Impaired responsiveness to gamma interferon of macrophages infected with lymphocytic choriomeningitis virus clone 13: Susceptibility to histoplasmosis

Abstract

Lymphocytic choriomeningitis virus clone 13 (LCMV clone 13), a variant isolated from the spleens of neonatally infected mice, causes persistent infections in mice infected as adults. Such persistently infected mice succumb to a normally sublethal dose of Histoplasma capsulatum, and their macrophages contain overwhelming numbers of yeast cells of the fungus. Both LCMV clone 13 and H. capsulatum yeast cells target and replicate in macrophages of the host. We sought to study the effects of LCMV clone 13 on the ability of macrophages to control growth of H. capsulatum in vitro. We show that the growth of H. capsulatum within macrophages was not directly affected by the presence of LCMV clone 13. However, macrophages containing LCMV clone 13 did not respond fully to gamma interferon (IFN-γ) stimulation. Such unresponsiveness resulted in proliferation of the fungus within macrophages cultured in the presence of IFN-γ. The addition of anti-IFN- α/β antibodies to LCMV clone 13-infected macrophage cultures restored macrophage responsiveness to IFN-γ. These results indicate that production of IFN-α/β by LCMV clone 13-infected macrophages antagonizes their responsiveness to IFN-γ. Such antagonism may be one of the mechanisms by means of which certain viruses cause immune suppression and susceptibility to opportunistic infections.