Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

Abstract

Mycobacterial diseases are a major public health challenge. Their causative agents include, in order of impact, members of the Mycobacterium tuberculosis complex (causing tuberculosis), Mycobacterium leprae (causing leprosy), and non-tuberculous mycobacterial pathogens including Mycobacterium ulcerans. Macrophages are mycobacterial targets and they play an essential role in the host immune response to mycobacteria. This review aims to provide a comprehensive understanding of the immune-metabolic adaptations of the macrophage to mycobacterial infections. This metabolic rewiring involves changes in glycolysis and oxidative metabolism, as well as in the use of fatty acids and that of metals such as iron, zinc and copper. The macrophage metabolic adaptations result in changes in intracellular metabolites, which can post-translationally modify proteins including histones, with potential for shaping the epigenetic landscape. This review will also cover how critical tuberculosis co-morbidities such as smoking, diabetes and HIV infection shape host metabolic responses and impact disease outcome. Finally, we will explore how the immune-metabolic knowledge gained in the last decades can be harnessed towards the design of novel diagnostic and therapeutic tools, as well as vaccines.

Clinical Characteristics and Mortality of Non-tuberculous Mycobacterial Infection in Immunocompromised vs. Immunocompetent Hosts

“…Non-tuberculous mycobacteria (NTM) include all species of mycobacteria except for M. tuberculosis and M. leprae and they are ubiquitous microorganisms that have an environmental origin. There are over 200 species of NTM identified to date, but only a few are pathogenic to susceptible hosts and are generally grouped with other opportunistic pathogens ( 1 , 2 ). The incidence and prevalence of NTM disease are increasing in some countries and regions, even surpassing the incidence and prevalence of tuberculosis ( 3 – 6 ).…”

Concurrent infections of cells by two pathogens can enable a reactivation of the first pathogen and the second pathogen's accelerated T-cell exhaustion

“…One conservative estimate is that worldwide, two billion people are latently infected with M. tuberculosis , ten million people are diagnosed with active or reactivated M. tuberculosis (TB) each year and it's yearly mortality world-wide is 1.5 million deaths [ 7 ]. HIV-induced impairment of innate immune system macrophages and monocytes also promotes active and reactivated TB infections in M. tuberculosis infected individuals [ 7 ]. Individuals concurrently infected with HIV and TB have a greatly elevated risk (estimated to be at least 16X and perhaps as high as 27X) of reactivating TB relative to individuals without HIV [ 7 ].…”

Proteomics in Biomarker Discovery for Tuberculosis: Current Status and Future Perspectives

“…Upon Mtb infection, the host cells’ response is to produce and secrete certain effectors to deal with the invading bacteria ( Dey and Bishai, 2014 ; Brites and Gagneux, 2015 ; Llibre et al, 2021 ). Blood is the primary vehicle for the transport of either host effectors or Mtb factors and is usually routinely sampled for clinical testing, making blood samples readily accessible for research purposes and diagnostic tests.…”