The Flagellar Regulator TviA Reduces Pyroptosis by Salmonella enterica Serovar Typhi

Abstract

To discern virulent from innocuous microbes, the innate immune system senses events associated with bacterial access to immunoprivileged sites such as the host cell cytosol. One such pathway is triggered by the cytosolic delivery of flagellin, the major subunit of the flagellum, by bacterial secretion systems. This leads to inflammasome activation and subsequent proinflammatory cell death (pyroptosis) of the infected phagocyte. In this study, we demonstrate that the causative agent of typhoid fever, Salmonella enterica serovar Typhi, can partially subvert this critical innate immune recognition event. The transcriptional regulator TviA, which is absent from Salmonella serovars associated with human gastroenteritis, repressed the expression of flagellin during infection of human macrophage-like (THP-1) cells. This mechanism allowed S. Typhi to dampen inflammasome activation, leading to reduced interleukin-1␤ (IL-1␤) secretion and diminished cell death. Likewise, the introduction of the tviA gene in nontyphoidal Salmonella enterica serovar Typhimurium reduced flagellin-induced pyroptosis. These data suggest that gene regulation of virulence factors enables S. Typhi to evade innate immune recognition by concealing a pathogen-induced process from being sensed by the inflammasome. To distinguish between self and nonself, the host employs a multitude of innate pattern recognition receptors (PRRs) to initiate adequate host responses aimed at eradicating invading microbes. Activation of PRRs can be achieved by two conceptually different types of events: recognition of conserved microbial structures (pathogen-associated molecular patterns [PAMPs]) (1) and recognition of virulence-associated strategies aimed at manipulating host cells (patterns of pathogenesis) (2, 3). PAMPs are specific for certain groups of microbes regardless of their pathogenic potential, while host cell manipulation is a trait found exclusively in pathogens (2, 3).PAMPs are typically detected by Toll-like receptors (TLRs), resulting in the activation of the NF-B pathway (4). For example, flagellin, the major component of the flagellum, is recognized by TLR5, which enables the innate immune system to detect flagellated bacteria, regardless of their pathogenic potential (5, 6). In contrast, detection of host cell manipulation events allows the host to discern virulent from commensal microbes and scale the host defenses commensurate with the threat (2, 3). A prime example is the translocation of bacterial flagellin into the host cell cytosol through virulence-associated type III secretion system or type IV secretion system, which triggers a proinflammatory form of cell death termed pyroptosis (7-9). Pyroptotic cell death is characterized by the assembly and activation of the inflammasome (10, 11). In the center of this multiprotein complex, active caspase-1 processes pro-interleukin-1␤ (IL-1␤) as well as pro-IL-18 into the biologically active forms by proteolytic cleavage. IL-1␤ and IL-18 are highly proinflammatory cytokines that are critical for coordi...

Live Attenuated Human Salmonella Vaccine Candidates: Tracking the Pathogen in Natural Infection and Stimulation of Host Immunity

“…Only 2/6 (33%) volunteers orally vaccinated with a single dose of 2.5 × 10 9 freshly harvested vaccine organisms mounted anti-LPS IgG serum antibody responses(110) versus 8/8 vaccinated with a 10-fold lower dose of 5 × 10 8 CFUs of CVD 908- htrA (105); similarly, only 1/6 CVD 909 vaccinated subjects had anti-flagellar serum IgG antibody responses versus 6/8 for CVD 908- htrA . This reduction in surface antigen-specific antibody responses is consistent with strong expression of the regulator TviA, which down-regulates flagellar expression while up-regulating synthesis of Vi capsule to mask surface LPS(31, 38). Curiously, despite over-expression of the capsular polysaccharide in CVD 909, Vi-specific serum immune responses were not observed(110).…”

“…Activation of TLR5 induces secretion of another potent cytokine IL-8, which is also a powerful recruiter of neutrophils and other inflammatory cells to the site of invading pathogens. Importantly, flagellin is not expressed once S. Typhi has invaded macrophages, thereby reducing pyroptosis of infected cells and further recruitment of neutrophils(38). This strategy of reducing pyroptosis also prevents release of S. Typhi from its protected intracellular niche, thus facilitating systemic dissemination.…”

Cutting Edge: Inflammasome Activation in Primary Human Macrophages Is Dependent on Flagellin

“…1B). S. Typhi has more effective immune evasion strategies, which explains the reduction in pyroptosis during its infection (21).…”

TyphoidalSalmonella: Distinctive virulence factors and pathogenesis

“…Vi expression is downregulated in the intestine, where flagella and SPI-1 play a role in invasion of epithelial cells, whereas it is upregulated in tissues during systemic dissemination, where it prevents antibodymediated induction of neutrophil responses (Hiyoshi, Wangdi, et al, 2018;Wangdi et al, 2014;Winter et al, 2009). TviA-mediated repression of flagellin expression results in limited recognition of flagellin by NAIP, leading to reduced levels of pyroptosis and IL-1β secretion by macrophages (Winter et al, 2015; Figure 1). Vi has been reported to bind cell surface prohibitin, thus dampening inflammation through MAPK signalling and IL-8 production (Sharma & Qadri, 2004).…”