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

Author:

Voss Oliver H.ORCID,Moin Imran,Gaytan Hodalis,Ullah Saif,Sadik Mohammad,Azad Abdu F.ORCID,Rahman M. SayeedurORCID

Abstract

AbstractSome arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. Upon entry,Rickettsiaspecies 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 howRickettsiaspecies 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 againstR. typhi- orR. 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 pathogenicR. typhiandR. rickettsiispecies, 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-1α and IL-1β 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.Significance StatementVector-borne diseases, which are transmitted by hematophagous arthropods, like ticks and fleas, present a perilous threat to public health. In fact, tick- and flea-borne rickettsial diseases are on the rise globally and our current inadequate understanding on howRickettsiainteracts with their mammalian host has significantly impaired the development of effective interventions against pathogenic rickettsial infections. Here, we identified the phosphatidylserine (PS)-receptor, CD300f, as an important mediator of pathogenic rickettsiae infectionin vivoandin vitro. Specifically, we showed that CD300f-expressing macrophages facilitate rickettsial infection by differentially modulating anti-inflammatory Interleukin (IL)-10 and anti-rickettsial IL-1α and IL-1β cytokine responses. In sum, our data described CD300f as an important regulator of rickettsial infection and may present a target for therapeutic intervention.

Publisher

Cold Spring Harbor Laboratory

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