Dysregulated inflammatory response to Candida albicans in a C5-deficient mouse strain.
Experimental infection of inbred mouse strains with Candida albicans provides a good model system to identify host genetic determinants that regulate onset of, response to, and ultimate outcome of disseminated candidiasis. The A/J mouse strain is exquisitely sensitive to infection with C. albicans, while the C57BL/6J strain is relatively resistant, as measured by survival following intravenous injection of Candida blastospores. This differential susceptibility is caused by an A/J-specific loss-of-function mutation in the C5 component of the complement pathway. C5 plays several critical roles in host response to infection, including target lysis and phagocyte recruitment. Therefore, to determine which of its functions were required for host resistance to candidiasis, a detailed comparative analysis of pathophysiology and host response to acute C. albicans infection was conducted in A/J and C57BL/6J mice. C5-sufficient C57BL/6J mice were found to succumb late in infection due to severe kidney pathology, typified by fungal replication and robust neutrophil-based inflammatory response associated with extensive tissue damage. In contrast, A/J mice were moribund within 24 h postinfection but displayed little if any kidney damage despite an inability to mobilize granulocytes and a high fungal load in the kidney. Rather, C5 deficiency in A/J mice was associated with higher levels of circulating cytokines tumor necrosis factor alpha, interleukin-6, monocyte chemotactic protein 1 (MCP-1), MCP-5, and eotaxin in response to C. albicans. Transfer of the C5-defective allele from A/J onto a C57BL/6J genetic background in recombinant congenic strain BcA17 recapitulated the phenotypic aspects of the susceptibility of A/J mice to C. albicans, confirming the causative role of C5 deficiency in the dysregulated cytokine response.
Mullick
Alaka
A
Biotechnology Research Institute, National Research Council, Montréal, Québec, Canada. alaka.mullick@cnrc-nrc.gc.ca
Elias
Miria
M
Picard
Serge
S
Bourget
Lucie
L
Jovcevski
Orce
O
Gauthier
Susan
S
Tuite
Ashleigh
A
Harakidas
Penelope
P
Bihun
Craig
C
Massie
Bernard
B
Gros
Philippe
P
D000818:Animals; D020296:Animals, Congenic; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000097:blood / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D003182:Complement C5 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000503:physiopathology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D013045:Species Specificity
D003182:Complement C5; D016207:Cytokines