IAI Accepts, published online ahead of print on 29 December 2008

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Infect. Immun. doi:10.1128/IAI.01119-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Role of Complement in Protection Against Cryptococcus gattii Infection

Kileen L. Mershon, Alex Vasuthasawat, Gregory W. Lawson, Sherie L. Morrison, and David O. Beenhouwer^*

Department of Microbiology, Immunology, & Molecular Genetics and the Molecular Biology Institute, Department of Laboratory Animal Medicine, and the David Geffen School of Medicine at the University of California, Los Angeles, California; and Division of Infectious Diseases, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

^* To whom correspondence should be addressed. Email: dbeenhou{at}ucla.edu.

Previous studies have shown that the alternative pathway of complement activation plays an important role in protection against infection with Cryptococcus neoformans. C. gattii does not activate the alternative pathway as well as C. neoformans in vitro. The role of complement in C. gattii infection in vivo has not been reported. In this study, we used mice deficient in complement components to investigate the role of complement in protection against a C. gattii isolate from the ongoing outbreak in northwestern North America. While factor B-deficient mice showed an enhanced rate of death, C3-deficient mice died even more rapidly, indicating the alternative pathway was not the only complement pathway contributing to protection against disease. Both C3- and factor B-deficient mice had increased fungal burdens in comparison to wild type mice. Histopathology revealed an overwhelming fungal burden in the lungs of these complement-deficient mice, which undoubtedly prevented efficient gas exchange, causing death. Following the fate of radiolabeled organisms showed both factor B- and C3-deficient mice were less effective than wild type mice in clearing organisms. However, opsonization of C. gattii with complement components was not sufficient to prolong life in mice deficient in complement. Killing of C. gattii by macrophages in vitro was decreased in the presence of serum from factor B- and C3-deficient versus wild type mice. In conclusion, we have demonstrated that complement activation is crucial for survival in C. gattii infection. Additionally, we have shown that the alternative pathway activation is not the only complement pathway contributing to protection.