Dexter H. Howard, Ph.D.  Professor, Emeritus  43-268 CHS  310-825-6661  Administrative Support   Room 43-319 CHS  310-206-0240

The intracellular fate of Histoplasma capsulatum.

The zoopathogenic fungus Histoplasma capsulatum is a facultative intracellular parasite of mononuclear phagocytes. In the tissues of an infected host yeast cells of the fungus reside within macrophages where they survive and multiply for a time. In most human cases of histoplasmosis and in those experimental infections designed to be sublethal, infected individuals recover. During the recovery the intracellular replication of H. capsulatum is arrested and the tissues are gradually rid of the fungus. The overall goal of our work is to discover how the intracellular growth of H. capsulatum is terminated within macrophages of a recovering host. Recombinant murine interferon gamma activates normal peritoneal, splenic, and cell-line macrophages to suppress the intracellular growth of the fungus. Definition of effector molecules of this growth suppression has been one of the aims of our work. One such substance is nitric oxide generated by the oxidation of L-arginine. Nitric oxide binds iron and may thereby cause iron-starvation of H. capsulatum in the phagocytic vacuole. Iron acquisition and storage by H. capsulatum are the subjects of our current work.

Lane, T., Wu-Hsieh, B., and Howard, D.H. the antihistoplasma effect of activated mouse splenic macrophages involves the production of reaction nitrogen intermediates. Infect. Immun. 61:1468-1473, 1993.

Nakamura, L.T., Odesa, S., and Howard, D.H. L-arginine is required for macrophage activation to inhibit Histoplasma capsulatum. Infect. Immun. 62:680-694, 1994.

Lane, T.E., Otero, G.C., Wu-Hsieh, B.A., and Howard, D.H. (1994) Expression of inducible nitric oxide synthase by stimulated macrophages correlates with these antihistoplasma activity. Infect. Immun. 62:1478-1479.

Rustchenko, E.P., Howard, D.H., and Sherman, F. (1994) Chromosomal alterations of Candida albicans are associated with gain and loss of assimilating functions. J.Bacteriol. 176:3231-3241.

Villarete, L., Ahmed, R., Howard, H.D., and Wu-Hsieh, B. (1995) Impaired responsiveness to gamma interferons of macrophages infected with lymphocytic choriomeningitis virus, clone 13: Susceptibility to histoplasmos. Infect. Immun. 63:1468-1432.

Romani, L. and Howard, D.H. (1995) Mechanisms of resistance to fungal infections. Curr. Opinion in Immunol. 7:517-523.