Pyrin is an inflammasome sensor in phagocytes that is activated in response to bacterial toxins and effectors that modify RhoA. Pathogen effector-triggered pyrin activation is analogous to an indirect guard mechanism in plants. Pyrin activation appears to be triggered when RhoA GTPases in a host cell are prevented from binding downstream signaling proteins (transducers). RhoA transducers that control this response include PRK kinases, which negatively regulate pyrin by phosphorylation and binding of 14-3-3 proteins. Microtubules regulate pyrin at different levels and may serve as a platform for inflammasome nucleation. Pyrin increases inflammation in the lung, gut or systemically during infection or intoxication in mouse models and protects against systemic infection by decreasing bacterial loads. Pathogenic Yersinia spp. overcome this protective response using effectors that inhibit the pyrin inflammasome. Gain of function mutations in MEFV, the gene encoding pyrin, cause the autoinflammatory disease Familial Mediterranean Fever. Yersinia pestis may have selected for gain of function MEFV mutations in the human population.