Histoplasma capsulatum (Hc) is a dimorphic fungal pathogen of worldwide importance that causes a broad spectrum of disease activity. Although the course of infection is mild in most immunocompetent individuals, Hc may produce progressive disseminated infections in individuals immunocompromised by hematologic malignancies, cytotoxic therapy, or in individuals with the acquired immunodeficiency syndrome (AIDS). Infection with Hc is acquired by inhalation of microconidia into the pulmonary alveoli. The conidia convert into the pathogenic yeast phase, and yeasts are phagocytized by alveolar macrophages (AM). Dividing yeasts destroy the AM, and then they are ingested by other AM, and by inflammatory neutrophils and macrophages (M-phi). Repetition of this cycle leads to dissemination of Hc via blood and lymphatics. Maturation of specific cell-mediated immunity (CMI) against Hc activates M-phi to halt yeast proliferation with gradual resolution of the disease process. ? ? Although, dendritic cells (DC) are the most potent antigen-presenting cells (APC) of the immune system, and are critical for the induction of CMI, their role in host defense against fungi has been largely ignored. The overall goal of the proposed research is to understand the biology and biochemistry of the interaction of Hc with DC, and to characterize the role of DC in the induction of protective immunity to Hc. The major objectives of the proposal are: 1) To determine if murine lung DC ingest and restrict the conversion of Hc conidia into yeasts. Specifically we will determine if lung DC phagocytose Hc conidia, determine if recognition is via VLA-5, determine the intracellular fate of conidia, identify the cytokines produced by Hc-infected DC, and determine why Hc is recognized by different receptors on M-phi and DC. 2) To identify the functional correlates for antigen presentation between Hc-infected DC and T cells with respect to T cell proliferation, cytokine production, and the requirement for co-stimulatory molecules, and to determine if DC-Hc-T cell interaction produces cytokines that activate M-phi anti-histoplasma activity. 3) To determine if Hc antigen-pulsed DC confer protective immunity in a murine model of pulmonary histoplasmosis, and to define the immunologic parameters of protective immunity in immunocompetent and immunocompromised mice. The results of these studies should provide significant insight into the pathogenesis of histoplasmosis and aid in the design of novel vaccine strategies for the prevention of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049358-02
Application #
6640168
Study Section
Special Emphasis Panel (ZRG1-BM-2 (01))
Program Officer
Duncan, Rory A
Project Start
2002-06-15
Project End
2007-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$337,659
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Newman, Simon L; Lemen, Wendy; Smulian, Alan G (2011) Dendritic cells restrict the transformation of Histoplasma capsulatum conidia into yeasts. Med Mycol 49:356-64
Hilty, Jeremy; George Smulian, A; Newman, Simon L (2011) Histoplasma capsulatum utilizes siderophores for intracellular iron acquisition in macrophages. Med Mycol 49:633-42
Gomez, Francisco J; Pilcher-Roberts, Robyn; Alborzi, Arash et al. (2008) Histoplasma capsulatum cyclophilin A mediates attachment to dendritic cell VLA-5. J Immunol 181:7106-14
Hilty, Jeremy; Smulian, A George; Newman, Simon L (2008) The Histoplasma capsulatum vacuolar ATPase is required for iron homeostasis, intracellular replication in macrophages and virulence in a murine model of histoplasmosis. Mol Microbiol 70:127-39
Newman, Simon L; Gootee, Lisa; Hilty, Jeremy et al. (2006) Human macrophages do not require phagosome acidification to mediate fungistatic/fungicidal activity against Histoplasma capsulatum. J Immunol 176:1806-13
Gildea, Lucy A; Ciraolo, Georgianne M; Morris, Randal E et al. (2005) Human dendritic cell activity against Histoplasma capsulatum is mediated via phagolysosomal fusion. Infect Immun 73:6803-11