Pathogenic, but not non-pathogenic, Rickettsia manipulate inflammasome-dependent IL-1 responses to facilitate their replication and host dissemination

Rickettsia species (spp.) are strict obligate intracellular bacteria, symbiotic in their arthropod vector, and some being pathogenic in their mammalian host, including humans. One critical feature of these stealthy group of pathogens is their ability to manipulate hostile cytosolic environments to their benefits. Although our understanding of Rickettsia cell biology and pathogenesis are evolving, the mechanisms of host innate immune defense evasion by pathogenic Rickettsia spp. remains to be elucidated. Here, we showed that disease severity in wild-type (WT) C57BL/6J mice infected with R. typhi- (etiologic agent of murine typhus) and R. rickettsii (etiologic agent of Rocky Mountain Spotted Fever), but not with non-pathogenic R. montanensis, correlated with levels of bacterial burden as detected in the spleens, as well as the serum concentrations of pro-inflammatory cytokine IL-1 and to a lesser extent IL-1{beta}. Antibody-mediated neutralization of IL-1 confirmed a key role in controlling mortality rates and bacterial burdens of rickettsiae-infected WT mice. As macrophages are a primary source of both IL-1 and IL-1{beta} cytokines, we determined the mechanism of the anti-rickettsial activities using bone-marrow-derived macrophages. We found that pathogenic R. typhi and R. rickettsii, but not non-pathogenic R. montanensis, induced autophagy, and avoided autophagolysosomal destruction, while simultaneously eluded pro-IL-1 induction and benefited from the dampening of IL-1 secretion, via Caspase-11-Gsdmd-dependent mechanism, to facilitate intracytosolic replication. Adoptative transfer experiments identified that IL-1 secretion by macrophages was critical for controlling rickettsiosis in WT mice. In sum, we identified a previously unappreciated pathway by which pathogenic, unlike non-pathogenic, rickettsiae preferentially target the Caspase-11-Gsdmd-IL-1 signaling axis in macrophages, possibly via an autophagy-dependent mechanism, to support their replication and dissemination within the host. Significance StatementCurrently, no vaccines are available to prevent rickettsioses, and tick- and flea-borne rickettsial infections in humans are on the rise globally. In fact, the insufficient understanding of how pathogenic Rickettsia species circumvent host immune defense mechanisms has significantly hindered the development of more effective therapeutics. Here, we identified a previously unappreciated role for the Caspase-11-Gsdmd-IL-1 signaling axis, to limiting the survival and dissemination of pathogenic R. rickettsia and R. typhi species in macrophages and wild-type C57BL/6J mice. Adoptative transfer studies further identified IL-1-secreting macrophages as critical mediators in controlling rickettsial infection in WT mice. Collectively, these findings provide insight into the potential mechanism of how pathogenic, but not non-pathogenic Rickettsia spp., become ubiquitinated, induce autophagy and benefit from the dampening of the Caspase-11-Gsdmd-mediated release of IL-1 to support host colonization.