Histoplasma capsulatum is an important endemic, intracellular fungal pathogen that can cause life threatening disseminated disease, particularly in individuals with impaired immunity. Despite the use of potent anti-fungal medications significant morbidity and mortality from histoplasmosis continues to occur, and current treatment regimens frequently fail to eradicate the organism in immuno-compromised individuals, particularly those with AIDS. Recent data from intracellular pathogens (i.e. Mycobacterium tuberculosis, Listeria monocytogenes) and other fungi (i.e. Cryptococcus neoformans, Candida albicans) demonstrates that specific antibody can improve the ability of the host to combat these infecting microbes. I have identified three murine monoclonal antibodies (mAb) that bind to the H. capsulatum yeast cell surface. Administration of the mAbs reduced fungal burden, decreased pulmonary inflammation, and prolonged survival in a murine infection model. MAb treatment was associated with enhanced production of lL-4, IL-6, and IFN- in the lungs of infected mice. The mAbs increased phagocytosis of yeast by macrophage via interactions dependent on CR3. Growth of mAb-opsonized H. capsulatum was inhibited after ingestion and killing of intracellular fungus occurred. The H. capsulatum-binding mAbs interact with a histone-like protein (histone H2B) expressed on the cell surface of the fungus. The goals of this application are to define the mechanism of antibody action against this fungus, to characterize the protective epitope on the antigen, and to use the protein in the generation of new mAbs and in vaccine development.
Four specific Aims are proposed: 1. To map the epitope of mAb 9C7 and generate additional mAbs to H. capsulatum. 2. To investigate the mechanism(s) of antibody-mediated protection against H. capsulatum in vivo. 3. To investigate the mechanism(s) of antibody-mediated protection against H. capsulatum in vitro. 4. To determine the efficacy of the histone H2B and the mAb 9C7 epitope as vaccines. These studies are expected to lead to insights into H. capsulatum pathogenesis and initiate the development of new therapeutic and diagnostic reagents.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
GuimarĂ£es, Allan J; de Cerqueira, Mariana Duarte; Zamith-Miranda, Daniel et al. (2018) Host membrane glycosphingolipids and lipid microdomains facilitate Histoplasma capsulatum internalisation by macrophages. Cell Microbiol :e12976
Qin, Min; Landriscina, Angelo; Rosen, Jamie M et al. (2015) Nitric Oxide-Releasing Nanoparticles Prevent Propionibacterium acnes-Induced Inflammation by Both Clearing the Organism and Inhibiting Microbial Stimulation of the Innate Immune Response. J Invest Dermatol 135:2723-2731
Youngchim, Sirida; Pornsuwan, Soraya; Nosanchuk, Joshua D et al. (2011) Melanogenesis in dermatophyte species in vitro and during infection. Microbiology 157:2348-56
Martinez, Luis R; Mihu, Mircea Radu; Tar, Moses et al. (2010) Demonstration of antibiofilm and antifungal efficacy of chitosan against candidal biofilms, using an in vivo central venous catheter model. J Infect Dis 201:1436-40
Lopes, Livia Cristina Liporagi; Guimaraes, Allan J; de Cerqueira, Mariana Duarte et al. (2010) A histoplasma capsulatum-specific IgG1 isotype monoclonal antibody, H1C, to a 70-kilodalton cell surface protein is not protective in murine histoplasmosis. Clin Vaccine Immunol 17:1155-8
Fabrizio, Kevin; Manix, Catherine; Guimaraes, Allan J et al. (2010) Aggregation of Streptococcus pneumoniae by a pneumococcal capsular polysaccharide-specific human monoclonal IgM correlates with antibody efficacy in vivo. Clin Vaccine Immunol 17:713-21
GuimarĂ£es, Allan Jefferson; Pizzini, Claudia Vera; De Abreu Almeida, Marcos et al. (2010) Evaluation of an enzyme-linked immunosorbent assay using purified, deglycosylated histoplasmin for different clinical manifestations of histoplasmosis. Microbiol Res (Pavia) 1:
Oliveira, Debora L; Nakayasu, Ernesto S; Joffe, Luna S et al. (2010) Characterization of yeast extracellular vesicles: evidence for the participation of different pathways of cellular traffic in vesicle biogenesis. PLoS One 5:e11113
Muniz, Mauro de Medeiros; Morais E Silva Tavares, Patricia; Meyer, Wieland et al. (2010) Comparison of different DNA-based methods for molecular typing of Histoplasma capsulatum. Appl Environ Microbiol 76:4438-47
Lopes, Livia C L; Rollin-Pinheiro, Rodrigo; Guimaraes, Allan J et al. (2010) Monoclonal antibodies against peptidorhamnomannans of Scedosporium apiospermum enhance the pathogenicity of the fungus. PLoS Negl Trop Dis 4:e853

Showing the most recent 10 out of 40 publications