Yersinia pestis, a highly virulent Gram-negative bacterium, is the causative agent of plague. An important mechanism behind its ability to cause disease is the capacity of Y. pestis to suppress innate immune functions via its Type III secretion system (T3SS) and translocated effector proteins. However, interactions between the T3SS and immune signaling pathways are complex, and they can promote or inhibit inflammation depending upon the specific conditions. Inflammasomes are signaling complexes that culminate with activation of caspase-1 or caspase-11 into enzymes that cleave pro-forms of inflammatory cytokines IL-1b and IL-18. Our work has suggested that IL-1b and IL-18 can have effective anti-bacterial actions against Y. pestis. Thus, for infection to proceed, the production of these cytokines is minimized by the pathogen. Our preliminary evidence suggests that the Y. pestis T3SS triggers at least three different inflammasome pathways. The effector YopJ activates a caspase-8 dependent pathway, and the T3SS needle/translocon triggers NLRP3/NLRC4 dependent caspase-1 cleavage and IL-1b release. One T3SS effector, YopM, appears to inhibit activation of a poorly characterized third inflammasome pathway involving the Pyrin protein, which is otherwise potently triggered by infection. Spontaneously activating alleles of Pyrin are linked to the auto-inflammatory disease familial Mediterranean fever (FMF) and activation of Pyrin inflammasomes by bacterial toxins and Type VI secretion systems has been previously reported. However, specific inhibition of this pathway is not yet reported. In vivo, Y. pestis YopM appears to cooperate with another effector called YopJ that blocks NF-kB and MAP kinase kinases, to limit IL-1b and IL-18 production. Thus, YopM minimizes caspase-1 cleavage and YopJ inhibits pro-IL-1b/IL-18 formation. Consistent with their role in limiting inflammasomes activity and IL-1b & IL-18 production, strains lacking both YopM and YopJ are attenuated in a fashion dependent upon caspase-1, IL-1b and IL-18. We hypothesize that YopM is an effective inhibitor of the Pyrin inflammasome pathway and that this contributes to the suppression of innate immunity during plague infection. Our goal is to describe the mechanism by which YopM inhibits Pyrin inflammasomes.
The work proposed in this application seeks to identify how Yersinia pestis, the causative agent of plague, blocks the innate immune system via a specialized secretion system. The knowledge we gain would lead to a greater understanding of highly virulent pathogens, and could also be helpful for designing therapies that block harmful inflammation.
