Inflammation and tuberculosis: host‐directed therapies

Abstract

Tuberculosis (TB) is an airborne infectious disease that kills almost two million individuals every year. Multidrug‐resistant (MDR) TB is caused by strains of Mycobacterium tuberculosis (M. tb) resistant to isoniazid and rifampin, the backbone of first‐line antitubercular treatment. MDR TB affects an estimated 500 000 new patients annually. Genetic analysis of drug‐resistant MDR‐TB showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. The need for new TB vaccines and faster diagnostics, as well as the development of new drugs, has recently been highlighted. The major problem in terms of current TB research and clinical demands is the increasing number of cases of extensively drug‐resistant and ‘treatment‐refractory’ TB. An emerging scenario of adjunct host‐directed therapies is intended to target pulmonary TB where inflammatory processes can be deleterious and lead to immune exhaustion. ‘Target‐organ‐saving’ strategies may be warranted to prevent damage to infected tissues and achieve focused, clinically relevant and long‐lasting anti‐M. tb cellular immune responses. Candidates for such interventions may be biological agents or already approved drugs that can be ‘re‐purposed’ to interfere with biologically relevant cellular checkpoints. Here, we review current concepts of inflammation in TB disease and discuss candidate pathways for host‐directed therapies to achieve better clinical outcomes.

Frequency of Mycobacterium tuberculosis-specific CD8+ T-cells in the course of anti-tuberculosis treatment

“…40 A similar phenomenon has already been observed in pulmonary TB and leprosy where T-cell activity could be restored with the addition of exogenous interleukin 2 (IL-2). 41 Since pulmonary TB is a disease characterized by a largely TNF-a-driven, tissue-destructive, hyper-inflammatory environment in the lung, 16 the quality of antigen-specific T-cell responses is inevitably perturbed. This has very recently been reconfirmed in patients with active TB who present with a large proportion of TNF-a single-positive CD4+ T-cells in peripheral blood.…”

“…Since the expression of MTB proteins is associated with different stages of MTB growth as well as TB disease, 16 the identification of a broader MTB epitope profile is essential for the discovery of markers associated with active or latent TB infection (LTBI). Half of the MTB epitopes associate with a single MHC class I allele (HLA-A*02:01) out of more than 3000 different alleles described in humans thus far.…”

New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

“…Drugs able to block these pathways represent novel therapeutic options and also reduce the likelihood of the development of resistance, unlike antibiotics (5)(6)(7). Some recent studies utilized such drug-repurposing approaches to identify both novel bactericidal and host-directed drugs as potential therapeutics against pathogens, such as Ebola virus, Borrelia burgdorferi, Coxiella burnetii, and Legionella pneumophila (5,(8)(9)(10).…”

Examining the Causal Link between and Air Pollution, Tuberculosis Type 2 Diabetes Mellitus

“…However strong Th1 responses characterized by inflammatory markers have been identified in patients presenting with severe forms of TB and a non-contained state of infection [26]. As explained, exposure to PM2.5 is associated with an onset of systemic inflammation.…”