Yersinia type III effectors perturb host innate immune responses

Abstract

The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis.

Keywords: Type III secretion; Yersinia; Effectors; Innate; Virulence

Core tip: The study of Yersinia type III secretion system effector proteins has provided critical insights into bacterial pathogenic strategies and host innate immune responses. Identification of the crystal structure of YpkA revealed how a bacterial effector can counteract phagocytosis at multiple levels including inhibition of actin polymerization by sequestering actin, inhibition of actin signaling molecules via both its kinase and dissociation-like inhibitor domains, and inhibition of actin-cytoskeletal components via phosphorylation. YpkA/YopO multisite autophosphorylation may allow YpkA/YopO to bypass regulation by host phosphatases and thus prolong its ability to interfere with phagocytosis. Additionally, an emerging theme is the role of caspases in anti-Yersinia host defenses.