Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic rickettsiae

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