Cryptococcosis is a major cause of mortality in patients with AIDS, causing over 600,000 deaths per year worldwide. In recent years, cryptococcosis has also emerged as a major problem among organ transplant recipients. The treatment of cryptococcosis is unsatisfactory since the disease is associated with a high morbidity and mortality even following treatment with antifungal drugs. There is an acute need for new approaches to treatment in these populations at risk. Passive antibody therapy is a particularly promising approach. This competing application proposes a research plan to investigate a new problem in immunology, which has direct relevance to the development of antibody therapy for C. neoformans-related diseases, passive antibody therapies in general and our understanding of humoral immunity. In the past funding period, we have established that the constant region (C) domain of an immunoglobulin can affect the specificity of the antibody by a mechanism that is proposed to involve structural changes in the antigen-binding site. This finding challenges the long-held dogma in immunology that viewed immunoglobulin molecules as bifunctional molecules with two independent domains, composed of a C region and a variable (V) region. Our findings challenge this dogma, and in doing so suggest a need for revisions to our views on idiotype regulation, isotype restriction, generation of antibody responses, and generation of diversity in antibody repertories. At a practical level, these findings are critically important for the design and development of chimeric and humanized antibodies for human therapy and impact our analysis of vaccine responses. The research program proposes four aims: 1) To determine the structures and antigen contact residues for V-region identical Fab fragments derived from IgG1, IgG2a, IgG2b and IgG3;2) To identify the amino acid that mediate isotype-related differences in specificity among Abs with identical V regions;3) To establish whether constant region-mediated changes in specificity extend to IgM, IgE and IgA isotypes;and 4) Construction of a second-generation mouse-human chimeric Ab suitable for human trials. At the completion of these studies we will know how the C region affects V region conformation to influence affinity, specificity, and idiotype and we will have improved immunoglobulins to C. neoformans glucuronoxylomannan suitable for subsequent clinical studies.
Antibodies are molecules that are critically important for defending against pathogenic microbes. This research proposal proposes to investigate how the structure of antibodies vary among different antibody types and how to then use this information to make better therapeutic reagents for treatment of a very serious fungal infection that affects individuals with compromised immune systems.
|Pirofski, Liise-Anne; Casadevall, Arturo (2017) Immune-Mediated Damage Completes the Parabola: Cryptococcus neoformans Pathogenesis Can Reflect the Outcome of a Weak or Strong Immune Response. MBio 8:|
|Stukes, Sabriya; Coelho, Carolina; Rivera, Johanna et al. (2016) The Membrane Phospholipid Binding Protein Annexin A2 Promotes Phagocytosis and Nonlytic Exocytosis of Cryptococcus neoformans and Impacts Survival in Fungal Infection. J Immunol 197:1252-61|
|Prados-Rosales, Rafael; Carreño, Leandro J; Weinrick, Brian et al. (2016) The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis. J Infect Dis 214:426-37|
|DeLeon-Rodriguez, Carlos M; Casadevall, Arturo (2016) Cryptococcus neoformans: Tripping on Acid in the Phagolysosome. Front Microbiol 7:164|
|Bowen, Anthony; Casadevall, Arturo (2016) Revisiting the Immunoglobulin Intramolecular Signaling Hypothesis. Trends Immunol 37:721-723|
|Cordero, Radames J B; Liedke, Susie Coutinho; de S Araújo, Glauber R et al. (2016) Enhanced virulence of Histoplasma capsulatum through transfer and surface incorporation of glycans from Cryptococcus neoformans during co-infection. Sci Rep 6:21765|
|Zolla, Valerio; Nizamutdinova, Irina Tsoy; Scharf, Brian et al. (2015) Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance. Aging Cell 14:582-94|
|Robert, Vincent; Cardinali, Gianluigi; Casadevall, Arturo (2015) Distribution and impact of yeast thermal tolerance permissive for mammalian infection. BMC Biol 13:18|
|Achkar, Jacqueline M; Chan, John; Casadevall, Arturo (2015) B cells and antibodies in the defense against Mycobacterium tuberculosis infection. Immunol Rev 264:167-81|
|Pirofski, Liise-anne; Casadevall, Arturo (2015) What is infectiveness and how is it involved in infection and immunity? BMC Immunol 16:13|
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