: Cryptococcus neoformans is a major fungal pathogen for individuals with impaired immunity, including those with advanced HIV infection, organ transplants, and on immunosuppressive regimens. Furthermore, there is increasing evidence that this fungus can establish latent infection in humans that could have profound consequences for the development of other chronic diseases, including possibly asthma. C. neoformans has several well-characterized virulence factors, among which a polysaccharide capsule is considered to be the most important. The capsule is composed of at least three components known as Glucuronoxylomannan (GXM), galactoxylomannan (GalXM) and highly mannosylated proteins known as mannoproteins. Antibody responses to the capsular GXM elicit protective and non-protective antibodies. Given the seriousness of cryptococcal infections there has been great interest in harnessing humoral immunity for therapy and prevention of disease. A monoclonal antibody (mAb) has completed preliminary clinical studies and continues in development. Immunization with GXM conjugated to protein carriers elicits protective antibodies. The mechanism of antibody action is multifactorial and includes opsonization, modulation of the inflammatory response, and abrogation of GXM release from yeast cells. Remarkably, protective and non- protective mAbs can be distinguished by their ability to affect GXM release and block biofilm formation in vitro. Although much is now known about the mechanism of antibody action in vivo, and in vitro, the molecular nature of the GXM epitopes recognized by protective and non-protective mAbs is unknown. Furthermore, the mechanisms of action of antibodies at the level of the yeast cell that abrogate polysaccharide release are not understood. This application proposes to continue the study of the interaction of antibodies with the capsule of C. neoformans. In contrast to the prior funding cycles when the effort was focused on molecular analysis of the antibody molecule, this proposal refocuses the research program on the polysaccharide antigen and the capsule. In addition to continuing to study antibodies to GXM this application proposes to explore the role of GalXM in capsule structure.
Three specific Aims are proposed: 1) To define the polysaccharide molecular structure(s) that bind protective and non-protective mAbs;2) To determine the mechanism by which protective mAbs prevent GXM release from C. neoformans;3) To determine how GalXM contributes to C. neoformans capsular structure organization and evaluate the efficacy of antibodies to this polysaccharide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AI033142-17S1
Application #
8051963
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2010-04-19
Project End
2012-04-18
Budget Start
2010-04-19
Budget End
2012-04-18
Support Year
17
Fiscal Year
2010
Total Cost
$441,075
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Rizzo, Juliana; Colombo, Ana C; Zamith-Miranda, Daniel et al. (2018) The putative flippase Apt1 is required for intracellular membrane architecture and biosynthesis of polysaccharide and lipids in Cryptococcus neoformans. Biochim Biophys Acta Mol Cell Res 1865:532-541
Casadevall, Arturo (2018) Antibody-based vaccine strategies against intracellular pathogens. Curr Opin Immunol 53:74-80
Jung, Eric H; Meyers, David J; Bosch, Jürgen et al. (2018) Novel Antifungal Compounds Discovered in Medicines for Malaria Venture's Malaria Box. mSphere 3:
Zamith-Miranda, D; Nimrichter, L; Rodrigues, M L et al. (2018) Fungal extracellular vesicles: modulating host-pathogen interactions by both the fungus and the host. Microbes Infect 20:501-504
Goldman, David L; Nieves, Edward; Nakouzi, Antonio et al. (2018) Serum-Mediated Cleavage of Bacillus anthracis Protective Antigen Is a Two-Step Process That Involves a Serum Carboxypeptidase. mSphere 3:
Casadevall, Arturo; Pirofski, Liise-Anne (2018) What Is a Host? Attributes of Individual Susceptibility. Infect Immun 86:
Fu, Man Shun; Casadevall, Arturo (2018) Divalent Metal Cations Potentiate the Predatory Capacity of Amoeba for Cryptococcus neoformans. Appl Environ Microbiol 84:
De Leon-Rodriguez, Carlos M; Rossi, Diego C P; Fu, Man Shun et al. (2018) The Outcome of the Cryptococcus neoformans-Macrophage Interaction Depends on Phagolysosomal Membrane Integrity. J Immunol 201:583-603
Walker, Louise; Sood, Prashant; Lenardon, Megan D et al. (2018) The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles. MBio 9:
De Leon-Rodriguez, Carlos M; Fu, Man Shun; Çorbali, M Osman et al. (2018) The Capsule of Cryptococcus neoformans Modulates Phagosomal pH through Its Acid-Base Properties. mSphere 3:

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