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

Lingli Zuo,Shuyan Wu,Yuanyuan Li,Yanlin Wang,Chaoyi Wu,Liting Zhou,Rui Huang

doi:10.3389/fmicb.2020.562491

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.

Highlights

Salmonella, a facultative intracellular Gram-negative bacterium, is responsible for a wide range of food- and water-borne diseases ranging from gastroenteritis to typhoid fever depending on hosts and serotypes
We showed that Salmonella spvB gene could reduce host cell autophagy and Salmonella plasmid virulence C (spvC) Suppresses Pyroptosis and Intestinal Inflammation regulate intracellular iron homeostasis (Chu et al, 2016; Yang et al, 2019). spvC is another essential factor of Salmonella virulence determinant, and its encoding product, SpvC, shares 63% identity at the amino acid level with OspF of Shigella flexneri and exhibits the same phosphothreonine lyase activity on host mitogen-activated protein kinase (MAPK). spvC leads to attenuation of the intestinal inflammatory response, which is thought to be important during systemic infection of Salmonella (Li et al, 2007; Mazurkiewicz et al, 2008; Haneda et al, 2012)
Pronounced cecal inflammation is observed in mice infected with STM- spvC than in those infected with STM-WT, including epithelial cell swelling and inflammatory cell infiltration in the lamina propria, as well as atrophy in the submucosa

Summary

Introduction

Salmonella, a facultative intracellular Gram-negative bacterium, is responsible for a wide range of food- and water-borne diseases ranging from gastroenteritis to typhoid fever depending on hosts and serotypes. We showed that Salmonella spvB gene could reduce host cell autophagy and spvC Suppresses Pyroptosis and Intestinal Inflammation regulate intracellular iron homeostasis (Chu et al, 2016; Yang et al, 2019). Canonical inflammasome pathway is activated in response to cytosolic pattern recognition receptors (PRRs) such as nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), and NLR with CARD domain-containing 4 (NLRC4). These receptors assemble Procaspase-1 into multiprotein complexes, which serve as Caspase-1-activating platforms. Host cells expose the intracellular pathogens by pyroptosis and capture the pathogens by pore-induced intracellular traps (PITs), and neutrophils phagocytize and remove PITs by efferocytosis to prevent the dissemination of bacteria (Jorgensen et al, 2016b; Kovacs and Miao, 2017)

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Conclusion