Inhibition of type III secretion system induced leukotriene B4 production by Yersinia pestis: A mechanism for early immune evasion

Subverting the host immune response to inhibit inflammation is a key virulence factor of Yersinia pestis . The inflammatory cascade is tightly controlled via the sequential action of lipid and protein mediators of inflammation. Because delayed inflammation is essential for Y. pestis to cause lethal infection, defining the mechanisms used by Y. pestis to manipulate the inflammatory cascade is necessary to understand this pathogen’s virulence. While previous studies have established that Y. pestis actively 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 that Y. pestis actively inhibited the synthesis of LTB4. Finally, using Y. pestis mutants in the Ysc type 3 secretion system (T3SS) and Yersinia outer protein (Yop) effectors, we demonstrate that leukocytes recognize the T3SS to initiate the synthesis of LTB4 rapidly. However, the Yop effectors secreted through the same system effectively inhibit this host response. Together, these data demonstrate that Y. pestis actively inhibits the synthesis of LTB4, an inflammatory lipid, required for rapid recruitment of leukocytes to the site of infection. Author Summary Yersinia 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 by Y. pestis to block inflammation. Lipid mediators are potent signaling molecules that regulate multiple host immune responses, including inflammation. While there have been studies on how Y. pestis blocks the proteins that mediate inflammation, there is a gap in our understanding of the inflammatory lipid mediator response during plague. Here we show that Y. pestis inhibits the production of one of these critical lipid mediators, leukotriene B4, by host immune cells. Furthermore, we identify both the signals that induce LTB4 production by leukocytes and the mechanisms used by Y. pestis to inhibit this process. Together, these data represent the first comprehensive analysis of inflammatory lipids produced during plague and improve our current understanding of how Y. pestis manipulates the host immune response to generate a permissive non-inflammatory environment required for bacterial colonization. ### Competing Interest Statement The authors have declared no competing interest.