Histoplasma capsulatum is a facultative intracellular parasite of mononuclear phagocytic cells. The behavior of the fungus within resident murine peritoneal macrophages cultured in vitro has been studied as a cellular model of the host-parasite interaction in histoplasmosis. Peritoneal macrophages from mice immunized by sublethal infection restrict the intracellular growth of H. capsulatum. Splenocytes from immune mice activate normal macrophages to suppress the intracellular growth of the fungus. This activation of normal macrophages is mediated by lymphokines found in supernatants from cultures of antigen stimulated immune splenocytes or those from concanavalin-A (ConA) stimulated T cell hybridomas. The lymphokines have no direct effect on H. capsulatum but act by stimulating macrophages to suppress fungal growth. The single most important activator of resident peritoneal macrophages is gamma interferon (IFN-gamma). These observations suggest that macrophages stimulated by INF- gamma play a role in recovery from natural disease or that induced in experimental animals. The overall goal of the proposal is to assess the relative importance of IFN-gamma in the host- parasite interaction in experimental murine histoplasmosis.
The specific aim i s to study the effect of IFN-gamma on Histoplasma- infection in the A/J and C57BL/6 mice, two strain of respectively low and high susceptibility to infection. The study will be conducted by: (i) measuring the levels of IFN-gamma in the two strains during an experimental infection, (ii) observing the effect of injection of recombinant IFN-gamma on the course of infection in the two strains, (iii) measuring the changes in cellular and humoral modulators of immune responsiveness induced by IFN- gamma in the two strains of mice during the course of infection. Candidate modulators will include helper cells, suppressor cells, NK cells, macrophages, and antibody.
| Lane, T E; Wu-Hsieh, B A; Howard, D H (1993) Gamma interferon cooperates with lipopolysaccharide to activate mouse splenic macrophages to an antihistoplasma state. Infect Immun 61:1468-73 |
| Wu-Hsieh, B A; Howard, D H (1992) Intracellular growth inhibition of Histoplasma capsulatum induced in murine macrophages by recombinant gamma interferon is not due to a limitation of the supply of methionine or cysteine to the fungus. Infect Immun 60:698-700 |
| Lane, T E; Wu-Hsieh, B A; Howard, D H (1991) Iron limitation and the gamma interferon-mediated antihistoplasma state of murine macrophages. Infect Immun 59:2274-8 |
| Wu-Hsieh, B (1989) Relative susceptibilities of inbred mouse strains C57BL/6 and A/J to infection with Histoplasma capsulatum. Infect Immun 57:3788-92 |
