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Infection and Immunity, October 2004, p. 5868-5876, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5868-5876.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Dysregulated Inflammatory Response to Candida albicans in a C5-Deficient Mouse Strain{dagger}

Alaka Mullick,1* Miria Elias,1 Serge Picard,1 Lucie Bourget,1 Orce Jovcevski,1 Susan Gauthier,2 Ashleigh Tuite,2 Penelope Harakidas,1 Craig Bihun,3 Bernard Massie,1,4,5 and Philippe Gros2

Biotechnology Research Institute,1 Départment de Microbiologie et Immunologie de l'Université de Montréal,5 Biochemistry Department, McGill University Montreal, and Centre Institut National de la Recherche Scientifique-Institut Armand Frappier,2 Université du Québec, Laval, Quebec,4 Institute of Biological Sciences, Ottawa, Ontario Canada3

Received 21 May 2004/ Returned for modification 16 June 2004/ Accepted 12 July 2004

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.

* Corresponding author. Mailing address: Biotechnology Research Institute, National Research Council, 6100 Royalmount Ave., Montréal, Québec, Canada H4P 2R2. Phone: (514) 496-6281. Fax: (514) 496-5143. E-mail: alaka.mullick{at}cnrc-nrc.gc.ca.

{dagger} This is National Research Council publication number 37728.

Editor: T. R. Kozel

Infection and Immunity, October 2004, p. 5868-5876, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5868-5876.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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