Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

Abstract

Infection with Mycobacterium tuberculosis (Mtb) leading to tuberculosis (TB) disease continues to be a major global health challenge. Critical barriers, including but not limited to the development of multi-drug resistance, lack of diagnostic assays that detect patients with latent TB, an effective vaccine that prevents Mtb infection, and infectious and non-infectious comorbidities that complicate active TB, continue to hinder progress toward a TB cure. To complement the ongoing development of new antimicrobial drugs, investigators in the field are exploring the value of host-directed therapies (HDTs). This therapeutic strategy targets the host, rather than Mtb, and is intended to augment host responses to infection such that the host is better equipped to prevent or clear infection and resolve chronic inflammation. Metabolic pathways of immune cells have been identified as promising HDT targets as more metabolites and metabolic pathways have shown to play a role in TB pathogenesis and disease progression. Specifically, this review highlights the potential role of lactate as both an immunomodulatory metabolite and a potentially important signaling molecule during the host response to Mtb infection. While long thought to be an inert end product of primarily glucose metabolism, the cancer research field has discovered the importance of lactate in carcinogenesis and resistance to chemotherapeutic drug treatment. Herein, we discuss similarities between the TB granuloma and tumor microenvironments in the context of lactate metabolism and identify key metabolic and signaling pathways that have been shown to play a role in tumor progression but have yet to be explored within the context of TB. Ultimately, lactate metabolism and signaling could be viable HDT targets for TB; however, critical additional research is needed to better understand the role of lactate at the host-pathogen interface during Mtb infection before adopting this HDT strategy.

Characterization of Proteins Regulated by Androgen and Protein Kinase a Signaling in VCaP Prostate Cancer Cells

“…LDHB is found at the highest densities in mitochondria; and, in normoxic cells, mitochondrial LDHB converts lactate to pyruvate. This lactate-derived pyruvate can then be used as fuel for the TCA cycle, oxidative phosphorylation, and mitochondrial respiration [68,69].…”

Lactate cross-talk in host–pathogen interactions

“…The observed discrepancies may be explained by strain and/or culture conditions differences [27]. The TB granuloma and the tumour microenvironment share relevant similarities such as nutrients and oxygen gradients potentially leading to hypoxia (a driver of anaerobic glycolysis and lactate release) and nutrient scarcity in certain regions [118][119][120]. As discussed previously, lung tissue from M.tb infected hosts present evidence of high glycolytic rates and lactate production.…”

Lactate-Dependent Regulation of Immune Responses by Dendritic Cells and Macrophages

“…The TME contains higher levels of immune regulatory factors such as IL-10, retinoic acid (RA), and TGF-β that actively suppress differentiation and expansion of tumor-specific effector T cells ( 114 , 115 ). Lactate in the TME condition DCs and macrophages to a regulatory or anti-inflammatory state ( 1 , 2 ). Accordingly, tumor DCs deficient in the lactate receptor GPR81 expressed markedly higher levels of IL-12 and IL-6 ( 32 ).…”

“…Furthermore, blocking GPR81 signaling can restore the IFNα production by pDCs. Lactate in the TME conditions DCs and macrophages to express higher levels of IL-10 ( 1 , 2 ). The effects of lactate on the expression of the regulatory and inflammatory cytokines in APCs also depend on MCTs.…”