GH18 family glycoside hydrolase Chitinase A of Salmonella enhances virulence by facilitating invasion and modulating host immune responses
PLOS PATHOGENS(2022)
Abstract
Author summaryChitinases and chitin-binding proteins have been implicated in the pathogenesis of several human pathogens associated with the mucosal barrier. Interestingly, chitinases from the major enteric pathogen, Salmonella enterica, were reported to be upregulated during macrophage and epithelial cell infection. Although Salmonella Chitinase ChiA (encoded by STM14_0022) shares sequence similarity with the pathogenic chitinases, its role as a virulence determinant remained obscured. Here we aim to investigate the role of chitinase in the context of Salmonella pathogenesis using cell culture, mouse, and nematode models. We found that Salmonella requires ChiA to remodel the intestinal epithelium and access the host system. In the phagocytes, chitinase-mediated upregulation of nitric oxide (NO) leads to inhibition of MHC-I bound antigen presentation and CD8(+) T cell proliferation. Furthermore, the absence of ChiA impairs bacterial adhesion and colonization in vivo. During the systemic phase in the murine host, Salmonella Typhimurium chitinase prevents immune activation and antimicrobial responses. Additionally, in the Caenorhabditis elegans, Salmonella Typhi chitinase promotes bacterial attachment to the intestinal epithelium and enhances pathogen colonization and persistence in the intestine by downregulating the antimicrobial peptides SPP1 and ABF2. In conclusion, our study provides novel insights into the role of Salmonella chitinase as a novel virulence factor. Salmonella is a facultative intracellular pathogen that has co-evolved with its host and has also developed various strategies to evade the host immune responses. Salmonella recruits an array of virulence factors to escape from host defense mechanisms. Previously chitinase A (chiA) was found to be upregulated in intracellular Salmonella. Although studies show that several structurally similar chitinases and chitin-binding proteins (CBP) of many human pathogens have a profound role in various aspects of pathogenesis, like adhesion, virulence, and immune evasion, the role of chitinase in the intravacuolar pathogen Salmonella has not yet been elucidated. Therefore, we made chromosomal deletions of the chitinase encoding gene (chiA) to study the role of chitinase of Salmonella enterica in the pathogenesis of the serovars, Typhimurium, and Typhi using in vitro cell culture model and two different in vivo hosts. Our data indicate that ChiA removes the terminal sialic acid moiety from the host cell surface, and facilitates the invasion of the pathogen into the epithelial cells. Interestingly we found that the mutant bacteria also quit the Salmonella-containing vacuole and hyper-proliferate in the cytoplasm of the epithelial cells. Further, we found that ChiA aids in reactive nitrogen species (RNS) and reactive oxygen species (ROS) production in the phagocytes, leading to MHCII downregulation followed by suppression of antigen presentation and antibacterial responses. Notably, in the murine host, the mutant shows compromised virulence, leading to immune activation and pathogen clearance. In continuation of the study in C. elegans, Salmonella Typhi ChiA was found to facilitate bacterial attachment to the intestinal epithelium, intestinal colonization, and persistence by downregulating antimicrobial peptides. This study provides new insights on chitinase as an important and novel virulence determinant that helps in immune evasion and increased pathogenesis of Salmonella.
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Key words
salmonella,immune responses,virulence
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