No abstract

Recent advances in immunometabolism link metabolic changes in stimulated macrophages to production of IL-1β, a crucial cytokine in the innate immune response to Mycobacterium tuberculosis. To investigate this pathway in the host response to M. tuberculosis, we performed metabolic and functional studies on human alveolar macrophages, human monocyte-derived macrophages, and murine bone marrow–derived macrophages following infection with the bacillus in vitro. M. tuberculosis infection induced a shift from oxidative phosphorylation to aerobic glycolysis in macrophages. Inhibition of this shift resulted in decreased levels of proinflammatory IL-1β and decreased transcription of PTGS2, increased levels of anti-inflammatory IL-10, and increased intracellular bacillary survival. Blockade or absence of IL-1R negated the impact of aerobic glycolysis on intracellular bacillary survival, demonstrating that infection-induced glycolysis limits M. tuberculosis survival in macrophages through induction of IL-1β. Drugs that manipulate host metabolism may be exploited as adjuvants for future therapeutic and vaccination strategies.

Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of G(alphai)-PI3K-AKT and G(alphai)-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process.

Successful phagolysosomal maturation is an important innate immune response to intracellular infection. However, Mycobacterium tuberculosis (Mtb) can manipulate and inhibit this host response to ensure survival within its niche cell. We investigate the role of the anti-inflammatory cytokine IL-10 on Mtb-phagosome maturation. Blocking IL-10, which was secreted from Mtb-infected macrophages, allowed phagosome maturation to proceed. Macrophage cytokine gene expression profiles were not significantly altered by blocking IL-10 3 hours after infection with Mtb. We demonstrate that IL-10 can regulate this protective phenotype in phorbol myristate acetate (PMA)-treated THP-1 cells, monocyte-derived macrophages (MDMs), and human alveolar macrophages (AMs) infected with Mtb. The regulatory effect of endogenous IL-10 was evident in macrophages infected with virulent Mtb H37Rv, as well as in attenuated strains of mycobacteria. Unlike live Mtb, dead bacilli occupy a mature, acidic phagosome. However, the addition of IL-10 to cells infected with killed Mtb successfully inhibited the maturation of this compartment. Importantly, we demonstrate that the addition of IL-10 to MDMs results in enhanced mycobacterial survival and growth. Our results suggest that IL-10 exerts its effects on this early macrophage response in a partly signal transducer and activator of transcription 3 (STAT3)-dependent manner, and independent of mitogen activated protein kinase p38 (MAPKp38) and extracellular regulated kinase 1/2 (ERK1/2) activity. IL-10 is a feature of human tuberculous granuloma, and these new findings support the hypothesis that this cytokine can promote pathogen persistence by contributing to Mtb-phagosome maturation arrest in human macrophages.