Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection

Abstract

HIF-1 induces LDH to decrease pyruvate in Mtb-infected macrophages

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy

“…Causally linking the two, treatment of BMDMs with the glucose uptake inhibitor 2-deoxyglucose (2-DG) abrogated the reduction in bacillary burden conferred by IFN-γ. This mechanistic analysis was supported by in vivo studies showing that whole-body HIF-1α −/− mice are more susceptible to TB (Braverman et al, 2016 ), and this was later enhanced by two studies showing that myeloid-specific conditional HIF-1α knockout mice are also more susceptible to TB (Osada-Oka et al, 2019 ; Resende et al, 2020 ). One of these studies also indicated that the transcription of lactate dehydrogenase A was controlled by HIF-1α in Mtb infected BMDMs independent of INF-γ, and demonstrate that HIF-1α reduces the pyruvate levels in the macrophages, which is used as a preferable source for intracellular Mtb replication over glucose (Osada-Oka et al, 2019 ).…”

“…This mechanistic analysis was supported by in vivo studies showing that whole-body HIF-1α −/− mice are more susceptible to TB (Braverman et al, 2016 ), and this was later enhanced by two studies showing that myeloid-specific conditional HIF-1α knockout mice are also more susceptible to TB (Osada-Oka et al, 2019 ; Resende et al, 2020 ). One of these studies also indicated that the transcription of lactate dehydrogenase A was controlled by HIF-1α in Mtb infected BMDMs independent of INF-γ, and demonstrate that HIF-1α reduces the pyruvate levels in the macrophages, which is used as a preferable source for intracellular Mtb replication over glucose (Osada-Oka et al, 2019 ). However, this study supports previous findings (Braverman et al, 2016 ) that the treatment of BMDMs with IFN-γ induces a greater increase in the secreted lactate levels and further reduces the bacillary loads than that observed in untreated BMDMs (Osada-Oka et al, 2019 ).…”

“…One of these studies also indicated that the transcription of lactate dehydrogenase A was controlled by HIF-1α in Mtb infected BMDMs independent of INF-γ, and demonstrate that HIF-1α reduces the pyruvate levels in the macrophages, which is used as a preferable source for intracellular Mtb replication over glucose (Osada-Oka et al, 2019 ). However, this study supports previous findings (Braverman et al, 2016 ) that the treatment of BMDMs with IFN-γ induces a greater increase in the secreted lactate levels and further reduces the bacillary loads than that observed in untreated BMDMs (Osada-Oka et al, 2019 ).…”

“…Inhibitors of LDH, such as sodium oxamate ( Figure 1 ), can be used to selectively decelerate glycolysis (Lustig and Redman, 1980 ). Another approach taken by Osada-Oka et al ( 2019 ), was to generate LDHA-deficient RAW264.7 cells that were impaired in their ability to control Mtb infection. While this is an immortalized, murine cell line that is relatively disconnected from humans, it provides an important validation that aerobic glycolysis is important in the anti- Mtb effector functions of macrophages.…”

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

“…In this respect, apart from host immune cells using their metabolism to initiate host defense responses, also pathogens are able to exploit these host metabolic pathways for their own benefit. On the one hand, they tap into these pathways to acquire nutrients and macromolecules that directly promote their own survival and replication [8][9][10][11][12][13][14][15]. On the other hand, it is now becoming clear that pathogens also manipulate metabolic pathways of host innate immune cells, to modulate, dampen, or evade the immune responses to further enhance their chances of survival.…”