GH18 family glycoside hydrolase Chitinase A of Salmonella enhances virulence by facilitating invasion and modulating host immune responses

Abstract

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.

Chitinase A, a tightly regulated virulence factor of Salmonella enterica serovar Typhimurium, is actively secreted by a Type 10 Secretion System

“…In line with these results of host cell-driven chiA inductions and potential targets on host cells, we found that the mutation of chiA leads to the diminished attachment of S. Typhimurium to human IEC and subsequently to less invasion (Fig 1A and 1B). Our results provide strongly increased evidence towards two very recent studies of S. Typhimurium and S. Typhi, which demonstrated that ChiA has an influence on virulence, promoting adhesion to human epithelial cells, followed by increased invasion [26,27]. However, those studies did not explore ChiA expression, regulation, and secretion phenotypes, dependent on polarized cells.…”

“…Chitinases are virulence factors in many pathogenic bacteria, important for the colonization of organs [18,19], attachment and invasion of host cells [20][21][22], promoting intracellular survival [23,24], and modulating the host immune response [25]. For S. Typhimurium and S. Typhi, a contribution of chitinases to the pathogenicity of both serovars has been shown very recently [26,27]. Chitinase-dependent remodeling and interaction with surface glycans promote the adhesion and invasion of intestinal epithelial cells (IEC) by Salmonella.…”

Multi-omics reveal Salmonella-liberated dietary L-arabinose promotes expansion in superspreaders

“…Interestingly, chitinases, which hydrolyze chitin polymers into N-acetyl glucosamine oligomers, are a well-studied family of glycoside hydrolases in pathogens. Recent work has characterized Salmonella’s GH18 family chitinases and have shown them to be important for epithelial adhesion and invasion (Devlin et al ., 2021; Chandra et al ., 2022). Chitinases have been identified as important virulence factors for several other pathogenic bacterial species including Legionella pneumophila (Rehman et al ., 2020), Listeria monocytogenes (Chaudhuri et al ., 2013), Vibrio cholerae (Mondal et al ., 2014), and Adherent-invasive Escherichia coli (Low et al ., 2013).…”

Lpp of Escherichia coli K1 inhibits host ROS production to counteract neutrophil-mediated elimination

“…By contrast, the bacteria develop a series of strategies to resist the damages by ROS. Some of the bacteria, such as Salmonella typhimurium [ 11 ], Listeria monocytogenes [ 12 ], and Pseudomonas aeruginosa [ 13 ], can interfere with the activity of ROS generation machinery in neutrophils. Unraveling the regulatory mechanism of ROS production in neutrophils in the context of pathogen-host interaction may lead to new strategies for the treatment of bacterial infection.…”