Modulating Iron for Metabolic Support of TB Host Defense

Abstract

Tuberculosis (TB) is the world's biggest infectious disease killer. The increasing prevalence of multidrug-resistant and extensively drug-resistant TB demonstrates that current treatments are inadequate and there is an urgent need for novel therapies. Research is now focused on the development of host-directed therapies (HDTs) which can be used in combination with existing antimicrobials, with a special focus on promoting host defense. Immunometabolic reprogramming is integral to TB host defense, therefore, understanding and supporting the immunometabolic pathways that are altered after infection will be important for the development of new HDTs. Moreover, TB pathophysiology is interconnected with iron metabolism. Iron is essential for the survival of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB disease. Mtb struggles to replicate and persist in low iron environments. Iron chelation has therefore been suggested as a HDT. In addition to its direct effects on iron availability, iron chelators modulate immunometabolism through the stabilization of HIF1α. This review examines immunometabolism in the context of Mtb and its links to iron metabolism. We suggest that iron chelation, and subsequent stabilization of HIF1α, will have multifaceted effects on immunometabolic function and holds potential to be utilized as a HDT to boost the host immune response to Mtb infection.

Desferrioxamine Supports Metabolic Function in Primary Human Macrophages Infected With Mycobacterium tuberculosis

“…Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death by a single infectious agent worldwide, killing approximately 1.7 million individuals in 2018 (1,2). The rise in bacterial resistance to antimicrobial treatment has increased morbidity and mortality among affected patients globally.…”

“…HDT predominantly aims to diminish damaging inflammation, however, in early bacterial infections, HDT may enhance antimicrobial properties of infected host immune cells to perturb the dissemination, progression and development of active disease (4)(5)(6)(7). As immunometabolic reprogramming is integral to host defense during bacterial infection, supporting these bioenergetic pathways through the use of HDTs may offer alternative therapeutic approaches (1). A shift from oxidative phosphorylation (OXPHOS) to glycolysis has been observed upon infection with Mtb (8,9).…”

“…HIF1α is a crucial molecular mediator during Mtb infection (14)(15)(16). Importantly, HIF1α is central to reprogramming metabolism toward using aerobic glycolysis and participates in the induction of glycolysis during Mtb infection (1,14). The stabilization and activity of HIF1α is regulated by the family of prolyl hydroxylase domain (PHD) proteins (17).…”

“…PHD proteins require iron, α-ketoglutarate (αKG), oxygen and ascorbate in order to inhibit HIF1α. Therefore, the regulation of HIF1α by PHD proteins is tightly coupled with iron availability (1,18). We previously hypothesized that therapeutic chelation of iron may inhibit PHD protein activity and promote HIF1α stabilization (1).…”

“…Therefore, the regulation of HIF1α by PHD proteins is tightly coupled with iron availability (1,18). We previously hypothesized that therapeutic chelation of iron may inhibit PHD protein activity and promote HIF1α stabilization (1). This stabilization of HIF1α may in turn support infected host cells through enhanced glycolysis and increased effector functions.…”