Open access peer-reviewed chapter

Immunopathogenesis of Salmonellosis

Written By

Mashooq Ahmad Dar, Peerzada Tajamul Mumtaz, Shakil Ahmad Bhat, Qamar Taban, Shabir Ahmad Khan, Tufail Banday and Syed Mudasir Ahmad

Submitted: November 13th, 2018 Reviewed: February 22nd, 2019 Published: May 24th, 2019

DOI: 10.5772/intechopen.85371

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Salmonella is an intracellular pathogenic, gram-negative, facultative anaerobe and non-spore-forming and usually a motile bacillus that leads to salmonellosis in the host. It is a common food-borne disease that ranges from local gastrointestinal inflammation and diarrhoea to life-threatening typhoid fever and presents usually a serious threat to public health due to its socio-economic value. Inadequate sanitation and impure water help in the propagation of this disease. Despite advancement in the sanitation standards, Salmonella enters the food chain and affects communities globally. There is an immediate need to develop improved vaccines to minimise Salmonella-related illnesses. Some Salmonella serovars infect a wide range of hosts, while others are known to be host restricted. Many different factors determine the adaptability and host specificity of Salmonella. The host-pathogen interactions play a unique role in Salmonella invasion and progression which needs to be studied in detail. This chapter shall focus on our current understanding of Salmonella invasion, pathogenesis and interactions with the host, host specificity and adaptability.


  • Salmonella
  • serovars
  • adaptability
  • specificity
  • invasion
  • non-typhoidal Salmonella
  • typhoidal Salmonella
  • immune response

1. Introduction

Salmonellae are facultative anaerobes and gram-negative, non-spore-forming and usually motile bacilli. Two species, namely, Salmonella enterica and Salmonella bongori, belong to genus Salmonella. Salmonella enterica is further subdivided into six subspecies that are distinguished by variations in O (somatic) and H (flagellar) antigens with at least 2500 serotypes. S. enterica subsp. enterica comprises of more than half of the known serotypes [1]. New serotypes are being discovered increasing the serotype complexity. Approximately 99% of the Salmonella serotypes that infect humans and other mammals belong to S. enterica subspecies. These serovars are mostly the inhabitants of intestinal tract of humans and other organisms that include reptiles, birds and insects. At farm level, sources of bacterial contamination are faecal matter, litter, feed and soil [2]. Salmonella most commonly causes food-borne illnesses worldwide; the two commonly associated foods are eggs and poultry meat [3]. Serovars S. Enteritidis, S. Typhimurium, S. Heidelberg and S. Newport are linked to such food-borne diseases, with farm animals being reservoirs for these serotypes [4, 5]. Salmonellosis is a big socio-economic threat worldwide that causes considerable mortality and morbidity in both humans and animals [6]. Most of the human-related diseases are food-borne, and exposure to these bacteria at different places has also been linked to human salmonellosis. The most orthodox mode of bacterial transmission is the faecal-oral route. Once the bacteria are transmitted, the initial site for bacterial infection is the small intestine. Following infection, different manifestations that arise range from gastroenteritis to enteric fever [7].


2. Epidemiology

The extensive investigation of the associated epidemiological risk factors that make an organism a persistent Salmonella carrier needs to be carried out. Non-typhoidal Salmonella (NTS) infections that cause self-limiting manifestations are the most common to occur globally. In comparison, typhoidal Salmonella (TS) causing enteric fever leads to a high rate of mortality and morbidity that predominantly affects the underdeveloped countries [8]. Recent studies conclude that Salmonella Paratyphi A incidences have risen especially in South East Asia where approximately half of the TS-infected enteric fever patients are reported to be infected with S. Paratyphi A [9]. The food chain can get contaminated at any stage, and most of the transmission can occur by contaminated foods like poultry and dairy-related products. Apart from contaminated food products, NTS transmission can also result from person-to-person contact or from contact with other bacterial reservoirs. After gaining entry into the host, both TS and NTS serovars initially invade the intestinal epithelium of the small intestine.


3. Diseases caused by Salmonella infection

Salmonella species cause a varying number of clinical manifestations in the host that can range from self-limiting gastroenteritis typically associated with non-typhoidal Salmonella (NTS) to typhoidal or paratyphoidal fevers, which can be life-threatening [6].

3.1 Typhoidal Salmonella (TS)

Humans are exclusive hosts for serovars such as S. Typhi, S. Sendai and S. Paratyphi A, B and C. These serovars are known as typhoidal serovars (TS) that can cause enteric fever/typhoidal/paratyphoidal fevers. Enteric fever is a systemic disease that is highly invasive and life threatening and is endemic in the developing world. Within an incubation period of around 2 weeks, bacteraemia occurs, which is marked by fever and malaise. The symptoms that start to appear after a week include fever, malaise, nausea, dry cough and abdominal discomfort. Common symptoms include tender abdomen, coated tongue, splenomegaly and hepatomegaly [10]. As the lack of adequate water and sanitation facilities in the developing countries help in the spread of Salmonella through faecal-oral route [11], so to prevent typhoidal Salmonella transmission, societal standards need to be improved. The development of improved societal infrastructures is generally cost prohibitive in developing countries, hence, having little significance in reducing the disease frequency. In comparison, the development of effective and safe typhoidal vaccines can have a significant effect on reducing typhoidal cases.

3.2 Non-typhoidal Salmonella (NTS)

Many industrialised and underdeveloped countries across the globe face a significant threat of non-typhoidal Salmonella (NTS). Worldwide, about 93.8 million gastroenteritis cases arise from Salmonella infections leading to 1.5 million deaths annually [7]. In infants, young, aged and immunologically compromised subjects NTS cause invasive bacterial infection [12, 13]. After post infection with NTS, symptoms that arise last for about 10 days that triggers a massive inflammatory response involving the release of pro-inflammatory cytokines and chemokines. The human NTS patients have higher serum levels of different interleukins and cytokines like IL-18, IL-12, IL-10, IL-15, TNF- α and IFN γ [14]. Non-typhoidal Salmonella serovars can cause severe extra-intestinal disease in patients with deficiencies in type 1 cytokine pathways such as IFN-γ/IL-12/IL-23 especially IL-12 abnormalities. Effective vaccination against NTS is lacking as there is a greater variance among different serovars. So, for generating effective vaccines against NTS, knowledge regarding different target antigens needs to be studied in detail. To disrupt the bacterial transmission and the incidence, effective preventive measures such as improving sanitation, hygiene and drinking clean water must be taken into consideration. Different host specificities and adaptability are shown by different Salmonella serovars that shall be discussed in detail.


4. Host specificity and adaptation

Salmonellosis susceptibly ranges from organism to organism and can occur in almost all animal species, but the clinical severity of this disease varies among the hosts. There are only specific serovars that cause severe clinical manifestations in their specific hosts [15]. Although most of the serovars of S. enterica subspecies cause infections which give rise to gastroenteritis that lasts for short durations, some serovars lead to severe systemic illness in humans and animals accompanied by septicaemia, fever and in some cases abortion. Based on the host specificity, these serovars can be grouped into two categories: the first category consists of serovars that are single-host restricted and the second category infecting a broad range of hosts. Different factors can be considered for grouping different serovars under the above-mentioned categories. Also, serovar pathogenicity and host epidemiology define host specificity. Keeping the above factors into account, different serovars have been grouped into three major groups. The first group comprises of serovars that mainly infect cattle and pigs but can also infect other animals including humans in some accidental cases. In this group, S. choleraesuis and dublin have been included that cause systemic diseases in the above-mentioned hosts. In humans and other animals, clinical symptoms may not be visible, thus making them asymptomatic. Salmonella carriers that can shed the bacteria in the surroundings thus leading to increased risk for susceptible hosts are also known as host-adapted serovars (HA) [16]. The second group infects specific hosts and is collectively known as host-restricted (HR) serovars. The HR serovars cause systemic diseases and can sometimes prove lethal in their hosts that include poultry, humans, sheep, equine and pigs. This group includes S. gallinarum, S. typhi, S. abortus and S. abortusequi. They interfere with the environment of their hosts in a way that paves their way for invading the host. This ability to cause mammalian abortions and loss in poultry egg production is due to their remarkable ability to multiply in the foetal tissues [16, 17, 18]. The serovars of the third group are known as unrestricted serovars that are of zoonotic, epidemiological importance and impose a great threat to many animals and humans. The serovars of this group that are of much clinical importance are S. typhimurium and S. enteritidis [18]. These cause mild symptoms in the adult host, and sometimes the host does not show any visible clinical symptoms despite infection. They severely invade young hosts as compared to adult hosts because the adult hosts have a well-built immune system that hinders the invasion by these serovars [16]. The host specificity and adaptability of different serovars are a complex process and involve many molecular mechanisms. The exact mechanisms are poorly studied, but certain factors have been found to be responsible for determining host specificity and adaptability.

4.1 Factors determining Salmonella host specificity and adaptation

Although the exact mechanisms to host specificity have not been fully deciphered, the existing evidence shows that serovars act independently of each other at the various phases of infection. The expression of serovar’s pathogenicity is affected by the environmental and genetic factors influencing each host during adaptation [19]. Each HA/HR serovar must overcome the encountered specific and non-specific immune mechanisms. Thus, pathogenicity of HA serovars results from the development of ways helping their survival in a host. Examples of this are serovars of S. enterica subsp. enterica, which have developed the ability to evade the immune mechanisms of warm-blooded animals. They have, during their evolution, acquired the ability to modify to their favour the physiological functions of their host, such as intracellular engulfment, apoptosis, transfer of antigens by M (microfold) cells, migration of macrophages and lymphocytes in the reticuloendothelial system and others [20]. A well-known serovar S. typhi has evolved to survive in human macrophages making it pathogenic to man, but not to mice [21]. Serovars such as the HR S. typhi, S. gallinarum and S. abortusovis show high tropism for the lymphatic organs of their hosts, thereby regulating their natural host’s biological environment in their favour [19]. By anchoring to the cells of the bone marrow, PPs and bursa of Fabricius in the development of B cells, thus immune response is affected. The result of such interactions, particularly in adult animals, helps in the establishment of chronic or subclinical infection and thus prolonged subclinical excretion, but they do not help in the development of severe gastroenteritis [22]. Serovars not fully adapted to evade the mature immune system lack specificity, causing deadly systemic disease in adult animals by invading their defence mechanisms compared to HR serovars [20]. HR serovars are mildly enteropathogenic compared to the unrestricted serovars; thus, they do not cause intestinal inflammation [23]. It has also been shown that the ability of a serovar to metabolise a wide range of amino acids adds to its virulence and is thought to be closely related [24, 25]; however, HR or HA serovars have most likely evolved independently. On the other hand, the heterogenicity of serovars in relation to different metabolic profiles facilitates either the completion of the pathway to infection [26] or, when lacking specificity, it is favouring host adaptation [19]. The process of Salmonella host adaptation is believed to be involving either the loss of genes or the acquisition of novel genetic elements that encode specific virulence factors, and thus an inconvenience is observed frequently in the pathogenic strains. Best examples of host specificity dependent on gene deletions are, perhaps, of S. enteritidis, Typhimurium, Choleraesuis, Gallinarum, Abortusovis, Pullorum and Paratyphi C [27]. Genome sequencing of HA/HR serovars, such as Typhi, Gallinarum, Choleraesuis and the newly emerging in sub-Saharan Africa invasive strains of S. Typhi, has divulged that these have encountered extensive gene deletions and truncation [28, 29]. In systemically noninvasive Salmonella, the majority of lost genes have functional orthologues, which play a key role in intestinal colonisation, thus resulting in the loss of an intestinal multiplication cycle for narrowly host-adapted Salmonellaefollowed by a concurrent acquisition of mechanisms helping the microorganism to survive in a systemic niche [30]. Point mutations, horizontal gene transfer, positive selection and genome degradation could be responsible for a differential pathoadaptive evolution of some Salmonella serovars [31]. It appears from the analysis of the mannose-sensitive fimbrial adhesin FimH that even single amino acid replacement, resulting in specific structural mutations in FimH variants of HA serovars, plays an important role in the differential adaptive evolution of Salmonella spp. Thus, activation or inactivation of mannose-specific adhesive properties in different systemically invasive serovars reflects the dynamic trajectories of adaptation to the biological environment of a specific host. Furthermore, phylogenetic analysis has indicated that these mutations are, most likely, of a convergent nature (common pathogenic traits incorporated into different genetic backgrounds) and occur under strong positive selection, illustrative of the role of point amino acid changes for HA Salmonella. Certainly, deep study for the molecular composition of flagella, chemotaxis genes [32], fimbriae and bacteriophages and the presence of virulence plasmids and subtypes of each specific serovar is needed, to understand mechanisms of pathogenicity and host specificity [19]. Correlation between some phage types of S. Typhi with their hosts has shown considerable host specificity [33]. However, the majority of phage types studied had a broad host range, perhaps, suggesting a phage transfer of virulent genes between hosts, leading eventually to host specificity. The unrestricted serovar Typhimurium may comprise a spectrum of variants differing in regard to virulence, reflecting a summation of the spatial and/or temporal selective pressures within a particular host [34]. Salmonella Typhimurium strains derived from animal cases were also virulent in mice, whereas many strains derived from a clinically ill man lacked this ability. Of interest was that many derived from human gastroenteritis lacked the Salmonella virulence plasmid, present in all animal strains and strains isolated from human bacteraemia. Furthermore, some strains harbouring the virulence plasmid isolated from the man were avirulent in mice, and the opposite was observed with those derived from animals. Altogether, isolates of a specific bacterial serovar obtained from human salmonellosis are different from those isolated from animals. This means that selective pressure within a specific host gives rise to bacterial strain variants that exhibit different pathogenicity determinants, thus varying degree of pathogenicity. Similarly, serovars of S. enterica subsp. enterica, associated with disease in mammals and birds, show different degrees of adaptability. Pathogenicity determinants, such as the FimH adhesins, play an important role. Type 1 FimH adhesins are expressed by serovars of S. enterica isolated from mammalian and avian hosts, while type 2 FimH is expressed exclusively by the avian-adapted serovar Gallinarum. Allelic variation of the S. enterica FimH adhesin directs host-cell-specific recognition, thus selectively binding to mammalian or avian receptors [35]. The distribution of SPIs, fimbriae operons and virulence plasmids has shown that various combinations of virulent determinants formed during the evolution of the microorganism are needed for a variant to become pathogenic in a particular range of host species. Mutations horizontally transmitted could have helped the development of host specificity by helping Salmonella serovars to harbour unique virulence factors [36]. Molecular and phylogenetic analyses of the SPI genes showed that these encode for translocon proteins (SipD, SseC and SseD) present on both Salmonella pathogenicity islands SPI-1 and SPI-2 and also encode an effector protein that inhibits the MAPK pathway of the host cells [37]. In addition, they encode effector proteins (SseF and SifA) important in placing the Salmonella-containing vacuole (SCV) in a juxtanuclear position. The products of SPI genes interact directly with the host and modulate its functions, thus favouring host specificity. Another study of the SPI genes has shown the close evolutionary relatedness between serovars Gallinarum and Enteritidis [38], although the former is highly adapted (restricted) to poultry and is the only known non-motile serovar, while serovar Enteritidis is unrestricted. Analysis of the functions of genes associated to SPI-1 showed that virulence genes might have evolved under positive selection imposed by a serovar’s respective host(s) contributing to the different host specificity observed between different serovars. This has displayed that a close similarity of core regions exists within as well as among different serovar genomes [39]. In particular, genomic comparisons of HR and HA serovars show that genomic degradation is a common evolutionary mechanism for host adaptation and increased pathogenicity [39, 40]. Others have shown that host restriction and change of ecological niche are associated with the accumulation of pseudogenes and an overall reduction in genome size [28]. For example, S. Typhi and Paratyphi A are restricted to the man and cause a similar systemic disease. Genome sequence similarity between Typhi and Paratyphi A serovars and their different pathogenicity when compared to the unrestricted serovars of S. enterica have been attributed to a relatively recent recombination of a quarter of their genomes, making the aggregation of pseudogenes a key feature of convergent evolution for these and other HA pathogens [31]. Another example supporting the role of convergent evolution is serovar Paratyphi C, which has diverged from the same ancestor as serovar Choleraesuis, by accumulating genomic novelty during its adaptation process to man. The genomic analysis of these two Salmonella serovars has revealed a highly similar genomic construction between the two and their distinct pathogenic features, making them excellent models for studying Salmonellas host adaptation and pathogenic divergence [39]. Hence, Salmonella adaptation to a particular host species is a complex phenomenon, which depends, apparently, on a large number of gene products. The prowess of understanding host-pathogen interactions requires analysis of the physiological associations between various animal species and genetic composition.


5. Salmonella invasion

After ingestion of Salmonella by the host organism, it travels from the stomach and invades intestinal epithelial cells. Bacterial recognition generates an inflammatory response following the recruitment of a variety of bone-marrow-derived phagocytes [41]. The ability of Salmonella to access intestinal epithelium (M cells) is due to the presence of virulence genes encoded by Salmonella pathogenicity island 1 (SPI-1). Proteins that are encoded by SPI-1 form a needle-like Type III secretion system which allows the transport of several bacterial proteins into the host cell cytosol. These proteins induce changes in the host cells such as the rearrangement of the cytoskeleton and cell membrane and disconnection of epithelial cell junctions, facilitating bacterial invasion [42]. The primary site of Salmonella infection occurs at specialised microfold, or M cells, that are dispersed among the enterocytes, covering the follicle-associated epithelium (FAE) of the Peyer’s patch (PP) [43] (Figure 1). Salmonella is considered to preferentially invade PPs in the distal ileum, but in practice, all intestinal PPs will harbour bacteria after moderate-to-high-dose infection. Once Salmonella is penetrated, it initiates destruction of M cell which disrupts the mucosal barrier and allows additional entry of bacteria through neighbouring enterocytes [43]. This process is extremely efficient, with M-cell penetration followed by M-cell destruction. Once access to PP via FAE is gained, invading bacteria enter the lymphatic system where they interact with professional killing cells (phagocytes) that ultimately determine the fate of the infection. Phagocytes are involved in both oxygen-dependent and oxygen-independent killing of the engulfed bacteria. During intestinal NTS infection, the release of reactive oxygen and nitrogen species creates a highly oxidative environment which is not permissive for the growth of bacteria. The subepithelial dome also contains dendritic cell (DC) subsets apart from macrophage populations, each of which can phagocytise the bacteria and then undergo apoptosis through a caspase-1-dependent mechanism [44]. Consequently, during Salmonella infection, the number of obligate anaerobes decline in the gut. Also, host-signalling environment is highly crucial for the disease development initiated by contact between microbe and host cells in various tissues, largely mediated by cytokine signalling. These cytokines aid in initiating and regulating the innate and adaptive branches of the immune response against Salmonella. In order to avoid damage to the host, the release of pro- and anti-inflammatory cytokines must be balanced [45]. M cells are not only abundant in PPs; they also predominate in other intestinal locations and so can, therefore, mediate infection of non-PP intestinal tissues (Figure 1). The most likely non-PP entry route is through the bacterial invasion of solitary intestinal lymphoid tissues (SILTs), which are heterogeneous intestinal lymphoid aggregates found in mice and humans that contain certain features of PPs, including the presence of FAE-containing M cells [46, 47]. These SILTs are invaded by bacteria in a much similar manner as described above for PPs [48]. SILTs can be important in humans since in a study of typhoid patients, both PPs and SILTs showed inflammation. It has also been reported that intravillous M cells, which are sparsely located along the intestinal tract, may serve as a portal of entry for invasive Salmonella bacteria [49, 50] (Figure 1).

Figure 1.

Salmonella entry in intestinal epithelial cells. SPI-1 facilitates uptake and destruction of M cells, SILTs. After invasion of under tissues, Salmonella is taken by phagocytes and transported to mesenteric lymph nodes.

5.1 Alternative route for invasion

The main entry route described above involve, bacterial interactions with M cells, the possibility is that it can invade the host by an alternative route that does not involve M cells. A population of phagocytes in the lamina propria capture bacteria directly from luminal contents which also allow bacterial entry [51, 52]. This is for those bacteria that lack SPI-1 genes as this route does not involve M cell-mediated uptake. These cells might have been referred to as DCs, but as this is not clear [53, 54], they will be referred to as lamina propria phagocytes in this chapter. Although this pathway has now become an alternative to our general understanding of bacterial entry through M cells, the physiological importance of this route to systemic salmonellosis is poorly defined. The compelling evidence for a non-M-cell pathway is largely derived from microbiological and immunological investigations. Recent interest was stimulated by demonstrating that strains lacking SPI-1 and the fimbrial lpfC gene that did not normally infect mice retained the ability to infect mice in a CD18-dependent manner and were rapidly detected in the blood after oral inoculation [55, 56]. This extremely rapid dissemination to the blood and lack of serovar specificity might be due to bacterial entry in the bloodstream of the host through abrasions caused during gavage. Many cervical lymph node infection cases that attributed to the entry through mucosal abrasions during gavage were revealed through bacterial imaging system [57]. Expression of the SPI-2 type-III secretion system effector protein (SrfH) of bacteria was required for very early dissemination of bacteria to the blood and spleen [58]. This finding supports the idea that rapid entry through an alternative pathway involves active processes, so, therefore, it is important to examine this route from a microbiological perspective. In vitro studies demonstrated that DCs could capture bacteria by extending processes between the tight junctions of a monolayer and the apical surface of epithelial cells [59]. Subsequently, a similar process was directly visualised in vivo when CX3CR1-expressing phagocytes were detected extending transepithelial dendrites in the lamina propria, and the number of dendrites increased in the terminal ileum after infection [60]. So, these studies suggested an alternative entry model, whereby Salmonella might commonly access the intestinal lamina propria by cell sampling, as large numbers of bacteria were detected within the lamina propria [60]. However, Salmonella is not normally recoverable in large numbers from the lamina propria unless the bacterial flora is first depleted before infection [48]. Also, the formation of transepithelial dendrites is dispensable for the uptake of other pathogenic microorganisms [61]. More importantly, it has been demonstrated that CX3CR1+ lamina propria cells are unlikely to migrate to the mesenteric lymph nodes (MLN) and have poor immunostimulatory capacity [53]. Thus, CX3CR1+ cells most likely represent a population of non-migrating phagocytes that provide innate immune defence against infection within the lamina propria. Surprisingly, the role of cell-mediated uptake has not been examined carefully in PPs or in SILTs, but still, phagocytic cells are often found in association with the epithelium of tissues [48, 62]. In summary, a prominent role for M cell-mediated intestinal entry by Salmonella is played both in the PPs and SILTs, whereas Salmonella entry of the lamina propria and the mechanisms like immune activation and bacterial dissemination associated with this pathway of entry remain largely speculative.


6. Salmonella infection of mesenteric lymph nodes (MLNs) and systemic tissues

After initial invasion through PPs, the ultimate fate of infection is decided in the lymphatic system. The indication for the bacterial migration is based on our understanding of the lymph and the conjectural finding that bacteria are detected initially in PPs, followed by the MLN and finally the liver and spleen [63, 64]. Salmonella after getting access to efferent lymphatics reaches the systemic tissues via the thoracic duct and blood after reaching the MLN [65, 66]. The immune cell population that aids in the transport of bacteria to the blood and other tissues is not well known; however, intestinal DCs are usually considered as a possibility. The majority of bacteria were found free in the lymph or were associated with non-DC phagocytes [67], but it is not clear whether this also occurs during exit from the MLN. Disseminated bacteria show a tropism of tissues that contain a high number of phagocytic cells, and in most circumstances, this involves the spleen, liver, and bone marrow [65, 68]. Disruption of erythropoiesis and splenomegaly by Salmonella can be explained majorly by the expansion of immature erythrocytes in the spleen in an erythropoietin-dependent manner. Cancer studies have demonstrated that bacteria preferentially accumulate in primary and metastatic tumours [69, 70], suggesting that it does not have a precise organ tropism but finds tissues that contain a sufficient number of cells that support bacterial replication. The large size of the spleen, liver, and bone marrow means that these tissues gradually comprise the major sites of bacterial replication [71, 72]. Thus, Salmonella causes systemic infection that uses intestinal lymphoid tissues as a portal of entry. Also that bacteria clearance from the host and resistance to secondary infection requires the coordinated action of both systemic and mucosal immunity.


7. Host innate immune response to Salmonella

After phagocytosis by macrophages, Salmonella can survive and replicate within modified intracellular vesicles, termed as Salmonella-containing vacuoles (SCV) [73, 74]. The ability of Salmonella to survive within the phagosome is mediated by SPI-2, which prevents movement of RNS and ROS into the phagosome where the bacteria reside [75, 76]. In addition, Salmonella phoP/phoQ regulon inhibits fusion of the SCV with toxic lysosomes and endosomes [77]. The natural resistance-associated macrophage protein encoding gene, which enables macrophages to transport ions into the SCV, provides resistance/susceptibility to infection [78]. Survival of bacteria intracellularly within tissue phagocytes is a prerequisite to the bacterial virulence, and bacterial mutants that cannot survive and replicate within macrophages are attenuated for virulence [79]. The initial invasion induces a massive inflammatory response, characterised by recruitment of neutrophils, DCs, inflammatory monocytes and macrophages [48, 80]. Neutrophils follow the chemokine gradient to the gut and extravagate into the mucosa. As they encounter and eliminate the bacteria by mechanisms that are not yet fully elucidated [81], neutrophils are believed to be important in preventing dissemination of the bacteria from the intestine to systemic tissues, so the patients with low neutrophil levels have a high risk of bacteraemia during infection with NTS strains [82]. Also, that depletion of neutrophils allows extracellular growth of bacteria, suggesting that neutrophils confine and reduce bacterial replication immediately after entry. Inflammatory monocytes are an important source of antimicrobial factors, such as TNFs and inducible NO synthase, during the initial stages of infection [80]. Myd88-dependent chemokine production within the PPs drives the recruitment of these inflammatory cells [81]. Indeed, Salmonella expresses several pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS) and flagellin, which can be detected by Toll-like receptors (TLRs) expressed by enterocytes and phagocytes [83]. Also, macrophages after sensing cytosolic flagellin through NLRC4 (also known as Ipaf) activate caspase-1 and induce the production of IL-18 (pro-inflammatory) [84, 85]. Dendritic cells are professional antigen-presenting cells and increase the expression of MHC class II and the co-stimulatory molecules CD86, CD80 and CD40 by responding to the recognition of Salmonella LPS or flagellin [86, 87]. DCs present antigen to naive CD4+ T cells, thus providing a vital link between innate immune responses and the induction of adaptive immunity. In the PPs, flagellin also induces the secretion of the inflammatory chemokine CCL20, which is an important ligand for CCR6 [88]. This response activates an early process whereby CCR6-expressing DCs are recruited to the FAE, for efficient activation of CD4+ T cells [89].


8. Host-adaptive immune response to Salmonella

Adaptive immune response to Salmonella can be mediated via early CD4+ T-cell activation. Due to the small size of intestinal lymphoid tissues and low frequency of naive CD4+ T cells specific for any given antigen [90], detecting initial bacterial specific T-cell activation in these tissues is challenging. However, studies with T-cell receptor transgenic mice visualised the processes of bacterial specific CD4+ T cells responding to oral infection [64, 91]. An artificially elevated naive precursor frequency of CD4+ T cells at a high dose of infection provides the most accurate assessment of Salmonella-specific CD4+ T-cell activation [92]. The earliest Salmonella-specific CD4+ T-cell activation occurs within the MLN after oral infection but usually peaks few hours after that in the PPs [91]. At very early time points, CD4+ T cells were not found to be activated in any other secondary lymphoid tissues [89], suggesting that whatever the explanation for early bacterial dissemination to blood as discussed above, no early adaptive immune response is initiated outside the gut-associated lymphoid tissue. Interestingly, the T-cell receptor transgenic model used recognises a bacterial peptide from the carboxy-terminal region of flagellin [93] which is also a ligand for TLR5 [94]. Generally, the early activation of flagellin-specific CD4+ T cells in the PPs is representative of the naive CD4+ response to other bacterial antigens [95, 96]. However, this is difficult to demonstrate conclusively as very few, naturally occurring bacterial specific MHC class-II peptides are known [97]. Interestingly, activation of CD4+ T cells in the MLN is also dependent on CD11c+ DCs and CCR6, indicating that T-cell activation in the MLN and PP has similar requirements. The evidence clearly suggests that the MLNs are an important site for immune protection during the course of Salmonella infection. Indeed, after MLNs were surgically removed, there was an elevated bacterial load and severe immunopathology in the liver [98]. The importance was also highlighted using a relapsing model of murine typhoid in which primary infection returns after apparent antibiotic clearance [57]. Although MLN is often considered a potential site of bacterial accumulation [99, 100], it acts as a protective firewall, preventing bacterial dissemination and relapsing Salmonella infection.


9. Host effector responses against Salmonella

The development of robust protective immunity against Salmonella infection requires the coordination of B and T cells. One hundred and sixteen CD4+ T cells have a critical role in clearing the primary infection and are also required for acquired resistance to secondary infection [100]. In contrast, B cells are dispensable for resolving primary infection but are required for protection against secondary challenge [101]. There is a massive expansion of Salmonella-specific CD4+ T cells and rapid acquisition of Th1 effector functions, i.e. the enhanced ability to secrete INF-γ, TNF α and IL-2 upon restimulation [102] (Figure 2). These activated Th1 cells can be clearly detected a week after infection, which is consistent with the rapid tempo of CD4+ T-cell activation. Optimal expansion of Th1 cells have been shown to require expression of both programmed death ligand-1 (PD-L1) and the TNF receptor family members, OX40 and CD30. Appropriately, expansion of activated Th1 cells eventually comprises ~50% of all CD4+ T cells few weeks after infection [103]. Furthermore, Th1 cells are capable of responding to innate signals such as Salmonella LPS by secreting cytokines [104]. This innate response is unexpected as effector Th1 cells are normally stimulated only after recognition of cognate peptide and MHCs [105]. This innate immune responsiveness suggests a means by which the host can rapidly produce INF-γ to activate macrophages within an infected tissue, even if bacteria are capable of inhibiting antigen presentation by infected phagocytes [106]. Despite the rapid and efficient development of Th1 effector cells, there is actually little evidence that suggests their contribution to bacterial clearance during primary infection. Thus, it was found that when CD4+ or CD4+ Th1 cells were completely absent, bacterial growth enhanced a few weeks after infection which indicates that Th1 cells contribute little to regulate bacterial growth before this point [107]. Many in vitro studies point to an inhibitory effect of Salmonella on antigen presentation to naive T cells in vitro [108], but in vivo, there is no effect on Salmonella-specific CD4+ expansion [109]. In contrast, the gradual loss of effector CD4+ T cells detected in the process of Salmonella infection that required the presence of live bacteria and the expression of SPI-2 genes indicated that the effector function of cells is specifically inhibited by actively replicating bacteria [110]. Effector Th1 cells are effective in providing immunity to salmonellosis [111]; however, effector CD4+ subsets including regulatory T cells (Tregs) and Th17 cells are also known to contribute. Tregs arise from the thymus or develop after naive T-cell activation in the presence of TNF β which suppresses effector T-cell responses [112]. In contrast, Th17 cells arise from naive CD4+ T-cell stimulation in the presence of IL-6 and TNF-β and are important in mediating immunity against extracellular bacterial infections [113, 114]. During the development of Th1 cells and Tregs after infection, it was found that changes in the cogency of Tregs reduced the efficacy of Th1 responses and increased bacterial growth [102]. After oral infection with Salmonella, cytokines associated with Th17 cells, IL-17 and IL-22 are rapidly produced within the intestinal mucosa [115], and the production is induced by innate responses to infection rather than Th17 cells, however, still indicating the potential for Th17 cytokines to participate in intestinal defence against bacteria. In vivo, production of IL-22 dependent on IL12B, rather than IL-17, contributed to bacterial clearance [116]. Taken together, it is suggested that Th17 cells contribute additionally to protection against Salmonella infection by not only initiating or enhancing neutrophil infiltration to intestinal tissues but by the production of antimicrobial peptides by the epithelium which is effective against luminal bacteria as well [117]. In summary, it has been suggested that Th17 cells have an additional role in defence against Salmonella in the intestine and a role for Tregs in modulating the potency of Salmonella-specific Th1 cells in vivo.

Figure 2.

Induction of IFN γ production by Salmonella-specific CD4+T cells. Expansion of activated CD4+T cells in secondary lymphoid tissues which in turn produces IFNγ at infection sites. Production of IFNγ finally activates macrophages.


10. Host antibody (Ab) response against Salmonella

Salmonella-specific B-cell responses contribute to bacterial clearance in the hosts [39, 120, 121]. Although the bacteria are generally found within SCV in phagocytic cells, there is a short period during the infection cycle when bacteria are expected to be extracellular. Salmonella is not only tightly associated with mononuclear phagocytes in vivo [118] but also induces these infected cells to undergo apoptosis [44]. After cell death, bacteria are presumably found in the extracellular compartment before infecting a neighbouring phagocyte. Thus, antibody might have direct access to the bacteria during this short period of time and prevent cell-to-cell transmission [92]. Bacterial colonisation obstructs the bacterial opsonization with Salmonella-specific Ab [119]. The Ab also plays a role in amplifying the processing and presentation of antigens to CD4+ T cells, thus affecting the Th1 response [120]. B-cell innate immune response to TLR-specific ligands is necessary for the development of Th1 responses in vivo [121]. New findings also suggest the suppression of protective immunity through B-cell MyD88 pathway during infection [122]. Therefore, innate immune signalling in B cells contributes to an important regulatory function but requires further analysis. The presence of Salmonella-specific Ab IgA in the intestinal mucosa may also prevent or reduce bacterial penetration of the intestinal barrier [123]. However, which of these mechanisms makes the greatest contribution to protective immunity is yet to be deciphered, but an important role for Ab is also suggested from human studies [124]. Although the specificity of Ab responses is undefined, Abs specific for the LPS O-antigen, flagellin, Vi capsular polysaccharide (ViCPS) antigen and outer membrane porin protein (OmpD) are all believed to be protective [125].

11. Conclusion

Members belonging to genus Salmonella are the major intestinal pathogens of human beings and animals. The increased food production and growth in human populations have led to the increase in dissemination potential of these ubiquitous microorganisms. Due to the systemic nature of some infections, where many tissues get involved to display immunity to specific infection, salmonellosis and the immune response that results are pliable. Deciphering the pathogenesis of invasive salmonellosis may hopefully lead to potential therapeutic treatment strategies that are urgently required in light of propagating antimicrobial resistance. Future studies must focus on the identification of molecular targets of Salmonella virulence factors during intracellular life in immune cells and designate the molecular mechanisms of interference. This would impart a novel perception into the cell biology of DCs and other immune cells. Furthermore, understanding the intracellular life of Salmonella may lead to new advancement in generating reliable vaccines against infections, to wield Salmonella strains as live carriers for recombinant vaccines and to evolve novel forms of treatment that target the function of specific virulence factors. Further explorations to clarify the contribution of genes differently represented/expressed in the genomes of various Salmonella serotypes during infection are required.


NTSnon-typhoidal Salmonella
TStyphoidal Salmonella
HAhost-adapted serovars
HRhost restricted
FAEfollicle-associated epithelium
PPPeyer’s patch
DCdendritic cells
MHCmajor histocompatibility complex
SPISalmonella pathogenicity island
SCVSalmonella-containing vacuoles
MLNmesenteric lymph nodes
PAMPspathogen-associated molecular patterns
Tregsregulatory T cells
PDLprogrammed death ligand
DCdendritic cell
Mydmyeloid differentiation primary response
TNFtumour necrosis factor
CDcluster of differentiation
MAPKmitogen-activated protein kinase
SILTssolitary intestinal lymphoid tissues
ViCPSVi capsular polysaccharide
TLRsToll-like receptors
OmpDouter membrane porin protein


  1. 1. Shu-Kee E, Pusparajah P, Nurul-Syakima AM, Hooi-Leng S, Kok-Gan C, Learn-Han L. Salmonella: A review on pathogenesis, epidemiology and antibiotic resistance. Frontiers in Life Science. 2015;8:284-293. DOI: 10.1080/21553769.2015.1051243
  2. 2. Andino A, Hanning I. Salmonella enterica: Survival, colonization, and virulence differences among serovars. The Scientific World Journal. 2015. DOI: 10.1155/2015/520179 (review article)
  3. 3. Dar MA, Ahmad SM, Bhat SA, Ahmad R, Urwat U, Mumtaz PT, et al. Salmonella typhimurium in poultry: A review. World’s Poultry Science Journal. 2017;73:345-354
  4. 4. Rabsch W, Tschäpe H, Baumler AJ. Non-typhoidal salmonellosis: Emerging problems. Microbes and Infection. 2001;3:237-247
  5. 5. Rodriguez A, Pangloli P, Richards HA, Mount JR, Draughon FA. Prevalence of Salmonella in diverse environmental farm samples. Journal of Food Protection. 2006;69:2576-2580
  6. 6. Smith SI, Seriki A, Ajayi A. Typhoidal and non-typhoidal Salmonella infections in Africa. European Journal of Clinical Microbiology & Infectious Diseases. 2016;35:1913-1922
  7. 7. Majowicz SE, Musto J, Scallan E, Angulo FJ, Kirk M, O’Brien SJ, et al. The global burden of nontyphoidal Salmonella gastroenteritis. Clinical Infectious Diseases. 2010;50:882-889
  8. 8. Hardy A. Salmonella: A continuing problem. Postgraduate Medical Journal. 2004;80:541-545. DOI: 10.1136/pgmj.2003.016584
  9. 9. Meltzer E, Schwartz E. Enteric fever: A travel medicine oriented view. Current Opinion in Infectious Diseases. 2010, 2010;23:432-437. DOI: 10.1097/QCO.0b013e32833c7cal
  10. 10. Chowdhury MAJ, Shumy F, Anam AM, Chowdhury MK. Current status of typhoid fever: A review. Bangladesh Medical Journal. 2014;43(2)
  11. 11. Ohad GM, Erin CB, Guntram AG. Same species, different diseases: How and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Frontiers in Microbiology. 2014;5(391)
  12. 12. Berkley JA, Lowe BS, Mwangi I, Williams T, Bauni E, Mwarumba S. Bacteremia among children admitted to a rural hospital in Kenya. The New England Journal of Medicine. 2005;352:39-47. DOI: 10.1056/NEJMoa040275
  13. 13. Brent AJ, Oundo JO, Mwangi I, Ochola L, Lowe B, Berkley JA. Salmonella bacteremia in Kenyan children. The Paediatrics Infectious Disease Journal. 2006;25:230-236. DOI: 10.1097/01.inf.0000202066.02212
  14. 14. Stoycheva M, Murdjeva M. Serum levels of interferon-gamma, interleukin-12, tumour necrosis factor-alpha, and interleukin-10, and bacterial clearance in patients with gastroenteric Salmonella infection. Scandinavian Journal of Infectious Diseases. 2005;37:11-14. DOI: 10.1080/00365540410026068
  15. 15. De Lappe N. Salmonella Taxonomy. Version 1. Ref and research of animal salmonelloses caused by NSRLFM041. Dept of Medical Microbiology, Division of Serovars having a Public Health Importance. Clinical Microbiology, Galway University Hospitals; 2009
  16. 16. Uzzau S, Leori GS, Petruzzi V, Watson PR, Schianchi G, Bacciu D, et al. Salmonella enterica serovar-host specificity does not correlate with the magnitude of intestinal invasion in sheep. Infection and Immunity. 2001;69:3092-3099
  17. 17. Wallis TS. Host-specificity of Salmonella infections in animal species. In: ‘Salmonella’ Infections: Clinical, Immunological and Molecular Aspects. Cambridge University Press; 2005. pp. 57-80
  18. 18. Ellermeier CD, Slauch JM. The Genus Salmonella. In: Dworkin M, Falkow S, Rosenberg E, Schleifer KH, Stackebrandt E, editors. The Prokaryotes: A Handbook on the Biology of Bacteria. 3rd ed. Vol. 6. Springer Science and Business Media, LLC; 2006. pp. 123-158
  19. 19. Uzzau S, Brown DJ, Wallis T, Rubino S, Leori G, Bernard S, et al. Host adapted serotypes of Salmonella enterica. Epidemiology and Infection. 2000;125:229 255
  20. 20. Baumler AJ, Tsolis RM, Ficht TA, Adams LG. Evolution of host adaptation in Salmonella enterica. Infection and Immunity. 1998;66:4579-4587
  21. 21. Knodler LA, Finlay BB. Salmonella and apoptosis; to live or let die? Microbes and Infection. 2001;3:1321-1326
  22. 22. Rubino S, Leori G, Rizzu P, Erre G, Colombo MM, Uzzau S, et al. TnphoA Salmonella abortusovis mutants unable to adhere to epithelial cells and with reduced virulence in mice. Infection and Immunity. 1993;61:1786-1792
  23. 23. Watson PR, Galyov EE, Paulin SM, Jones PW, Wallis TS. Mutation of invH, but not stn, reduces Salmonella-induced enteritis in cattle. Infection and Immunity. 1998;30:210-219
  24. 24. Pan Z, Carter B, Nunez-Garcia J, Abuoun M, Fookes M, Ivens A, et al. Identification of genetic and phenotypic differences associated with prevalent and non-prevalent Salmonella enteritidis in amino acid transport. Microbiology. 2009;155:3200-3213
  25. 25. Gantois I, Ducatelle R, Pasmans F, Haesebrouck F, Van Immerseel F. Salmonella enterica serovar Enteritidis genes induced during oviduct colonization and egg contamination in laying hens. Applied and Environmental Microbiology. 2008;74:6616-6622
  26. 26. Guard J, Shah DH, Morales CA, Call DR. Evolutionary trends associated with niche specialization as modelled by whole genome analysis of egg contaminating Salmonella enterica serovar Enteritidis. In: Porwollik S, editor. Salmonella: From Genome to Function. San Diego, CA: Caister Academic Press; 2011. pp. 91-106
  27. 27. Clarke RC, Gyles CL. Salmonella. In: Pathogenesis of Bacterial Infections in Animals. 2nd ed. Ames, Iowa: Iowa State University Press; 1993. pp. 133-153
  28. 28. Chiu CH, Tang P, Chu C, Hu S, Bao Q , Yu J, et al. The genome sequence of Salmonella enterica serovar Choleraesuis, a highly invasive and resistant zoonotic pathogen. Nucleic Acids Research. 2005;33:1690-1698
  29. 29. Kingsley RA, Msefula CL, Thomson NR, Kariuki S, Holt KE, Gordon MA, et al. Epidemic multiple drug resistant Salmonella typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome Research. 2009;19:2279-2287
  30. 30. Thomson NR, Clayton DJ, Windhorst D, Vernikos G, Davidson S, Churcher C, et al. Comparative genome analysis of Salmonella enteritidis PT4 and Salmonella gallinarum 287/91 provides insights into evolutionary and host adaptation pathways. Genome Research. 2008;18:1624-1637
  31. 31. Kisiela DI, Chattopadhyay S, Libby SJ, Karlinsey JE, Fang FC, Tchesnokova V, et al. Evolution of Salmonella enterica virulence via point mutations in the fimbrial adhesin. PLoS Pathogens. 2012;8:e1002733
  32. 32. Olsen JE, Hoegh-Andersen KH, Casadesús J, Rosenkranzt J, Chadfield MS, Thomsen LE. The role of flagella and chemotaxis genes in host pathogen interaction of the host adapted Salmonella enterica serovar Dublin compared to the broad host range serovar S. Typhimurium. BMC Microbiology. 2013;13:67
  33. 33. Rabsch W, Andrews HL, Kingsley RA, Prager R, Tschäpe H, Adams LG, et al. Salmonella enterica serotype Typhimurium and its host adapted variants. Infection and Immunity. 2002;70:2249-2255
  34. 34. Heithoff DM, Shimp WR, Lau PW, Badie G, Enioutina EY, Daynes RA, et al. Human Salmonella clinical isolates distinct from those of animal origin. Applied and Environmental Microbiology. 2008;74:1757-1766
  35. 35. Guo A, Cao S, Tu L, Chen P, Zhang C, Jia A, et al. FimH alleles direct preferential binding of Salmonella to distinct mammalian cells or to avian cells. Microbiology. 2009;155:1623-1633
  36. 36. De Jong HK, Parry CM, van der Poll T, Wiersinga WJ. Host–pathogen interaction in invasive Salmonellosis. PLoS Pathogens. 2012;8:e1002933
  37. 37. Eswarappa SM, Janice J, Nagarajan AG, Balasundaram SV, Karnam G, Dixit NM, et al. Differentially evolved genes of Salmonella pathogenicity islands: Insights into the mechanism of host specificity in Salmonella. PLoS One. 2008;3(12):e3829
  38. 38. Eswarappa SM, Janice J, Balasundaram SV, Dixit NM, Chakravortty D. Host-specificity of Salmonella enterica serovar gallinarum: Insights from comparative genomics. Infection, Genetics and Evolution. 2009;9:468-473
  39. 39. Liu WQ , Feng Y, Wang Y, Zou QH, Chen F, Guo JT, et al. Salmonella paratyphi C: Genetic divergence from Salmonella choleraesuis and pathogenic convergence with Salmonella typhi. PLoS One. 2009;4:e4510
  40. 40. Scheelings TF, Lightfoot D, Holz P. Prevalence of Salmonella in Australian reptiles. Journal of Wildlife Diseases. 2011;47:1-11
  41. 41. Kaiser P, Hardt WD. Salmonella typhimurium diarrhea: Switching the mucosal epithelium from homeostasis to defense. Current Opinion in Immunology. 2011;23:456-463
  42. 42. Oanh HP, Stephen JM. Protective host immune responses to Salmonella infection. Future Microbiology. 2015;10:101-110
  43. 43. Jones BD, Ghori N, Falkow S. Salmonella typhimurium initiates murine infection by penetrating and destroying the specialized epithelial M cells of the Peyer’s patches. The Journal of Experimental Medicine. 1994;180:15-23
  44. 44. Van der Velden AW, Velasquez M, Starnbach MN. Salmonella rapidly kill dendritic cells via a caspase-1-dependent mechanism. Journal of Immunology. 2003;171:6742-6749
  45. 45. Bryan C, Guntram AG, Finlay BB. Salmonella, the host and disease: A brief review. Immunology and Cell Biology. 2007;85:112-118
  46. 46. Hamada H, Hiroi T, Nishiyama Y, Takahashi H, Masunaga Y, Hachimura S, et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. Journal of Immunology. 2002;168:57-64
  47. 47. Pabst O, Bernhardt G. The puzzle of intestinal lamina propria dendritic cells and macrophages. European Journal of Immunology. 2010;40:2107-2111
  48. 48. Halle S, Bumann D, Herbrand H, Willer Y, Dähne S, Förster R, et al. Solitary intestinal lymphoid tissue provides a productive port of entry for Salmonella enterica serovar Typhimurium. Infection and Immunity. 2007;75:1577-1585
  49. 49. Kraus MD, Amatya B, Kimula Y. Histopathology of typhoid enteritis: Morphologic and immunophenotypic findings. Modern Pathology. 1999;12:949-955
  50. 50. Jang MH, Kweon MN, Yamamoto M, Terahara K, Sasakawa C, Suzuki T, et al. Intestinal villous M cells: An antigen entry site in the mucosal epithelium. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:6110-6115
  51. 51. Martinoli C, Chiavelli A, Rescigno M. Entry route of Salmonella typhimurium directs the type of induced immune response. Immunity. 2007;27:975-984
  52. 52. Niess JH, Reinecker HC. Dendritic cells in the recognition of intestinal microbiota. Cellular Microbiology. 2006;8:558-564
  53. 53. Schulz O, Jaensson E, Emma KP, Xiaosun L, Worbs T, Agace WW, et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. The Journal of Experimental Medicine. 2009;206:3101-3114
  54. 54. Persson EK, Jaensson E, Agace WW. The diverse ontogeny and function of murine small intestinal dendritic cell/macrophage subsets. Immunobiology. 2010;215:692-697
  55. 55. Vazquez-Torres A, Jones-Carson J, Bäumler AJ, Falkow S, Valdivia R, Brown W, et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature. 1999;401:804-808
  56. 56. Gerichter CB. The dissemination of Salmonella typhi, S. paratyphi A and S. paratyphi B through the organs of the white mouse by oral infection. The Journal of Hygiene (Lond.). 1960;58:307-319
  57. 57. Griffin AJ, Li LX, Voedisch S, Pabst O, McSorley SJ. Dissemination of persistent intestinal bacteria via the mesenteric lymph nodes causes typhoid relapse. Infection and Immunity. 2001
  58. 58. Worley MJ, Nieman GS, Geddes K, Heffron F. Salmonella typhimurium disseminates within its host by manipulating the motility of infected cells. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:17915-17920
  59. 59. Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunology. 2001;2:361-367
  60. 60. Niess JH, Brand S, Gu X, Landsman L, Jung S, McCormick BA, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science. 2005;307:254-258
  61. 61. Vallon-Eberhard A, Landsman L, Yogev N, Verrier B, Jung S. Transepithelial pathogen uptake into the small intestinal lamina propria. Journal of Immunology. 2006;176:2465-2469
  62. 62. Iwasaki A, Kelsall BL. Localization of distinct Peyer’s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3 beta, and secondary lymphoid organ chemokine. The Journal of Experimental Medicine. 2000;191:1381-1394
  63. 63. Carter PB, Collins FM. The route of enteric infection in normal mice. The Journal of Experimental Medicine. 1974;139:1189-1203
  64. 64. McSorley SJ, Asch S, Costalonga M, Rieinhardt RL, Jenkins MK. Tracking Salmonella-specific CD4 T cells in vivo reveals a local mucosal response to a disseminated infection. Immunity. 2002;16:365-377
  65. 65. Tam MA, Rydstrom A, Sundquist M, Wick MJ. Early cellular responses to Salmonella infection: Dendritic cells, monocytes, and more. Immunological Reviews. 2008;225:140-162
  66. 66. Moon JJ, McSorley SJ. Tracking the dynamics of Salmonella specific T cell responses. Current Topics in Microbiology and Immunology. 2009;334:179-198
  67. 67. Bonneau M, Epardaud M, Payot F, Niborski V, Thoulouze MI, Bernex F, et al. Migratory monocytes and granulocytes are major lymphatic carriers of Salmonella from tissue to draining lymph node. Journal of Leukocyte Biology. 2006;79:268-276
  68. 68. Jones BD, Falkow S. Salmonellosis: Host immune responses and bacterial virulence determinants. Annual Review of Immunology. 1996;14:533-561
  69. 69. Griffin AJ, McSorley SJ. Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda. Mucosal Immunology. 2011;4:371-382
  70. 70. Yu YA, Shabahang S, Timiryasova TM, Zhang Q , Beltz R, Gentschev I, et al. Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nature Biotechnology. 2004;22:313-320
  71. 71. Low KB, Ittensohn M, Le T, Platt J, Sodi S, Amoss M, et al. Lipid A mutant Salmonella with suppressed virulence and TNF alpha induction retain tumor-targeting in vivo. Nature Biotechnology. 1999;17:37-41
  72. 72. McSorley SJ, Jenkins MK. Antibody is required for protection against virulent but not attenuated Salmonella enterica serovar typhimurium. Infection and Immunity. 2000;68:3344-3348
  73. 73. Sheppard M. Dynamics of bacterial growth and distribution within the liver during Salmonella infection. Cellular Microbiology. 2003;5:593-600
  74. 74. Richter-Dahlfors A, Buchan AM, Finlay BB. Murine salmonellosis studied by confocal microscopy: Salmonella typhimurium resides intracellularly inside macrophages and exerts a cytotoxic effect on phagocytes in vivo. The Journal of Experimental Medicine. 1997;186:569-580
  75. 75. Vazquez-Torres A, Jones-Carson J, Mastroeni P, Ischiropoulos H, Fang FC. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro. The Journal of Experimental Medicine. 2000;192:227-236
  76. 76. Chakravortty D, Hansen-Wester I, Hensel M. Salmonella Pathogenicity Island 2 mediates protection of intracellular Salmonella from reactive nitrogen intermediates. The Journal of Experimental Medicine. 2002;195:1155-1166
  77. 77. Garvis SG, Beuzon CR, Holden DW. A role for the PhoP/Q regulon in inhibition of fusion between lysosomes and Salmonella-containing vacuoles in macrophages. Cellular Microbiology. 2001;3:731-744
  78. 78. White JK, Mastroeni P, Popoff JF, Evans CA, Blackwell JM. Slc11a1-mediated resistance to Salmonella enterica serovar Typhimurium and Leishmania donovani infections does not require functional inducible nitric oxide synthase or phagocyte oxidase activity. Journal of Leukocyte Biology. 2005;77:311-320
  79. 79. Fields PI, Swanson RV, Haidaris CG, Heffron F. Mutants of Salmonella typhimurium that cannot survive within the macrophage are avirulent. Proceedings of the National Academy of Sciences of the United States of America. 1986;83:5189-5193
  80. 80. Rydstrom A, Wick MJ. Monocyte recruitment, activation, and function in the gut-associated lymphoid tissue during oral Salmonella infection. Journal of Immunology. 2007;178:5789-5801
  81. 81. Judith B, Perez-Lopez A, Sean-Paul N, Manuela R. Exploiting host immunity: The Salmonella paradigm. Trends in Immunology. 2015;36(2). DOI: 10.1016/
  82. 82. Tumbarello M, Tacconelli E, Caponera S, Cauda R, Ortona L. The impact of bacteraemia on HIV infection. Nine years experience in a large Italian university hospital. The Journal of Infection. 1995;31:123-131
  83. 83. Barton GM, Medzhitov R. Toll-like receptors and their ligands. Current Topics in Microbiology and Immunology. 2002;270:81-92
  84. 84. Winter SE, Thiennimitr P, Sean-Paul N, Haneda T, Maria GW. Contribution of flagellin pattern recognition to intestinal inflammation during Salmonella enterica serotype typhimurium infection. Infection and Immunity. 2009;77:1904-1916
  85. 85. Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit VM, Monack DM. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. The Journal of Experimental Medicine. 2010;207:1745-1755
  86. 86. McSorley SJ, Ehst BD, Yu Y, Gewirtz AT. Bacterial flagellin is an effective adjuvant for CD4 T cells in vivo. Journal of Immunology. 2002;169:3914
  87. 87. Salazar-Gonzalez RM, Srinivasan A, Griffin A, Muralimohan G, James M, Rajesh ER, et al. Salmonella flagellin induces bystander activation of splenic dendritic cells and hinders bacterial replication in vivo. Journal of Immunology. 2007;179:6169-6175
  88. 88. Sierro F, Dubois B, Coste A, Kaiserlian D, Kraehenbuhl JP, Sirard JC. Flagellin stimulation of intestinal epithelial cells triggers CCL20-mediated migration of dendritic cells. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:13722-13727
  89. 89. Salazar-Gonzalez RM, Niess JH, Zammit DJ, Ravindran R, Srinivasan A, Maxwell JR, et al. CCR6-mediated dendritic cell activation of pathogen-specific T cells in Peyer’s patches. Immunity. 2006;24:623-632
  90. 90. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, et al. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity. 2007;27:203-213
  91. 91. Bumann D. In vivo visualization of bacterial colonization, antigen expression and specific T-cell induction following oral administration of live recombinant Salmonella enterica serovar typhimurium. Infection and Immunity. 2001;69:4618-4626
  92. 92. Ravindran R, Foley J, Stoklasek T, Glimcher LH, McSorley SJ. Expression of T-bet by CD4 T cells is essential for resistance to Salmonella infection. Journal of Immunology. 2005;175:4603-4610
  93. 93. McSorley SJ, Cookson BT, Jenkins MK. Characterization of CD4+ T cell responses during natural infection with Salmonella typhimurium. Journal of Immunology. 2000;164:986-993
  94. 94. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410:1099-1103
  95. 95. Ravindran R, McSorley SJ. Tracking the dynamics of T-cell activation in response to Salmonella infection. Immunology. 2005;114:450-458
  96. 96. Srinivasan A, McSorley SJ. Activation of Salmonella-specific immune responses in the intestinal mucosa. Archivum Immunologiae et Therapiae Experimentalis. 2006;54:25-31
  97. 97. Letran SE, Lee SJ, Atif SM, Uematsu S, Akira S, McSorley SJ. TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. European Journal of Immunology. 2011;41:29-38
  98. 98. Voedisch S, Koenecke C, David S, Herbrand H, Förster R, Rhen M, et al. Mesenteric lymph nodes confine dendritic cell mediated dissemination of Salmonella enterica serovar Typhimurium and limit systemic disease in mice. Infection and Immunity. 2009;77:3170-3180
  99. 99. Monack DM, Bouley DM, Falkow S. Salmonella typhimurium persists within macrophages in the mesenteric lymph nodes of chronically infected Nramp1+/+ mice and can be reactivated by IFN gamma neutralization. The Journal of Experimental Medicine. 2004;199:231-241
  100. 100. Sinha K, Mastroeni P, Harrison J, de Hormaeche RD, Hormaeche CE. Salmonella typhimurium aroA, htrA, and AroD htrA mutants cause progressive infections in athymic (nu/nu) BALB/c mice. Infection and Immunity. 1997;65:1566-1569
  101. 101. Mittrucker HW, Raupach B, Kohler A, Kaufmann SH. Cutting edge: Role of B lymphocytes in protective immunity against Salmonella typhimurium infection. Journal of Immunology. 2000;164:1648-1652
  102. 102. Johanns TM, Ertelt JM, Rowe JH, Way SS. Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection. PLoS Pathogens. 2010;6:e1001043
  103. 103. Srinivasan A, Foley J, McSorley SJ. Massive number of antigen specific CD4 T cells during vaccination with live attenuated Salmonella causes interclonal competition. Journal of Immunology. 2004;172:6884-6893
  104. 104. Srinivasan A, McSorley SJ. Visualizing the immune response to pathogens. Current Opinion in Immunology. 2004;16:494-498
  105. 105. McLachlan JB, Catron DM, Moon JJ, Jenkins MK. Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin. Immunity. 2009;30:277-288
  106. 106. Tobar JA, Leandro JC, Susan MB, Pablo AG, Jorge EM, Sergio AQ , et al. Virulent Salmonella enterica serovar typhimurium evades adaptive immunity by preventing dendritic cells from activating T cells. Infection and Immunity. 2006;74:6438-6448
  107. 107. Hess J, Ladel C, Miko D, Kaufmann SH. Salmonella typhimurium aroA-infection in gene-targeted immunodeficient mice: Major role of CD4+ TCR-alpha beta cells and IFN-gamma in bacterial clearance independent of intracellular location. Journal of Immunology. 1996;156:3321-3326
  108. 108. Halici S, Zenk SF, Jantsch J, Hensel M. Functional analysis of the Salmonella pathogenicity island 2-mediated inhibition of antigen presentation in dendritic cells. Infection and Immunity. 2008;76:4924-4933
  109. 109. Yrlid U, Wick MJ. Antigen presentation capacity and cytokine production by murine splenic dendritic cell subsets upon Salmonella encounter. Journal of Immunology. 2002;169:108-116
  110. 110. Srinivasan A, Nanton M, Griffin A, McSorley SJ. Culling of activated CD4 T cells during typhoid is driven by Salmonella virulence genes. Journal of Immunology. 2009;182:7838-7845
  111. 111. VanCott JL, Chatfield SN, Roberts M, Hone DM, Hohmann EL, Pascual DW, et al. Regulation of host immune responses by modification of Salmonella virulence genes. Nature Medicine. 1998;4:1247-1252
  112. 112. Xu L, Kitani A, Strober W. Molecular mechanisms regulating TGF beta-induced Foxp3 expression. Mucosal Immunology. 2010;3:230-238
  113. 113. Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annual Review of Immunology. 2007;25:821-852
  114. 114. Curtis MM, Way SS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology. 2009;126:177-185
  115. 115. Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, Winter SE, et al. Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nature Medicine. 2008;14:421-428
  116. 116. Schulz SM, Kohler G, Holscher C, Iwakura Y, Alber G. IL-17A is produced by Th17, gamma delta T cells and other CD4- lymphocytes during infection with Salmonella enterica serovar enteritidis and has a mild effect in bacterial clearance. International Immunology. 2008;20:1129-1138
  117. 117. Santos RL, Raffatellu M, Bevins CL, Adams LG, Tükel C, Tsolis RM, et al. Life in the inflamed intestine, Salmonella style. Trends in Microbiology. 2009;17:498-506
  118. 118. MacLennan CA, Esther NG, Chisomo LM, Robert AK, Nicholas R, Thomson SA. The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children. The Journal of Clinical Investigation. 2008;118:1553-1562
  119. 119. Cunningham AF, Gaspal F, Serre K, Mohr E, Henderson IR, Scott-Tucker A, et al. Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. Journal of Immunology. 2007;178:6200-6207
  120. 120. Bueno SM, Gonzalez PA, Schwebach JR, Kalergis AM. T cell immunity evasion by virulent Salmonella enterica. Immunology Letters. 2007;111:14-20
  121. 121. Barr TA, Brown S, Mastroeni P, Gray D. TLR and B cell receptor signals to B cells differentially program primary and memory Th1 responses to Salmonella enterica. Journal of Immunology. 2010;185:2783-2789
  122. 122. Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P, et al. Signaling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity. 2010;33:777-790
  123. 123. Wijburg OL, Uren TK, Simpfendorfer K, Johansen FE, Brandtzaeg P, Strugnell RA. Innate secretory antibodies protect against natural Salmonella typhimurium infection. The Journal of Experimental Medicine. 2006;203:21-26
  124. 124. Guzman CA, Borsutzky S, Griot-Wenk M, Metcalfe IC, Pearman J, Collioud A, et al. Vaccines against typhoid fever. Vaccine. 2006;24:3804-3811
  125. 125. Gil-Cruz C, Bobat S, Jennifer L, Marshall RA, Kingsley EA, Ross IR. The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. Proceedings of the National Academy of Sciences of the United States of America. 2009;106:9803-9808

Written By

Mashooq Ahmad Dar, Peerzada Tajamul Mumtaz, Shakil Ahmad Bhat, Qamar Taban, Shabir Ahmad Khan, Tufail Banday and Syed Mudasir Ahmad

Submitted: November 13th, 2018 Reviewed: February 22nd, 2019 Published: May 24th, 2019