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Phosphatidylserine-binding receptor, CD300f, on macrophages mediates host invasion of pathogenic and non-pathogenic
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. 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 invade host cells, including MΦ, 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 MΦ. Using bone marrow-derived macrophages (BMDMΦ) 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-/- BMDMΦ as compared to that of WT BMDMΦ. 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 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 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 use phosphatidylserine to engage the CD300f receptor on macrophages, facilitating host cell invasion. Blocking this interaction protects mice from lethal rickettsiosis, highlighting CD300f as a key target for controlling infection.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Rickettsia species are virulent pathogens transmitted by arthropods, causing severe human diseases.
- Macrophages (MΦ) are critical immune cells that can either eliminate or succumb to Rickettsia infections.
- The precise mechanisms by which Rickettsia invade host cells, including MΦ, are not fully understood.
Purpose of the Study:
- To elucidate the mechanism of Rickettsia invasion into host cells, particularly macrophages.
- To investigate the role of rickettsial phosphatidylserine (PS) and the CD300f receptor in host cell entry.
- To evaluate the therapeutic potential of targeting the CD300f-mediated invasion pathway.
Main Methods:
- Utilized bone marrow-derived macrophages (BMDMΦ) from wild-type and CD300f knockout mice.
- Assessed the engulfment of Rickettsia species (R. typhi, R. rickettsii, R. montanensis) by BMDMΦ.
- Conducted in vivo infection studies in wild-type and CD300f knockout mice, including adoptive transfer experiments.
Main Results:
- Engulfment of Rickettsia species by BMDMΦ was significantly reduced in CD300f knockout cells compared to wild-type.
- Bacterial phosphatidylserine was identified as the likely ligand mediating CD300f-dependent engulfment.
- CD300f knockout mice exhibited protection against lethal Rickettsia infections, with lower bacterial burdens.
- Adoptive transfer studies confirmed the crucial role of CD300f-expressing MΦ in controlling rickettsiosis.
Conclusions:
- Rickettsia species utilize their surface phosphatidylserine to bind the CD300f receptor on macrophages, promoting bacterial engulfment.
- The CD300f receptor plays a significant role in facilitating Rickettsia host cell invasion and subsequent pathogenesis.
- Targeting the CD300f-mediated invasion pathway offers a promising strategy for developing novel therapies against Rickettsia infections.
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