Candida albicans yeast cells and hyphae and the surfaces of all other fungi studied to date activate the complement system. The importance of the complement system in host resistance is demonstrated by the markedly increased susceptibility of experimental animals with complement deficiencies to experimental fungal infection. Less well appreciated is the role of naturally occurring antibodies and other putative initiators, e.g., mannan-binding lectin (MBL), in initiation and/or regulation of C3 deposition. Recent studies in the Kozel laboratory found that anti-mannan IgG in normal human serum plays a critical role in C3 deposition on C. albicans via both the classical and alternative pathways. In the absence of this anti- mannan antibody, C3 deposition is profoundly delayed, suggesting that anti-mannan antibody or near initiators of the complement system such as MBL may be critical components in host resistance. The overall hypothesis for this proposal is that naturally occurring antibodies or other initiators found in normal human serum are essential for efficient deposition of C3 on C. albicans. As a corollary to this deposition.
The Specific Aims for the study are: 1) to evaluate the contribution of epitope specificity of anti-mannan antibodies to C3 deposition on C. albicans, 2) to determine the contribution of antibody isotype to C3 deposition via the classical and alternative pathways, 3) to assess the contribution of mannan-binding lectin to activation and binding of C3, and 4) to compare individual sera with high and low C3 deposition activity for the presence of factors that would support C3 deposition. Results of this study will contribute to our understanding of natural host resistance system. An understanding of this system is fundamental to identification of individuals at possible risk for opportunistic Candida infections and the development of immunological means to prevent infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044786-04
Application #
6627882
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
2000-02-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$249,773
Indirect Cost
Name
University of Nevada Reno
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Boxx, Gayle M; Kozel, Thomas R; Nishiya, Casey T et al. (2010) Influence of mannan and glucan on complement activation and C3 binding by Candida albicans. Infect Immun 78:1250-9
Boxx, Gayle M; Nishiya, Casey T; Kozel, Thomas R et al. (2009) Characteristics of Fc-independent human antimannan antibody-mediated alternative pathway initiation of C3 deposition to Candida albicans. Mol Immunol 46:473-80
Lillegard, Joseph B; Sim, Robert B; Thorkildson, Peter et al. (2006) Recognition of Candida albicans by mannan-binding lectin in vitro and in vivo. J Infect Dis 193:1589-97
Kozel, Thomas R; MacGill, Randall S; Percival, Ann et al. (2004) Biological activities of naturally occurring antibodies reactive with Candida albicans mannan. Infect Immun 72:209-18
Netski, Dale; Kozel, Thomas R (2002) Fc-dependent and Fc-independent opsonization of Cryptococcus neoformans by anticapsular monoclonal antibodies: importance of epitope specificity. Infect Immun 70:2812-9
Han, Y; Kozel, T R; Zhang, M X et al. (2001) Complement is essential for protection by an IgM and an IgG3 monoclonal antibody against experimental, hematogenously disseminated candidiasis. J Immunol 167:1550-7