A novel role for C–C motif chemokine receptor 2 during infection with hypervirulent Mycobacterium tuberculosis

Abstract

C-C motif chemokine receptor 2 (CCR2) is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2 mice have not been found to be susceptible to infection with Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 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. We show that AMs accumulate early in the airways following infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas. RNA-sequencing of sorted airway and non-airway AMs from infected mice show distinct gene expression profiles, suggesting that upon exit from airways and localization within granulomas, AMs become classically activated. The absence of CCR2 cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection. Furthermore, infection with an Mtb HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2 mice. Together, these data show a novel role for CCR2 in protective immunity against clinically relevant Mtb infections.

The Rate of CD4 T Cell Entry into the Lungs during Mycobacterium tuberculosis Infection Is Determined by Partial and Opposing Effects of Multiple Chemokine Receptors

“…KLRG1 Ϫ I-A b ESAT-6 4 -17 -specific CD4 T cells displayed a slight defect in localization into the parenchyma (93% for WT cells versus 89% for CXCR6-deficient cells), indicating that CXCR6 is largely dispensable for T cell migration into the lung parenchyma during M. tuberculosis infection. Mice deficient in CCR2 are susceptible to high-dose intravenous infection with M. tuberculosis H37Rv (18,19) or low-level infection with the hypervirulent strain HN878 (20), but in both of these settings, this seems to be due to defective myeloid cell migration. CCR2-KO mice do not display the enhanced susceptibility to low-dose M. tuberculosis H37Rv infection (21).…”

S100A8/A9 regulates CD11b expression and neutrophil recruitment during chronic tuberculosis

“…Cell populations were gated based on their forward by side scatter characteristics, and the frequency of specific cell types was analyzed using FlowJo, version 7.6.5 (Tree Star Inc.). Lung AMs were gated as CD11c + CD11b -, lung myeloid DCs were gated on CD11c + CD11b + , neutrophils were gated as CD11b + Gr-1 hi , RMs were annotated as CD11b + Gr-1 lo , and monocytes were gated on CD11b + Gr1 int cells as in Dunlap et al (43).…”

Thinking Outside the Box: Innate- and B Cell-Memory Responses as Novel Protective Mechanisms Against Tuberculosis

“…Furthermore, although trained AMs contribute to the clearance of other respiratory pathogens (51), recent findings suggest that AMs are indeed more permissive than blood-derived monocytes to sustain the intracellular growth of Mtb (55). This contrasts with other data showing that CCR2+ AMs induce protective responses against Mtb (29). Therefore, it is likely that different subpopulations of AMs with variable bactericidal capacity against Mtb exist, mirroring M1 and M2 macrophages.…”

“…Precursors of alveolar macrophages (AMs) from the yolk sac infiltrate the alveolar epithelium during fetal development, maintaining themselves through a self-renewal process independent of circulating monocytes (28). These phagocytes eliminate infectious agents that reach the lumen of distal airways, including Mtb (29). On the other hand, monocytederived macrophages migrate to the lung interstitium to participate in the elimination of pathogens, as well as in antigen presentation, and the recruitment of other leukocytes during inflammation (30).…”

“…AMs are among the first cells of the host immune system to encounter Mtb. After engulfing the bacillus, they leave the airways and initiate a cascade of inflammatory signals that will lead to the recruitment of more leukocytes around the sites of Mtb exposure (29). Over time, infiltrating leukocytes form structures called "granulomas" where different subtypes of phagocytes interact with the bacillus (31).…”