Regulation of host innate and adaptive immunity by bacterial type III effectors

Project Summary/Abstract
Bacterial pathogens use type III secretion systems to translocate effectors into host cells to promote virulence.
Type III secretion can also activate compensatory innate immune responses that are host protective. For
example, type III secretion can trigger inflammasome assembly in host cells, resulting in release of the cytokine
IL-1b. Virulent pathogens can inhibit compensatory protective immune responses triggered by type III secretion
but how this is achieved at the cellular and molecular levels in vivo remains poorly understood. To address this
knowledge gap, this project seeks to determine at the cellular and molecular levels how type III secretion
effectors in virulent Yersinia species inhibit a protective inflammasome pathway in vivo. Yersinia uses two
effectors, YopM and YopJ, to inhibit the pyrin inflammasome. It is not known if YopM and YopJ promote virulence
by inhibiting the pyrin inflammasome in a cell specific manner. During invasive infections of lymphoid tissues
Yersinia grow as extracellular microcolonies in direct contact with neutrophils within an organize immune
structure known as a pyogranuloma. Pyogranulomas can be considered battlefields where Yersinia virulence
factors combat protective immune responses in neutrophils acting as foot soldiers. Yersinia mutants lacking
YopM and YopJ have a significant survival defect in lymphoid tissues suggesting that these effectors inhibit the
pyrin inflammasome in pyogranuloma neutrophils. Additionally, IL-1b is important for host protection against
infection by Yersinia lacking YopM and YopJ. Based on these published data and preliminary results we
hypothesize that YopM and YopJ promote Yersinia virulence by inhibiting the pyrin inflammasome in neutrophils
to prevent release of IL-1b in pyogranulomas. This hypothesis will be tested in Aim 1. YopM binds to pyrin in
infected host cells and in purified form, but the molecular basis of this interaction is undefined. Based on
published and preliminary we hypothesize that YopM targets the pyrin domain to inhibit the inflammasome in
vivo and promote Yersinia virulence. This hypothesis will be tested in Aim 2. Completion of these aims will fill
important knowledge gaps, move Yersinia pathogenesis research forward, have a broad impact on the field of
neutrophil inflammasomes and inform new therapeutic strategies aimed at augmenting protective neutrophil
inflammasome responses to bacterial pathogens.

Grant Number: 4R01AI099222-14
NIH Institute/Center: NIH
Principal Investigator: James Bliska