Role of Oxidative Stress in the Pathology and Management of Human Tuberculosis.

Gregory M. Peterson,Philip M. Hansbro,Madhur D. Shastri,Wai Chin Chong,Rajaraman Eri,Ronan F. O’Toole,Shakti Dhar Shukla,Kamal Dua,Rahul P. Patel

doi:10.1155/2018/7695364

Abstract

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis, is the leading cause of mortality worldwide due to a single infectious agent. The pathogen spreads primarily via aerosols and especially infects the alveolar macrophages in the lungs. The lung has evolved various biological mechanisms, including oxidative stress (OS) responses, to counteract TB infection. M. tuberculosis infection triggers the generation of reactive oxygen species by host phagocytic cells (primarily macrophages). The development of resistance to commonly prescribed antibiotics poses a challenge to treat TB; this commonly manifests as multidrug resistant tuberculosis (MDR-TB). OS and antioxidant defense mechanisms play key roles during TB infection and treatment. For instance, several established first-/second-line antitubercle antibiotics are administered in an inactive form and subsequently transformed into their active form by components of the OS responses of both host (nitric oxide, S-oxidation) and pathogen (catalase/peroxidase enzyme, EthA). Additionally, M. tuberculosis has developed mechanisms to survive high OS burden in the host, including the increased bacterial NADH/NAD+ ratio and enhanced intracellular survival (Eis) protein, peroxiredoxin, superoxide dismutases, and catalases. Here, we review the interplay between lung OS and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes. We then outline potential new therapies that are based on combining standard antitubercular antibiotics with adjuvant agents that could limit the ability of M. tuberculosis to counter the host's OS response.

Highlights

Introduction to TuberculosisTuberculosis (TB) is the leading cause of mortality worldwide due to a single infectious agent, killing approximately 1.67 million people in 2016 alone [1, 2]
We review the interplay between lung oxidative stress (OS) and its effects on both activation of antitubercle antibiotics and the strategies employed by M. tuberculosis that are essential for survival of both drug-susceptible and drug-resistant bacterial subtypes
Oxidative stress mediated by host cells, especially macrophages, plays a pivotal role to prevent the vicious cycle of M. tuberculosis

Summary

Introduction to Tuberculosis

Tuberculosis (TB) is the leading cause of mortality worldwide due to a single infectious agent, killing approximately 1.67 million people in 2016 alone [1, 2]. The World Health Organization (WHO) has set End TB Strategy targets to reduce global TB mortality by 95% and the incidence of TB by 90% to less than 10 cases per 100,000 by 2035, with respect to 2015 levels [3] While industrialised countries such as Australia are considered to have a low TB burden (incidence rate of 5.7/100,000 nationally in 2014 [4]), the WHO has established specific targets for low TB incidence countries for the pre-elimination of TB by 2035 (defined as

Pathogenesis of Tuberculosis

Effect of Oxidative Stress on the Lungs

Oxidative Stress Response against Mycobacterium tuberculosis Infection

Chemotherapy of Tuberculosis

Role of Oxidative Processes in the Activation of TB Prodrugs

Potential New TB Therapies Targeting the Oxidant : Antioxidant Balance

Findings

Conclusions