Effects of host‐directed therapies on the pathology of tuberculosis

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has co-evolved with the human immune system and utilizes multiple strategies to persist within infected cells, to hijack several immune mechanisms, and to cause severe pathology and tissue damage in the host. This delays the efficacy of current antibiotic therapy and contributes to the evolution of multi-drug-resistant strains. These challenges led to the development of the novel approach in TB treatment that involves therapeutic targeting of host immune response to control disease pathogenesis and pathogen growth, namely, host-directed therapies (HDTs). Such HDT approaches can (1) enhance the effect of antibiotics, (2) shorten treatment duration for any clinical form of TB, (3) promote development of immunological memory that could protect against relapse, and (4) ameliorate the immunopathology including matrix destruction and fibrosis associated with TB. In this review we discuss TB-HDT candidates shown to be of clinical relevance that thus could be developed to reduce pathology, tissue damage, and subsequent impairment of pulmonary function.

P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis

“…This emerging scenario has encouraged the combined use of standard anti-microbial treatments for TB with host-directed therapies based on anti-inflammatory interventions. This therapeutic approach directly targets the inflammatory response triggered by the infection to prevent and repair tissue damage, promote pathogen elimination and reduce disease sequelae ( Kaufmann et al., 2014 ; Zumla et al., 2016 ; Tsenova and Singhal, 2020 ). Accelerating the patient healing and reducing the adverse effects of anti-microbial drugs are both desirable outcomes of adjunctive therapies ( Hawn et al., 2013 ; Tobin, 2015 ).…”

Inhibition of Fatty Acid Oxidation Promotes Macrophage Control of Mycobacterium tuberculosis

“…In the context of antimicrobial therapy, HDTs would need to be used in combination with directly acting antimicrobials, where their addition might contribute to treatment-shortening regimens. While the in vivo effects of FAO inhibition were modest during Mtb infection, they occurred at drug concentrations that are used clinically and were on par with other host-directed approaches, such as those taking an autophagy-based strategy, which are currently being evaluated in clinical trials (21,22,(63)(64)(65). The effect in mice will reflect that impact of impairing FAO in a variety of cell types, and addressing this complexity, as well as their activity in combination with directly acting antimicrobials, is an area for future investigation.…”

Recent Advances in Pathology: the 2020 Annual Review Issue of The Journal of Pathology

“…They emphasise recent data on HDT with already available drugs such as metformin, statins, corticosteroids, imatinib, inhibitors of phosphodiesterase or indolamine dioxygenase, and the gastric proton-pump inhibitor, lansoprazole. They conclude that HDT is a promising line of approach, tailored to the individual's lesions and their immune status [12]. The third review in this section comes from Bill McBride and Dörthe Schaue on the damaging effects of ionising radiation and the subsequent tissue responses.…”