Gaytan, H. | Search bioRxiv

bioRxiv2024

Pathogenic rickettsiae utilize the phosphatidylserine binding receptor CD300f on macrophages for host invasion and pathogenesis.

Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Rickettsia species modulate immune (e.g., macrophages; M{Phi}) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, M{Phi} play a crucial role in either terminating an infection at an early stage or succumbing to bacterial replication and colonization. However, our understanding on how Rickettsia species invade host cells, including M{Phi}, remain poorly defined. In this study, we describe a mechanism of host invasion by Rickettsia species, involving rickettsial phosphatidylserine (PS), as a ligand, and the CD300f receptor on M{Phi}. Using bone marrow-derived macrophages (BMDM{Phi}) from wild-type (WT) and CD300f-/- mice, we demonstrated that engulfment of both pathogenic R. typhi (the etiologic agent of murine typhus) and R. rickettsii (the etiologic agent of Rocky Mountain spotted fever) species as well as the non-pathogenic R. montanensis was significantly reduced in CD300f-/- BMDM{Phi} as compared to that of WT BMDM{Phi}. Furthermore, our mechanistic analysis suggests bacterial PS as the potential source for the CD300f-mediated rickettsiae engulfment by M{Phi}. In vivo infection studies using WT and CD300f-/- C57BL/6J mice showed that CD300f-/- animals were protected against R. typhi-or R. rickettsii-induced fatal rickettsiosis, which correlated with levels of bacterial burden detected in the spleens of mice. Adoptive transfer studies further revealed that CD300f-expressing M{Phi} are important mediators to control rickettsiosis in vivo. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment of rickettsiae within the host.

microbiology↗

bioRxiv2022

Pathogenic Rickettsia species evade autophagosomal maturation and reduce anti-microbicidal pro-inflammatory IL-1 responses to support their intracellular survival.

Species of genus Rickettsia are obligate intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some Rickettsia species are responsible for several serious human diseases. One fascinating feature of these stealthy group of pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia elude host immune defense responses remains to be determined. Here, we observed that pathogenic R. typhi and R. rickettsii, but not non-pathogenic R. montanensis become ubiquitinated and induce autophagy upon entry into bone-marrow-derived macrophages. Moreover, unlike R. montanensis, R. typhi, and R. rickettsii colocalized with LC3B but not with Lamp2 upon host cell entry. Finally, we observed that pathogenic but not non-pathogenic Rickettsia reduce pro-inflammatory IL-1 responses. In sum, we identified a previously unappreciated pathway by which pathogenic, but not non-pathogenic, Rickettsia become ubiquitinated and induced autophagy, but avoided autophagolysosomal destruction as well as inflammasome-mediated anti-microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages.

microbiology↗