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Published on: July 29, 2021
Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic
Oliver H Voss1, Imran Moin1, Hodalis Gaytan1
1Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Abstract:
Some arthropod-borne obligate intracellular rickettsiae are among the most virulent human pathogens. 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. 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 Rickettsia species invade host cells, including MΦ, remains 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 MΦ. Our data reveal that engulfment of both pathogenic Rickettsia typhi (the etiologic agent of murine typhus) and Rickettsia rickettsii (the etiologic agent of Rocky Mountain spotted fever) species, as well as the non-pathogenic Rickettsia montanensis, 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. In vivo infection studies using WT and CD300f-/- C57BL/6J mice show that CD300f-/- animals are protected against R. typhi- or R. rickettsii-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 in vivo. Collectively, our findings describe a previously unappreciated role for the efferocytic receptor, CD300f, to facilitate engulfment of rickettsiae within the host.
Insights
Rickettsia bacteria invade macrophages using phosphatidylserine (PS) to bind the CD300f receptor. Blocking this interaction protects mice from lethal infections, revealing CD300f as a key target for controlling rickettsial diseases.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Rickettsiae are virulent arthropod-borne pathogens that infect host cells, including macrophages (MΦ).
- The precise mechanisms by which Rickettsia species invade host cells, particularly MΦ, are not fully understood.
- Macrophages play a critical role in controlling or succumbing to Rickettsia infections.
Purpose of the Study:
- To elucidate the mechanism of Rickettsia invasion into macrophages.
- To investigate the role of bacterial phosphatidylserine (PS) and the host CD300f receptor in Rickettsia engulfment.
- To evaluate the therapeutic potential of targeting the CD300f-mediated invasion pathway in vivo.
Main Methods:
- Utilized bone marrow-derived macrophages (BMDMΦ) from wild-type (WT) and CD300f knockout (CD300f-/-) mice.
- Quantified Rickettsia engulfment by BMDMΦ using pathogenic (R. typhi, R. rickettsii) and non-pathogenic (R. montanensis) species.
- Conducted in vivo infection studies in WT and CD300f-/- mice, followed by bacterial burden assessment and adoptive transfer experiments.
Main Results:
- Engulfment of Rickettsia species by BMDMΦ was significantly reduced in CD300f-/- mice compared to WT mice.
- Bacterial PS was identified as a potential ligand mediating CD300f-dependent Rickettsia uptake by macrophages.
- CD300f-/- mice exhibited protection against lethal R. typhi and R. rickettsii infections, with reduced bacterial loads in spleens.
- Adoptive transfer studies confirmed that CD300f-expressing MΦ are crucial for controlling rickettsiosis in vivo.
Conclusions:
- The study identifies a novel mechanism of Rickettsia host cell invasion mediated by bacterial PS and the macrophage receptor CD300f.
- CD300f facilitates the engulfment of Rickettsia species by macrophages, playing a critical role in host defense.
- Targeting the CD300f-mediated pathway offers a potential strategy for developing new therapies against severe rickettsial diseases.
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