Salmonella spvC Gene Inhibits Pyroptosis and Intestinal Inflammation to Aggravate Systemic Infection in Mice

Abstract

Salmonella enterica serovar Typhimurium (S). Typhimurium is a primary foodborne pathogen infecting both humans and animals. Salmonella plasmid virulence C (spvC) gene is closely related to S. Typhimurium dissemination in mice, while the mechanisms remain to be fully elucidated. Pyroptosis, a gasdermin-mediated inflammatory cell death, plays a role in host defense against bacterial infection, whereas the effect of spvC on pyroptosis and its function in inflammatory injury induced by S. Typhimurium are rather limited. In our study, C57BL/6 mice and J774A.1 cells infected with S. Typhimurium wild-type strain SL1344, spvC deletion mutant, spvC K136A site-directed mutant, and complemented strain were used to investigate potential pathogenesis of spvC. We verity that SpvC attenuates intestinal inflammation, suppresses pyroptosis through phosphothreonine lyase activity, and reduces pyroptosis in the ceca. Moreover, the reduction of inflammation via spvC results in systemic infection. These findings demonstrate that spvC inhibits pyroptosis and intestinal inflammation to promote bacterial dissemination, which provide new strategies for controlling systemic infection caused by Salmonella and novel insights for the treatment of other corresponding diseases.

Salmonella spvC Gene Inhibits Autophagy of Host Cells and Suppresses NLRP3 as Well as NLRC4

“…We next examined the effect of the Salmonella spvC gene on intracellular bacterial loads. In agreement with our previous studies in vivo (18), macrophages J774A.1 infected with STM-DspvC showed significantly lower bacterial burden than those infected with STM-WT or STM-DspvC/pspvC since 2 hpi in vitro (Figure 1C). The aforementioned results suggest spvC restricts elimination of pathogens in host cells which may be related to its contribution to autophagy, while the underlying mechanism remains elusive.…”

“…We demonstrated that spvC affects the formation of autophagosomes in an ERK dependent manner. Besides we have proved that spvC inactivates phospho-ERK1/2, phospho-JNK and phospho-p38, leading to the interference of NLRP3 and NLRC4 in S. Typhimurium infected macrophages J774A.1 (18). Given all this, whether JNK and p38 are involved in spvC suppressed autophagy remains to be fully elucidated.…”

“…This pathway is independent on the effect of autophagy on NLRP3 and NLRC4. Hence, repression of NLRP3 and NLRC4 by spvC contributes to the alleviation of pyroptosis, subsequently promotes bacterial dissemination in mice (18). Therefore, the role of NLRP3 and NLRC4 regulated by spvC to drive cell fate decisions between autophagy and pytoptosis in Salmonella infection deserves further investigation.…”

A Severe Gastroenteritis Outbreak of Salmonella enterica Serovar Enteritidis Linked to Contaminated Egg Fried Rice, China, 2021

“…The majority of important gene-encoded virulence factors are mainly located on pathogenicity islands (SPIs), which are highly conserved in Salmonella ( Michael et al, 2006 ). Several genes are important in Salmonella virulence, included inv A, spv C spa N, sip B, and sop B, are associated with the ability to invade the intestinal epithelial cells ( Klein et al, 2000 ; Liebl et al, 2017 ; Zuo et al, 2020 ; Krishna and Dhanashree, 2021 ). The outbreak strains also carried a series of genes associated with adhesion ( lefA-E ), colonization ( Rat B and Sin H) and biofilm formation ( csgA- G), which promote invasion and survival of strains in unsuitable environments ( Desai et al, 2019 ; Elkenany et al, 2019 ).…”

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“…The majority of important gene-encoded virulence factors are mainly located on pathogenicity islands (SPIs), which are highly conserved in Salmonella (Michael et al, 2006). Several genes are important in Salmonella virulence, included invA, spvC spaN, sipB, and sopB, are associated with the ability to invade the intestinal epithelial cells (Klein et al, 2000;Liebl et al, 2017;Zuo et al, 2020;Krishna and Dhanashree, 2021). The outbreak strains also carried a series of genes associated with adhesion (lefA-E), colonization (RatB and SinH) and biofilm formation (csgA-G), which promote invasion and survival of strains in unsuitable environments (Desai et al, 2019;Elkenany et al, 2019).…”