Pathogenic, but not non-pathogenic,Rickettsiaevade inflammasome-dependent IL-1 responses to establish an intracytosolic replication niche

ABSTRACT Rickettsia species (spp.) are strict obligate intracellular bacteria, with 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 by which pathogenic Rickettsia spp. evade host innate immune detection remains elusive. 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-1α and to a lesser extent IL- 1β. Antibody-mediated neutralization of IL-1α 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-1α and IL-1β 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 , eluded pro- IL-1α induction and benefited pre-dominantly from the reduced IL-1α secretion, via a Caspase-11-Gsdmd-dependent pathway, to facilitate intracytosolic replication. Adoptative transfer experiments identified that IL-1α 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-1α signaling axis in macrophages thus supporting their replication within the host. IMPORTANCE Currently, no vaccines are available to prevent rickettsioses, while vector-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-1α signaling axis, to limiting the replication of pathogenic R. rickettsia and R. typhi species in murine macrophages and wild-type ( WT ) C57BL/6J mice. Adoptative transfer studies further identified IL-1α-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., benefit from a reduction in the Caspase-11-Gsdmd-mediated release of IL-1α to support host colonization.