Inhibition of type III secretion system induced leukotriene B₄production byYersinia pestis: A mechanism for early immune evasion

AbstractSubverting the host immune response to inhibit inflammation is a key virulence factor ofYersinia pestis. The inflammatory cascade is tightly controlled via the sequential action of lipid and protein mediators of inflammation. Because delayed inflammation is essential forY. pestisto cause lethal infection, defining the mechanisms used byY. pestisto manipulate the inflammatory cascade is necessary to understand this pathogen’s virulence. While previous studies have established thatY. pestisactively inhibits the expression of host proteins that mediate inflammation, there is currently a gap in our understanding of inflammatory lipid mediator response during plague. Here we use in vivo lipidomics to define the synthesis of lipid mediators of inflammation within the lungs during pneumonic plague. Interestingly, while we observed an early cyclooxygenase response during pneumonic plague, there was a significant delay in the synthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid chemoattractant and activator of immune cells. Furthermore, in vitro studies with primary leukocytes from mice and humans further revealed thatY. pestisactively inhibited the synthesis of LTB4. Finally, usingY. pestismutants in the Ysc type 3 secretion system (T3SS) andYersiniaouter protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the synthesis of LTB4rapidly. However, the Yop effectors secreted through the same system effectively inhibit this host response. Together, these data demonstrate thatY. pestisactively inhibits the synthesis of LTB4, an inflammatory lipid, required for rapid recruitment of leukocytes to the site of infection.Author SummaryYersinia pestis, the bacteria that causes plague, targets the host’s innate immune response to inhibit inflammation. Because the generation of this non-inflammatory environment is required for infection, we are interested in mechanisms used byY. pestisto block inflammation. Lipid mediators are potent signaling molecules that regulate multiple host immune responses, including inflammation. While there have been studies on howY. pestisblocks the proteins that mediate inflammation, there is a gap in our understanding of the inflammatory lipid mediator response during plague. Here we show thatY. pestisinhibits the production of one of these critical lipid mediators, leukotriene B4, by host immune cells. Furthermore, we identify both the signals that induce LTB4production by leukocytes and the mechanisms used byY. pestisto inhibit this process. Together, these data represent the first comprehensive analysis of inflammatory lipids produced during plague and improve our current understanding of howY. pestismanipulates the host immune response to generate a permissive non-inflammatory environment required for bacterial colonization.