Macrophage immunometabolism in the host response to Mycobacterium tuberculosis infection

Abstract

Tuberculosis (TB) is the leading infectious disease killer in the world, alongside HIV. Our understanding of the complex host immune response to Mycobacterium tuberculosis (Mtb) remains incomplete, but varied clinical outcomes of infection seen in humans (ranging from death to complete asymptomatic clearance of the bug) suggest that understanding host defence mechanisms may provide new insights and novel approaches to vaccine and treatment development. Integral to the host immune response to infection is the tissue-resident alveolar macrophage (AM), capable of early eradication of the bacillus but, conversely, vulnerable to subversion by the bacillus to be used as a nidus for survival and replication. Specifically, the pro-inflammatory cytokine Interleukin-1? (IL-1?) is essential for its mycobactericidal activity. Recent work in the burgeoning field of immunometabolism has linked TLR-induced changes in intracellular macrophage glucose metabolism ? namely, a shift towards aerobic glycolysis, known as the Warburg effect ? to production of IL-1?. Thus, in this body of work we investigate the metabolic impact of Mtb infection on human macrophage glucose metabolism and examine downstream functional effects of infection-induced metabolic alterations. The results presented in this body of work offer new insights into the metabolic characteristics of primary human monocyte-derived macrophages (MDM) and primary human AM. We demonstrate infection-induced glycolytic reprogramming in human and murine macrophages, mediated through TLR2/6 signalling. We find glycolytic reprogramming to be essential for optimal production of IL1B mRNA at a transcriptional level, with consequent secretion of mature IL-1?. This glycolysis-driven increase in IL-1? leads to upregulation of the eicosanoid Prostaglandin E2 (PGE2) and suppression of the anti-inflammatory cytokine Interleukin-10 (IL-10), with ultimate enhancement of macrophage mycobactericidal activity in both human and murine macrophages. We further demonstrate a similar requirement for glycolytic reprogramming in Salmonella typhimurium-infected murine macrophages. Pharmacological augmentation of glycolysis using meclizine dihydrochloride enhanced early bacillary clearance by human MDM, suggesting this newly delineated pathway of host defence may warrant exploration in the search for host-directed therapies for TB disease. Finally, we demonstrate reduced baseline metabolic activity and reduced metabolic reserves in macrophages exposed to cigarette smoke. Smoke-exposed macrophages had an attenuated metabolic response to Mtb infection, concurrent with impaired production of IL-1? and PGE2. This work demonstrates for the first time a functional role for glycolytic reprogramming in the context of host defence. This novel mechanism of the anti-mycobacterial macrophage response may be targeted for the development of new therapies and vaccines to combat this global pathogen, particularly given our observation of pharmacological manipulation of glycolytic metabolism enhancing macrophage mycobactericidal activity. Experiments with S. typhi also suggest that this metabolic/immune axis is not specific to mycobacterial infection, thus exploration of this pathway may yield insights that can combat many infectious diseases. Impairments in metabolic responses in smoke-exposed macrophages may partly explain the increased susceptibility to infection observed in the smoking population, and possibly highlighting this group as one which may particularly benefit from metabolism-targeted host-directed therapies in the future.