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Rising rates of Histoplasma capsulatum infection are an emerging problem among the rapidly growing population of immune-compromised individuals. Although there is a growing understanding of systemic immunity against Histoplasma, little is known about the local granulomatous response, which is an important component in the control of infection. The focus of this article is the characterization of Histoplasma-induced granulomas. Five days after i.p. infection, infected macrophage appear in the liver and lung; however, no granulomas are apparent. Two days later, well-formed sarcoid granulomas are abundant in the lung and liver of infected mice, which contain all visible Histoplasma. Granulomas are dominated by macrophage and lymphocytes. Most of the Histoplasma and most of the apoptotic cells are found in the center of the lesions. We isolated liver granulomas at multiple time points after infection and analyzed the cellular composition, TCR gene usage, and cytokine production of granuloma-infiltrating cells. The lesions contain both CD4+ and CD8+ T cell subsets, and T cells are the primary source of IFN-γ and IL-17. The main source of local TNF-α is macrophage. Chemokines are produced by both infiltrating macrophage and lymphocytes. Dendritic cells are present in granulomas; however, T cell expansion seems to occur systemically because TCR usage is very heterogeneous even at the level of individual lesions. This study is the first direct examination of host cellular responses in the Histoplasma-induced granuloma representing the specific interface between host and pathogen. Our studies will allow further analysis of key elements of host Histoplasma interactions at the site of chronic infection.

WI-1 is a 120-kDa surface protein adhesin on Blastomyces dermatitidis yeasts that binds CD18 and CD14 receptors on human macrophages. We isolated and analyzed a clone of genomic WI-1 to characterize this key adherence mechanism of the yeast.

Recent studies of the dimorphic fungal pathogens Histoplasma capsulatum and Paracoccidioides brasiliensis have suggested a role in virulence for the cell surface carbohydrate a-(1,3)-glucan. To investigate a possible basis for a-(1,3)-glucan in the pathogenicity and virulence of the dimorphic fungus Blastomyces dermatitidis, we examined three genetically related strains of B. dermatitidis that differ in their virulence for mice: wild-type virulent strain ATCC 26199; mutant strain ATCC 60915, which is 10,000-fold reduced in virulence; and mutant strain ATCC 60916, which is avirulent. Immunologic quantitation of cell wall a-(1,3)-glucan revealed that the mutant yeasts were almost devoid of this sugar moiety, in contrast to the high concentration of a-(1,3)-glucan on the cell wall of the wild-type yeasts. These differences are discussed in relation to previous studies of yeast surface expression of the WI-i antigen and recognition and binding of the related strains by human monocyte-derived macrophages.