Type I IFN Protects Permissive Macrophages from Legionella pneumophila Infection through an IFN-γ-Independent Pathway

Abstract

Legionella pneumophila is an intracellular pathogen whose replication in macrophages is mainly controlled by IFN-γ. Freshly isolated peritoneal macrophages elicited in vivo with thioglycolate (TG) from A/J mice are highly permissive to L. pneumophila growth in vitro, while TG-elicited macrophages from CD1 mice are resistant. In this study, we show that when CD1 TG-macrophages are cultured for 7 days, they become permissive to Legionella infection. We demonstrate that treatment with type I IFN (IFN-αβ) totally inhibits the growth of L. pneumophila in both freshly isolated A/J and in vitro-aged CD1 TG-macrophages. IFN-αβ protective effect on permissive macrophages was comparable to that induced by IFN-γ. Even low doses of either IFN-α or IFN-β alone were effective in inhibiting L. pneumophila multiplication in macrophage cultures. Notably, treatment of resistant, freshly isolated CD1 TG-macrophages with Ab to mouse IFN-αβ significantly enhanced their susceptibility to Legionella infection in vitro, thus implying a role of endogenous IFN-αβ in mediating the natural resistance of macrophages to L. pneumophila infection. Finally, addition of anti-IFN-γ-neutralizing Ab did not restore Legionella growth in IFN-α- or IFN-β-treated A/J or CD1 permissive macrophages, indicating that IFN-αβ effect was not mediated by IFN-γ. This observation was further confirmed by the finding that IFN-αβ was effective in inhibiting L. pneumophila replication in macrophages from IFN-γ receptor-deficient mice. Taken together, our results provide the first evidence for a role of IFN-αβ in the control of L. pneumophila infection in mouse models of susceptible macrophages and suggest the existence of different pathways for the control of intracellular bacteria in macrophages.