Type I IFN Protects Permissive Macrophages fromLegionella pneumophilaInfection 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.

Interferon‐Gamma Reverses the Evasion of Birc1e/Naip5 Gene Mediated Murine Macrophage Immunity by Legionella pneumophila Mutant Lacking Flagellin

“…IL-12p40 secretion from the infected macrophages was similar at all time points in both infection groups. Schiavoni et al (31) reported that aged C57BL/6 macrophages are equally permissive for the intracellular growth of Legionella as fresh A/J macrophages, because of their reduced production of type I IFNs. However, we found no difference in the production of type I IFNs in C57BL/6 macrophages regardless of the infective strain, contradicting the contribution of type I IFNs on restriction of Legionella replication in infected macrophages.…”

“…IL-12p40 was produced at significant level and there was no difference in the amounts of IL-12p40 produced by macrophages infected with the flaA mutant bacteria compared to those cells infected with the parent Corby strain (data not shown). Recent work revealed that type I IFNs is important for resistance to Legionella infection in murine macrophages (31). Therefore, IFN-α and -β were determined in supernatant of either the parental strain or the flaA mutant infected macrophages, which revealed that type 1 IFNs production was minimal (data not shown).…”

NAIP and Ipaf Control Legionella pneumophila Replication in Human Cells

“…On the other hand, full innate intracellular resistance to L. pneumophila (and certainly other intracellular bacteria) depends on many additional mechanisms such as types I and II IFN-as well as TNF-␣-mediated effects, and perhaps also on Nramp1, antimicrobial peptides, or immunity-related GTPases (13,15,(45)(46)(47)(48)(49)(50). It might thus be conceivable that in case of L. pneumophila infection, one of these last mentioned resistance mechanisms is less functional in human cells compared with mice resulting in an overall stronger replication of Legionella in human cells compared with, for example, C57BL/6 macrophages despite functional hNAIP and hIpaf.…”

Type I IFNs Enhance Susceptibility toChlamydia muridarumLung Infection by Enhancing Apoptosis of Local Macrophages

“…Studies on Legionella pneumonphila (11), Salmonella typhimurium (12), Shigella flexneri (13), Bacillus anthrasis (14) and Mycobacterium bovis bacillus Calmette-Guérin (15) showed that IFNIs are protective for host, at least partially through enhancing IFN-␥/NO production and suppressing bacterial invasion. In contrast, some studies have shown that IFNIs are detrimental, especially in certain bacterial infections.…”