Date on Master's Thesis/Doctoral Dissertation

5-2024

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Lawrenz, Matthew B.

Committee Co-Chair (if applicable)

Uriarte, Silvia M.

Committee Member

Bagaitkar, Juhi

Committee Member

Bodduluri, Hari

Committee Member

Abu-Kwaik, Yousef

Author's Keywords

Yersinia pestis; leukotriene B4; neutrophils; macrophages; inflammation; lipid mediators

Abstract

Yersinia pestis causes the human disease known as plague. A key manifestation of plague is a delayed inflammatory response. Because this delay in inflammation is required for virulence, I was interested in defining the molecular mechanisms used by Y. pestis to evade immune recognition. Eicosanoids are produced early during infection and necessary to initiate a rapid inflammatory response. Despite the importance of these lipids in mediating inflammation, the role of eicosanoids during plague has not been previously investigated. Using an intranasal mouse model infection, I determined the kinetics of eicosanoid synthesis during pneumonic plague. I further demonstrated that LTB4 synthesis by neutrophils, macrophages, and mast cells is actively inhibited by a set of Y. pestis proteins that are directly injected into host leukocytes via a type 3 secretion system (T3SS). I also showed that the T3SS is a conserved PAMP recognized by leukocytes. While phagocytosis is not required for LTB4 synthesis by neutrophils, inhibition of phagocytosis in macrophages significantly decreases LTB4 production. Furthermore, I showed that activation of the CASP1/11 inflammasome is required for an enhanced LTB4 response in macrophages, but CASP1/11 is not required for synthesis by neutrophils. Instead, the SKAP2 signaling pathway is required for T3SS-mediated LTB4 production by neutrophils. Together, these data represent the first characterization of the eicosanoid response during pneumonic plague and suggest that Y. pestis inhibition of LTB4 synthesis is important for the delayed inflammatory response associated with plague. These data also highlight significant differences in the signaling pathways induced by the T3SS between macrophages and neutrophils. Importantly, despite multiple mechanisms to recognize the Y. pestis T3SS, Y. pestis has evolved virulence mechanisms to counteract these signaling pathways to inhibit LTB4 synthesis.

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