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.

• Authors: Micah D Dunlap, Nicole Howard, Shibali Das, Ninecia Scott, Mushtaq Ahmed, Oliver Prince, Javier Rangel-Moreno, Bruce A Rosa, John Martin, Deepak Kaushal, Gilla Kaplan, Makedonka Mitreva, Ki-Wook Kim, Gwendalyn J Randolph, Shabaana A Khader
• Journal: Mucosal immunology (Mucosal Immunol) Vol. 11 Issue 6 Pg. 1727-1742 (11 2018) ISSN: 1935-3456 [Electronic] United States
• PMID: 30115997 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL2
• Receptors, CCR2

Topics

• Animals
• Cell Movement
• Chemokine CCL2 (metabolism)
• Genetic Predisposition to Disease
• Granuloma (immunology)
• Humans
• Lung (pathology)
• Macrophage Activation (genetics)
• Macrophages (immunology, microbiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mycobacterium tuberculosis (pathogenicity, physiology)
• Receptors, CCR2 (genetics, metabolism)
• Transcriptome
• Tuberculosis (immunology)
• Virulence