inflammation in bovine ligated
ileal loops [99]. However, a mutation in hilA has little or
no effect on mouse virulence of this pathogen [99]. These
data demonstrate that attenuation in the mouse model
caused by mutations in serotype Typhimurium virulence
genes are not always predictive of the degree of attenua-
tion observed in the calf.
5. Conclusions
Virulence is a complex phenotype which fully mani-
fests only during host pathogen interactions in vivo. Study-
ing a natural infection in an animal which develops signs
of disease similar to those observed in humans is thus
essential for a complete understanding of Salmonella
pathogenesis. For instance, in vitro experiments using
epithelial cell lines have shown that the SPI1 secreted
effector protein SipA (SspA) binds and stabilizes actin
filaments, modulates the actin-bundling activity of T-plastin
and contributes to transepithelial migration of polymor-
phonuclear leukocytes [100–102]. A mutation in sipA
(sspA) of serotype Typhimurium results neither in attenua-
tion in the mouse typhoid model nor in an obvious inva-
sion defect in tissue culture cells, although entry is delayed
at early time points [102–104]. Furthermore, this mutation
causes neither reduced invasion of the bovine intestinal
mucosa nor does it reduce the severity of diarrhea or
intestinal lesions during an oral infection of calves [83].
However, a sipA mutant is unable to cause mortality in
calves when administered orally at a dose of 1010 CFU/
animal, a phenotype that is not predicted by experimental
infection of mice [83]. Furthermore, there is currently no
obvious connection between the role of SipA in modulat-
ing processes in epithelial cell lines in vitro and its involve-
ment in causing lethal morbidity in calves. This example
illustrates the importance of using an animal model, which
resembles the natural course of infection and the typical
signs of disease to elucidate mechanisms important for the
pathogenesis of enteritis. Thus, an appropriate animal
model is still an invaluable tool for the study of human
disease syndromes caused by Salmonella serotypes.
Microbes and Infection
2001, 1335-0
Animal models of Salmonella infections
Acknowledgments
This material is based in part upon work supported by
the Texas Advanced Research (Technology) Program under
grant number 000089-0051-1999. Work in A. Bäumler’s
laboratory is supported by Public Health Service grants
#AI40124 and #AI44170.
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