Thursday, November 21, 2024
11/21/2024
Summary Ail is a multifunctional surface protein required for virulence in Yersinia pestis, the etiological agent of plague. Ail confers serum-resistance, facilitates Type Three Secretion (T3S) of cytotoxins into host cells and mediates adhesion to host cells via extracellular matrix (ECM) proteins. While Ail is required for Y. pestis virulence in animal models, it remains unclear which activities make major contributions to the establishment of plague. Our previous studies have defined the mechanism for Ail binding to host cells to provide Ail-mediated Yop delivery. While some such Ail mutants are nearly completely defective for Ail-mediated Yop delivery, they still impart strong serum resistance. In this proposal we will determine the mechanism(s) by which Ail confers serum resistance to Y. pestis. This involves investigating Ail interaction with various complement proteins involved in assembly of the membrane attack complex (MAC) including C6-C9 and the complement regulatory proteins Factor H and vitronectin. Using a newly generated serum-sensitive mutant of Ail that maintains Yop delivery activity, we will test the effects of serum-sensitive or adhesion/Yop delivery defective derivatives of Ail on plague pathogenesis in rats (rats are a good model for serum-related aspects of human disease). We hypothesize that loss of Ail- mediated cell binding or serum-resistance will lead to intermediate defects in host colonization, but loss of both activities will result in attenuation similar to a Dail mutant. In all, this proposal focuses on the critical nature of interaction between Ail and the host. Specifically, we will establish the roles of Ail-mediated serum-resistance and adhesion/Yop translocation in plague pathogenesis, a longstanding challenge for the field.
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