C-C motif chemokine receptor 2 drives protective immunity by mediating alveolar macrophage localization in tuberculosis granulomas

Abstract

Abstract C-C motif chemokine receptor 2 (CCR2) axis is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2−/− mice have not been found to be more susceptible to infection with Euro-American lineage 4 strains of Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 clinical Mtb strain, HN878, we show that CCR2−/− mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. Using a novel labeling technique, we show that AMs accumulate early in the airways following Mtb HN878 infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas to mediate protective immunity. RNA-sequencing of sorted airway and non-airway AMs show distinct gene expression profiles, suggesting that upon exit from airways, AMs become classically activated. Furthermore, absence of CCR2+ cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection, increased accumulation of neutrophils, and loss of Mtb control. Interestingly, we provide new evidence that infection with an Mtb strain HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2−/− mice. Together, our data provide novel evidence for a critical protective role for CCR2 in AM localization within the TB granulomas to mediate protective immunity against clinically relevant and emerging Mtb infections.