Interleukin-6 signaling, lung injury, and post-TB lung disease in TB-HIV

ABSTRACT Tuberculosis (TB) is among the leading infectious killers worldwide with over 10 million new cases and 1.5 million deaths each year. Pulmonary TB, the most common form of the disease, is associated with lung injury that can persist beyond treatment completion. Post-TB lung disease (PTLD) is an important contributor to excess disability and mortality that can affect an estimated 155 million TB survivors globally. Yet there are no known interventions to prevent TB-associated lung injury and the likelihood of subsequent PTLD. The goal of this R01 proposal is to characterize the burden, severity, and phenotypic presentation of PTLD, and its association with interleukin-6 (IL-6) signaling pathways, in TB patients with and without HIV. We will leverage the ongoing NIH and Indian Government funded RePORT-India TB Research Consortium, a multi-site study that is prospectively evaluating HIV-uninfected adults with drug-sensitive TB for lung injury during and after TB treatment, by enrolling a comparison cohort of HIV-positive drug-sensitive TB patients matched on age, sex, and smoking exposure who will follow identical study protocols. Through Aim-1, we will extensively characterize and compare the phenotypic differences in lung injury at TB treatment initiation, its resolution during treatment, and subsequent PTLD between TB patients with versus without HIV using a multi-dimensional approach of pulmonary function testing, respiratory health and functional status assessments, and novel lung imaging approaches. Through Aim- 2, we will use induced sputum samples to comprehensively investigate the role of different IL-6 signaling pathways in determining the extent of lung injury, and its resolution during TB treatment, by measuring key immune, cellular, and gene expression markers, along with downstream inflammatory pathways linked to acute lung injury and fibrotic remodeling. This R01 application will expand upon our prior and ongoing research in India and generate evidence to support the design of clinical trials of host-directed therapies for selectively modulating IL-6 signaling pathways to improve pulmonary outcomes in TB patients with and without HIV.