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Characterization of the Histoplasma capsulatum-Induced Granuloma¹

Erika Heninger^*, Laura H. Hogan^*, Jozsef Karman, Sinarack Macvilay^*, Bjork Hill^*, Jon P. Woods^2, and Matyas Sandor^2,3,*,

^* Department of Pathology and Laboratory Medicine, Cellular and Molecular Pathology Graduate Program, and Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI 53706

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- and IL-17. The main source of local TNF- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was funded by National Institutes of Health Grants R01 AI48087 (to M.S.), R01 AI52303 (to J.P.W), R01 HL55949 (to J.P.W.), and R37 AI42747 (J.P.W. subcontract on award to George S. Deepe, Jr.).

² J.P.W. and M.S. are co-senior authors of this study.

³ Address correspondence and reprint requests to Dr. Matyas Sandor, Department of Pathology and Laboratory Medicine, University of Wisconsin, 5460 MSC, 1300 University Avenue, Madison, WI 53706. E-mail address: msandor{at}wisc.edu

⁴ Abbreviations used in this paper: HMM, Histoplasma-macrophage medium; GMS, Gomori’s methenamine silver; MFI: mean fluorescence intensity; cRPMI, complete RPMI.

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