Abstract
To understand how infection by Mycobacterium tuberculosis (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Using fluorescent Mtb reporter strains, we found that bacilli in AM exhibited lower stress and higher bacterial replication than those in IM. Interestingly, depletion of AM reduced bacterial burden, whereas depletion of IM increased bacterial burden. Transcriptomic analysis revealed that IMs were glycolytically active, whereas AMs were committed to fatty acid oxidation. Intoxication of infected mice with the glycolytic inhibitor, 2-deoxyglucose, decreased the number of IMs yet increased the bacterial burden in the lung. Furthermore, in in vitro macrophage infections, 2-deoxyglucose treatment increased bacterial growth, whereas the fatty acid oxidation inhibitor etomoxir constrained bacterial growth. We hypothesize that different macrophage lineages respond divergently to Mtb infection, with IMs exhibiting nutritional restriction and controlling bacterial growth and AMs representing a more nutritionally permissive environment.
Highlights
Under homeostatic conditions, macrophages derived from different ontogenies coexist in many tissues
Mycobacterium tuberculosis (Mtb) infection induces accumulation of lung interstitial macrophage (IM) We chose to focus on a 2-wk time point because (1) it is a period of rapid bacterial expansion, (2) the bacteria are relatively distributed between the alveolar macrophage (AM) and IM populations, and (3) the early innate immune response is well established (North and Jung, 2004)
Glycolysis and fatty acid oxidation pathways in macrophages differentially control the growth of Mtb Lastly, to establish a functional linkage between host macrophage metabolism and bacterial growth, we examined the impact of the metabolic inhibitors 2-DG and etomoxir (ETO; fatty acid oxidation) on the growth of Mtb in murine bone marrow– derived macrophages (BMDMs)
Summary
Macrophages derived from different ontogenies coexist in many tissues In these situations, it is unclear the extent to which macrophage origin versus its tissue location and immune environment determines phagocyte phenotype and function. Some studies suggest that macrophages of different origins can exhibit both redundant and distinct functions in the same tissue in nondisease settings (Epelman et al, 2014; Gibbings et al, 2015; van de Laar et al, 2016). These data indicate that both tissue niche and cell origin contribute significantly to macrophage function at steady state. Several studies using phenotypic markers to define IMs through expression of the integrins CD11c and CD11b have indicated these cells are recruited during Mtb infection (Srivastava et al, 2014)
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