Interferon-γ and tumor necrosis factor-α exert their antirickettsial effect via induction of synthesis of nitric oxide

How the host defenses control rickettsiae in the cytosol of nonphagocytic host cells, where they are not exposed to antibodies or phagocytes, has posed a difficult question. Rickettsia conorii infection of a mouse fibroblast cell line was inhibited in a dose-dependent manner by nitrogen oxide synthesized by eukaryotic host cells stimulated by interferon-γ or tumor necrosis factor-α. L-arginine was the source of the nitric oxide as demonstrated by competitive inhibition by N(G)-monomethyl-L-arginine. Nitric oxide synthesis required host cell protein synthesis and had an approximately 48-hour lag phase following cytokine stimulation. At low doses of interferon-γ and tumor necrosis factor-α, which had no detectable response as single agents, dramatic synergistic nitric oxide synthesis and antirickettsial effects were observed.