IAI Accepts, published online ahead of print on 9 November 2009

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Infect. Immun. doi:10.1128/IAI.00506-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Improved survival of mice deficient in secretory IgM following systemic infection with Cryptococcus neoformans

Krishanthi S. Subramaniam, Kausik Datta, Matthew S Marks, and Liise-anne Pirofski^*

Department of Microbiology & Immunology, and Medicine, Albert Einstein College of Medicine, Bronx, NY; Johns Hopkins University School of Medicine, Baltimore, MD

^* To whom correspondence should be addressed. Email: pirofski{at}aecom.yu.edu.

Cryptococcus neoformans (CN) causes severe, often fatal, disease (cryptococcosis) in immunocompromised patients, particularly those with HIV/AIDS. Although resistance to cryptococcosis requires intact T cell immunity, a possible role for antibody/B cells in protection against natural disease has not been definitively established. Previous studies of the antibody response to the CN capsular polysaccharide glucuronoxylomannan (GXM) have demonstrated that patients who are at increased risk for cryptococcosis have lower serum levels of GXM-reactive IgM than those not at risk, leading to the hypothesis that IgM might contribute to resistance to cryptococcosis. To determine the influence of IgM on susceptibility to systemic cryptococcosis in a murine model, we compared the survival of mice deficient in serum IgM (secretory IgM deficient, sIgM^-/-) and C57Bl/6x129Sv (control) mice after intraperitoneal infection with CN strain 24067, and analyzed the splenic B and T cell subsets by flow cytometry, and serum and splenic cytokine/chemokine profiles by ELISA of each mouse strain. The results showed that sIgM^-/- mice survived significantly longer than control mice when challenged with 10⁵ CFU of CN 24067. Naïve sIgM^-/- mice had higher levels of B-1 (CD5+) B cells and pro- (IL-6, IL-1, MIP-1, TNF-, IFN-) and anti- (IL-10, IL-13) inflammatory mediators and significantly higher titers of GXM-specific IgG2a three weeks post-infection. In addition, CD5+ splenocytes from both mouse strains had fungicidal activity against CN. Taken together, these results suggest that the inflammatory milieu in sIgM^-/- mice might confer enhanced resistance to systemic cryptococcosis stemming in part from the antifungal activity of B-1 B cells.