Telomere length and outcome of treatment for pulmonary tuberculosis in a gold mining community

Abstract

Telomere length (TL) is a marker of ageing and mitochondrial DNA (mtDNA) is an early marker of inflammation caused by oxidative stress. We determined TL and mtDNA content among active pulmonary tuberculosis (PTB) patients to assess if these cellular biomarkers differed between artisanal miners and non-miners, and to assess if they were predictive of treatment outcome. We conducted a prospective cohort study from August 2018 to May 2019 involving newly diagnosed PTB patients at three outpatient TB clinics in a rural Democratic Republic of Congo. We measured relative TL and mtDNA content in peripheral blood leukocytes (at inclusion) via qPCR and assessed their association with PTB treatment outcome. We included 129 patients (85 miners and 44 non-miners) with PTB (median age 40 years; range 5-71 years, 22% HIV-coinfected). For each increase in year and HIV-coinfection, TL shortened by − 0.85% (− 0.19 to − 0.52) (p ≤ 0.0001) and − 14% (− 28.22 to − 1.79) (p = 0.02) respectively. Independent of these covariates, patients with longer TL were more likely to have successful TB treatment [adjusted hazard ratio; 95% CI 1.27 for a doubling of leucocyte telomere length at baseline; 1.05-1.44] than patients with a shorter TL. Blood mtDNA content was not predictive for PTB outcome. For a given chronological age, PTB patients with longer telomeres at time of diagnosis were more likely to have successful PTB treatment outcome. Pulmonary tuberculosis (PTB) kills almost 2 million individuals every year and is thus a leading cause of death among adults worldwide. Mycobacterium tuberculosis (Mtb) infects more than 10 million people each year 1-3. Mtb potently induces cytokines and chemokines from polymorphonuclear cells and monocytes, thus resulting in intense local inflammation in the lungs 4. Alveolar macrophages are anti-inflammatory in nature, but their function can be impaired by pollutants, including mineral dusts, thereby diminishing the body's ability to clear infections 5-8. This is probably why mineworkers are more susceptible to develop PTB. Telomere length (TL) reflects the history of oxidative stress and chronic inflammation, and is a marker for age-related disease susceptibility 9-12. In normal physiology, mitochondria are important in the cell as they generate most of the adenosine triphosphate (ATP) through the oxidative phosphorylation mechanism (OXPHOS), which is a critical energy supply for cellular processes and partially encoded with mitochondrial DNA (mtDNA). The OXPHOS mechanism uses dietary intake to produce ATP, but it also produces ROS which can destroy mitochon-drial DNA, impairs respiratory chain function and cause nuclear DNA damage 12-14. Further, Mitochondrial DNA (mtDNA) damage can result in genomic instability, cellular senescence and altered intercellular communication. Hallmarks of aging genomic instability and deregulated nutrient sensing can contribute to reduced mitochondrial OPEN