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

Abstract

Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry, Rickettsia species modulate immune (e.g., macrophages; MΦ) and non-immune cell (e.g., endothelial cells) responses to create a habitable environment for host colonization. In particular, MΦ 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 modulate crucial cellular processes within MΦ, including phagocytosis, and host cell defenses, to establish an intracytosolic replication niche, remain poorly defined. In this study, we describe a previously unappreciated mechanism, in which pathogenic rickettsiae infection is mediated by the phosphatidylserine (PS)-binding receptor, CD300f. We found that CD300f-/- mice but not wild-type (WT) C57BL/6J mice were protected against R. typhi- or R. rickettsii [Shelia Smith]-induced fatal rickettsiosis. Adoptative transfer studies further revealed that CD300f-expressing bone marrow-derived macrophages (BMDMΦ) are important mediators to control rickettsiosis in WT mice. Mechanistical analysis, using WT or CD300f-/- BMDMΦ, showed that CD300f facilitates the engulfment of both pathogenic R. typhi and R. rickettsii species, likely via a PS-mediated mechanism. Furthermore, CD300f was involved in the intracytosolic replication of both pathogenic rickettsiae by differentially modulating the anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1alpha and IL-1beta cytokine responses. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment and the intracellular survival of pathogenic rickettsiae within the host.