Host and Bacterial Iron Homeostasis, an Underexplored Area in Tuberculosis Biomarker Research

Abstract

Mycobacterium tuberculosis (Mtb) “a human adapted pathogen” has found multiple ways to manipulate the host immune response during infection. The human immune response to Mtb infection is a highly complex cascade of reactions, with macrophages as preferred intracellular location. Interaction with the host through infection gives rise to expression of specific gene products for survival and multiplication within the host. The signals that the pathogens encounter during infection cause them to selectively express genes in response to signals. One strategy to identify Mtb antigens with diagnostic potential is to identify genes that are specifically induced during infection or in specific disease stages. The shortcomings of current immunodiagnostics include the failure to detect progression from latent infection to active tuberculosis disease, and the inability to monitor treatment efficacy. This highlights the need for new tuberculosis biomarkers. These biomarkers should be highly sensitive and specific diagnosing TB infection, specifically distinguishing between latent infection and active disease. The regulation of iron levels by the host plays a crucial role in the susceptibility and outcome of Mtb infection. Of interest are the siderophore biosynthetic genes, encoded by the mbt-1 and mbt-2 loci and the SUF (mobilization of sulphur) operon (sufR-sufB-sufD-sufC-csd-nifU-sufT), which encodes the primary iron-sulphur cluster biogenesis system. These genes are induced during iron limitation and intracellular growth of Mtb, pointing to their importance during infection.

Heme oxygenase-1 modulates ferroptosis by fine-tuning levels of intracellular iron and reactive oxygen species of macrophages in response to Bacillus Calmette-Guerin infection

“…Metabolic interactions between host cells (macrophages) and pathogen (Mtb) significantly affect the host immune responses and the proliferation of pathogen, and the outcome of Mtb infection (Cambier et al, 2014;Olive and Sassetti, 2016). Iron is one of the most important substances essential to the growth of both pathogen and host cells, which is required for the maintenance of macrophage functions, and the survival of intracellular Mtb (Baatjies et al, 2021). Therefore, the competition in the use of iron (Fe 2+ ) source between the macrophages and Mtb may affect the intracellular level of Fe 2+ , and may be critical for the determination of the form of host cell death (necroptosis or apoptosis) and the fate of intracellular pathogens (eliminated or escaped) (Jones and Niederweis, 2011;Mitra et al, 2019;Zhang et al, 2020;Rodriguez et al, 2022).…”

“…In addition to necroptosis and pyroptosis, the two most studied forms of Mtb-induced macrophage necrosis, ferroptosis is another form of programmed cell death (PCD) that is a type of necrosis dependent on iron (Dixon et al, 2012;Amaral et al, 2019). Interestingly, macrophage necrosis induced by Mtb infection shared the typical characteristics of ferroptosis (Shastri et al, 2018;Amaral et al, 2021;Baatjies et al, 2021). In this regard, an external stress such as Mtb infection could elevate intracellular levels of Fe 2+ and reactive oxygen species (ROS) to trigger the Fenton reaction, and result in the production of large amounts of hydroxyl radicals, sequentially impair glutathione peroxidase 4 (GPX4) activity and anti-lipid peroxidation capacity, and ultimately lead to overwhelming lipid peroxidation of intracellular membrane phospholipids and cell disintegration and death (Dixon et al, 2012;Li et al, 2020).…”

Molecular Imaging of Tuberculosis

“…116 Microbes obtain iron from these protein-bound iron by secreting siderophores. 117 Gallium is an iron-mimetic element that binds to transferrin following its intravenous administration. Increased vascular permeability at the site of infection increases the extravascular trafficking of the gallium-transferrin complex to the infection sites where the complex is phagocytosed by macrophages.…”

Advancing personalized medicine for tuberculosis through the application of immune profiling

“…Various host cytokines and chemokines are released once Mtbspecific antigens encounter and stimulate the immune responses of an Mtb-infected individual (Baatjies et al, 2021). The intricate relationship between Mtb and the immune system is attributed to the production of various cytokines in response to Mtb infection (Etna et al, 2014) which could restrict bacterial growth and modulate inflammatory responses that contribute to the development of TB (Bai et al, 2018).…”