Dysregulated Inflammatory Response toCandida albicansin a C5-Deficient Mouse Strain

Abstract

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.

Genetic control of suceptibility to Candida albicans in susceptible A/J and resistant C57BL/6J mice

“…The highest fungal loads in both strains of mice were detected in the kidney, with the kidneys of A/J mice containing an approximately 100-fold greater number of fungi at this point in the infection process. The levels of several cytokines that had previously been reported to be elevated during systemic C. albicans infection 8,[23][24][25][26] were measured in A/J and B6. Cytokine levels were measured by ELISA in serum isolated from A/J and B6 mice 48 h after low dose injection with C. albicans blastospores.…”

“…Elevated levels of the proinflammatory cytokines TNF-a and IL-6 are observed early in infection, suggesting that these mice undergo a heightened, and possibly unregulated, inflammatory response after challenge with C. albicans. 8 In contrast, B6 is relatively resistant to systemic candidiasis, with an approximately 100-fold lower fungal load in the kidney and a muted production of IL-6 and TNF-a compared to A/J. Genetic control of suceptibility to Candida albicans A Tuite et al A genome-wide scan was conducted in an informative F 2 population derived from A/J and B6, in order to study the genetic control of susceptibility to C. albicans.…”

“…In the absence of C5a, mice have a reduced recruitment of effector cells to the site of infection. 8 The G-protein coupled C5a receptor (C5aR/CD88) is expressed on neutrophils, monocytes, macrophages, dendritic cells, basophils, eosinophils, and mast cells, among other cell types. 38 Neutrophils express high levels of this receptor, 39 explaining their rapid infiltration to sites of infection and the ensuing phagocytosis of C. albicans in response to C5.…”

“…Inbred mouse strains display a spectrum of responses to systemic C. albicans infection, ranging from highly susceptible to resistant, as assessed by fungal burden in affected organs, type and extent of cytokine response elicited and overall survival. 7,8 Studies in animal models have helped to clarify the aspects of innate and adaptive immunity that are required to protect the host against invasive infections with C. albicans. Neutrophils are rapidly recruited to sites of infection, where they can kill both the yeast and hyphal forms of C. albicans.…”

“…8 The dramatically different response elicited in A/J and B6 mice following systemic challenge with C. albicans prompted us to investigate whether these phenotypic differences have an underlying genetic basis. To do this, we analyzed infection progression and outcome in A/J and B6 mice following i.v.…”