IFN-gamma mediated inflammatory monocyte recruitment neutralizes iNOS-dependent parasite killing by expanding the permissive host cell reservoir during early Leishmania amazonensis infection

Abstract

Abstract IFN-γ is a key factor in the elimination of intracellular parasites. However, during early L. amazonensis infection IFN-γ production does not correlate with a reduction in parasite growth and IFN-γ−/− mice do not have enhanced parasite loads. The reason why IFN-γ production does not reduce parasite loads during early L.a. infection is controversial. In order to investigate the role of IFN-γ during early L.a. infection we infected C57BL/6 Wt and IFN-γ−/− mice with 104 RFP+ parasites in the ear and followed disease for 6 wks. IFN-γ−/− mice showed equivalent lesion sizes and parasite numbers compared to Wt mice for the first 4 wks p.i., despite higher expression of the putative disease promoting factors IL-4 and arginase I. IFN-γ−/− mice had no CD11b+iNOS+ phagocytes while iNOS production was detected as early as 2 wks p.i. in Wt mice. Interestingly, Wt mice had higher numbers of inflammatory monocytes per ear during early infection. Inflammatory monocytes represented the majority of total infected cells and parasites within inflammatory monocytes cells were viable. Inflammatory monocytes were a small proportion of CD11b+iNOS+ cells in Wt mice and had significantly reduced levels of IFN-γR versus dendritic cells and macrophages. The enhanced host cell infiltrate observed in Wt mice may counteract the protective role of IFN-γ mediated iNOS expression. This could explain, in part, why IFN-γ production does not lead to a reduction in parasite load during early L. amazonesis infection. We propose IFN-γ plays a dual role, inducing both the expression of iNOS and parasite killing and the recruitment of inflammatory monocytes that support parasite replication during early infection.