The ability of the HIV-associated fungal pathogen Histoplasma capsulatum (Hc) to cause severe invasive disease is attributed to the fungus' ability to efficiently subvert host responses. For example, the capacity of the fungus to impair phagosome maturation and the presence of melanin in the fungal cell wall contribute to intracellular survival through avoidance of host surveillance as well as blocking the effects of host effector responses. We have shown that Hc produces extracellular vesicles containing biologically active molecules. However, many questions on disease pathogenesis arise from this process of vesiculogenesis. In the first Aim, we will explore how protective and non-protective antibodies (Abs) regulate the production and release of extracellular vesicles from Hc. We are pursuing this work based on our findings that protective Abs to Hc alter gene expression and that cross-linking by Abs changes the outcome of interactions with host effector cells. Using a pair of protective and non-protective monoclonal antibodies (mAbs) that bind to the same region on heat shock protein 60 expressed on the Hc cell surface, we will determine (Aim 1) the mAbs' capacity to alter the formation and secretion of these bilayered vesicles as well as (Aim 2) their impact on the protein and lipid cargo within the vesicles. We are pursuing this work based on our observations that the vesicles can alter the behavior of host cells and that the cargo within the vesicles includes compounds that are immunomodulatory. The results of the studies in this R21 will provide new insights into the basic biology of Hc, elucidate new activities of Abs, and serve as a potential foundation for new therapeutic approaches to combat this important fungus as well as other eukaryotic pathogens.

Public Health Relevance

The HIV-related pathogen Histoplasma capsulatum is an important cause of death. In this work, we will determine whether antibodies targeting the fungus have the capacity to alter the production of extracellular vesicles that carry diverse compounds toxic to host cells. The results will provide new insights into basic fungal biology, reveal new activities of antibody, and serve as a foundation for new treatment approaches against this and other pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI124797-02
Application #
9220715
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Love, Dona
Project Start
2016-02-15
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
2
Fiscal Year
2017
Total Cost
$242,911
Indirect Cost
$58,960
Name
Albert Einstein College of Medicine, Inc
Department
Type
Domestic Higher Education
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Cleare, Levi G; Zamith-Miranda, Daniel; Nosanchuk, Joshua D (2017) Heat Shock Proteins in Histoplasma and Paracoccidioides. Clin Vaccine Immunol 24:
Liedke, Susie Coutinho; Miranda, Daniel Zamith; Gomes, Kamilla Xavier et al. (2017) Characterization of the antifungal functions of a WGA-Fc (IgG2a) fusion protein binding to cell wall chitin oligomers. Sci Rep 7:12187
Nimrichter, Leonardo; de Souza, Marcio M; Del Poeta, Maurizio et al. (2016) Extracellular Vesicle-Associated Transitory Cell Wall Components and Their Impact on the Interaction of Fungi with Host Cells. Front Microbiol 7:1034
Matos Baltazar, Ludmila; Nakayasu, Ernesto S; Sobreira, Tiago J P et al. (2016) Antibody Binding Alters the Characteristics and Contents of Extracellular Vesicles Released by Histoplasma capsulatum. mSphere 1: