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.
Highlights
Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent worldwide, with 10 million new cases and 1.2 million deaths due to tuberculosis (TB) disease in 2018 alone according to the most recent World Health Organization (WHO) Global Tuberculosis Report (WHO | Global tuberculosis report, 2019)
In Mtb infection, shifts to glycolytic metabolism are observed within macrophages leading to increased lactate production (Qualls and Murray, 2015; Shi et al, 2015; Gleeson et al, 2016; Osada-Oka et al, 2019; Shi et al, 2019) and high lactate concentrations are observable within granuloma lesions, reaching levels comparable to tumors (Somashekar et al, 2011; Somashekar et al, 2012)
Increased glycolysis and lactate production by macrophages within the granuloma may serve to promote an Mtb survival niche, as lactate contributes to immune evasion and immunosuppression in the tumor microenvironment
Summary
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. Lactate metabolism and signaling could be viable HDT targets for TB; 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
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