Host-pathogen interaction in invasive Salmonellosis

Abstract

Salmonella enterica infections result in diverse clinical manifestations. Typhoid fever, caused by S. enterica serovar Typhi (S. Typhi) and S. Paratyphi A, is a bacteremic illness but whose clinical features differ from other Gram-negative bacteremias. Non-typhoidal Salmonella (NTS) serovars cause self-limiting diarrhea with occasional secondary bacteremia. Primary NTS bacteremia can occur in the immunocompromised host and infants in sub-Saharan Africa. Recent studies on host-pathogen interactions in Salmonellosis using genome sequencing, murine models, and patient studies have provided new insights. The full genome sequences of numerous S. enterica serovars have been determined. The S. Typhi genome, compared to that of S. Typhimurium, harbors many inactivated or disrupted genes. This can partly explain the different immune responses both serovars induce upon entering their host. Similar genome degradation is also observed in the ST313 S. Typhimurium strain implicated in invasive infection in sub-Saharan Africa. Virulence factors, most notably, type III secretion systems, Vi antigen, lipopolysaccharide and other surface polysaccharides, flagella, and various factors essential for the intracellular life cycle of S. enterica have been characterized. Genes for these factors are commonly carried on Salmonella Pathogenicity Islands (SPIs). Plasmids also carry putative virulence-associated genes as well as those responsible for antimicrobial resistance. The interaction of Salmonella pathogen-associated molecular patterns (PAMPs) with Toll-like receptors (TLRs) and NOD-like receptors (NLRs) leads to inflammasome formation, activation, and recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines, most notably interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and interferon-gamma (IFN)-γ. The gut microbiome may be an important modulator of this immune response. S. Typhimurium usually causes a local intestinal immune response, whereas S. Typhi, by preventing neutrophil attraction resulting from activation of TLRs, evades the local response and causes systemic infection. Potential new therapeutic strategies may lead from an increased understanding of infection pathogenesis.

Figure 1. Dissemination of S. Typhi during systemic infection.

Typhoid is usually contracted by ingestion of food or water contaminated by fecal or urinary carriers excreting S. Typhi. The incubation period is usually 7 to 14 d. In the small intestine the bacteria adhere to the mucosa and then invade the epithelial cells. The Peyer's patches, which are aggregrated lymphoid nodules of the terminal ileum, play an important role in the transport to the underlying lymphoid tissue. Specialized epithelial cells such as M cells overlying these Peyer's patches are probably the site of internalization of S. Typhi. Once the bacteria have penetrated the mucosal barrier, the invading organism translocates to the intestinal lymphoid follicles and the draining mesenteric lymph nodes, and some pass on to the reticuloendothelial cells of the liver and spleen. During the bacteremic phase, the bacteria are widely disseminated throughout the body. Secondary infection can occur with liver, spleen, bone-marrow, gallbladder, and Peyer's patches as the most preferred sites. The gallbladder is the main reservoir during a chronic infection with S. Typhi and invasion occurs either directly from the blood or by retrograde spread from the bile. Of interest, the ability of Salmonella to form biofilms on gallstones is likely to be a critical factor in establishment of chronic carriage and shedding of S. Typhi . The bacteria that are excreted in the bile can then reinvade the intestinal wall by the mechanism previously described or are excreted by feces. Typical clinical symptoms are fever, malaise, and abdominal discomfort. Clinical features such as a tender abdomen, hepatomegaly, splenomegaly, and a relative bradycardia are common. Rose spots, the classical skin lesions associated with typhoid fever, are relatively uncommon and occur in 5%–30% of cases. The most severe manifestations of typhoid leading to sepsis and death are either necrosis of the Peyer's patches resulting in gut perforation and peritonitis or a toxic encephalopathy associated with myocarditis and haemodynamic shock , .

Figure 2. Virulence of S. Typhimurium and S. Typhi.

S. Typhimurium and S. Typhi possess partly overlapping and a partly distinct repertoire of virulence factors. Both serovars express the type III secretion system, lipopolysaccharide, and other surface polysaccharides, fimbrae, flagellin, and bacterial DNA. The Vi antigen is exclusively expressed by S. Typhi and is able to circumvent the innate immune response by repressing flagellin and LPS expression. SPI, Salmonella pathogenicity islands.

Figure 3. Salmonella and its first encounter with the host.

(a) The intracellular life of Salmonella. Invasion of phagocytic and non-phagocytic cells. Salmonella is a facultative intracellular pathogen that can be found in a variety of phagocytic and non-phagocytic cells, in which it is able to survive and replicate. To establish this intracellular niche, the T3SS1 and -2 play a predominant role; key virulence factors are involved in accessing and utilizing these cells . After ingestion, intestinal colonization follows and Salmonella enters enterocytes and dendritic cells in the intestinal epithelium . Subsequently, Salmonella that reach the submucosa can be internalized by resident macrophages via different mechanisms: by phagocytosis, active invasion using the T3SS1 or T3SS1-independent invasion using fimbriae or other adhesins on the bacterial surface. (1) Salmonella-containing-vacuole. Following internalization Salmonella remains within a modified phagosome known as the Salmonella containing vacuole (SCV) and injects a limited number of effector proteins, such as SipA, SipC, SopB/SigD, SodC-1, SopE2, and SptP into the cytoplasm. These effectors cause rearrangements of the actin cytoskeleton and SCV morphology among other changes. (2) Replication within the SCV. Salmonella survives and replicates within the SCV, where it is able to avoid host antimicrobial effector mechanisms. The T3SS2 is required for systemic virulence in the mouse and survival within macrophages. (3) Transport of Salmonella to distant sites. After penetration of the M cells, the invading microorganisms translocate to the intestinal lymphoid follicles and the draining mesenteric lymph nodes, and some pass on to the reticuloendothelial cells of the liver and spleen. Salmonella organisms are able to survive and multiply within the mononuclear phagocytic cells of the lymphoid follicles, liver, and spleen . (b) Host–pathogen interaction in typhoid and non-typhoid Salmonella. Simplified scheme of the first encounter between Salmonella spp. and the immune system. Specified cells such as neutrophils, macrophages, dendritic, phagocytic, and epithelial cells recognize specific pathogen associated molecular patterns (PAMPs) and danger-associated-molecular patterns (DAMPs), thereby eliciting an immune response. PAMPs such as LPS, Flagella, and bacterial DNA can trigger TRL4, TRL5, and TRL9, respectively. TLR-induced activation of NF-κB is essential for the production of pro-IL-1β, pro-IL-18, which can be negatively regulated by IRAK-M . The NLRs are situated in the cytosol and can also recognize PAMPs. However, NLRP3 is triggered by a different, yet unknown, mechanism, although DAMPs are thought to play a crucial role. TLR, toll-like receptors; LPS, lipopolysaccharide; NF-κB, regulated nuclear factor kappa-light-chain-enhancer of activated B cells; IRAK-M, IL-1R-assiociated kinase-M; IL, Interleukin; ASC, apoptotic speck protein containing a caspase recruitment domain; NLR, NOD-like receptors (including NLRP3 and NLRC4); MyD88, myeloid differentiation primary response gene .