C5ar1-dependent phagocyte effector functions protect against systemic candidiasis. (4th October 2017)

• Record Type: Journal Article
• Authors: Desai, Jigar V; Kemper, Claudia; Köhl, Jörg; Lionakis, Michail
• Is Part Of: Open forum infectious diseases. Volume 4(2017)Supplement 1
• Page Start: S115
• Page End: S115
• Publication Date: 2017-10-04
• Subjects: Communicable diseases -- Periodicals; Medical microbiology -- Periodicals; Infection -- Periodicals; 616.9
• DOI: 10.1093/ofid/ofx163.131
• Languages: English
• ISSNs: 2328-8957

Abstract

Abstract: Background: Systemic candidiasis, the most common nosocomial human fungal infection, leads to mortality of >40% despite antifungal therapy. Myeloid phagocytes, not lymphocytes, are critical for protection; yet, the molecular basis of phagocyte-mediated protection remains elusive. Since patients with inherited C5 deficiency and those treated with the anti-C5 humanized monoclonal antibody eculizumab have been reported to occasionally develop candidiasis, we examined the role of C5a signaling in anti- Candida host defense. Methods: Wild-type (WT) and C5ar1 knockout (KO) mice were infected iv with C. albicans and were euthanized on days 1 and 3 post-infection for fungal burden, histological, mRNA, ELISA and FACS analyses. Bone marrow (BM) radiation chimeras, GFP-C5ar1 reporter and conditional C5ar1 KO mice were used to examine the role of myeloid C5ar1 expression in protection. A Candida strain that simultaneously reports phagocytosis and fungal viability in vivo was generated to probe phagocyte effector functions. Results: C5ar1 and C5ar2 transcripts and their ligand C5a were induced post-infection in WT mouse kidney. C5ar1 KO mice showed dramatically increased susceptibility as compared with WT mice (100% mortality vs. 40%; P < 0.0001). Significantly greater fungal burden and tissue injury were observed in C5ar1 KO, but not in C5ar2 KO kidneys. BM radiation chimera experiments showed that hematopoietic, not stromal, C5ar1 expression promotes protection. Using GFP-C5ar1-reporter mice, we found that neutrophils, monocytes and macrophages, not dendritic cells, express C5ar1 in the infected kidney; phagocyte C5ar1 expression was essential for survival as LysM-Cre tg GFP-C5ar1 fl/fl mice succumbed to infection similar to C5ar1 KO mice. Mechanistically, C5ar1 does not mediate phagocyte recruitment in the infected kidney, but mediates neutrophil and macrophage fungal killing. The myeloid cell-type specific contribution is under investigation using S100a8-Cre tg GFP-C5ar1 fl/fl and Cx3cr1-Cre tg GFP-C5ar1 fl/fl mice as are the molecular mechanisms that promote C5ar1-dependent effector function. Conclusion: C5ar1 is required for host survival during systemic candidiasis via regulating the antifungal effector function of phagocytes. Disclosures: All authors: No reported disclosures.