Something Old, Something New: Ion Channel Blockers as Potential Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a challenging global health concern and claims more than a million lives every year. We lack an effective vaccine and understanding of what constitutes protective immunity against TB to inform rational vaccine design. Moreover, treatment of TB requires prolonged use of multi-drug regimens and is complicated by problems of compliance and drug resistance. While most Mycobacterium tuberculosis (Mtb) bacilli are quickly killed by the drugs, the prolonged course of treatment is required to clear persistent drug-tolerant subpopulations. Mtb's differential sensitivity to drugs is, at least in part, determined by the interaction between the bacilli and different host macrophage populations. Therefore, to design better treatment regimens for TB, we need to understand and modulate the heterogeneity and divergent responses that Mtb bacilli exhibit within macrophages. However, developing drugs de-novo is a long and expensive process. An alternative approach to expedite the development of new TB treatments is to repurpose existing drugs that were developed for other therapeutic purposes if they also possess anti-tuberculosis activity. There is growing interest in the use of immune modulators to supplement current anti-TB drugs by enhancing the host's antimycobacterial responses. Ion channel blocking agents are among the most promising of the host-directed therapeutics. Some ion channel blockers also interfere with the activity of mycobacterial efflux pumps. In this review, we discuss some of the ion channel blockers that have shown promise as potential anti-TB agents.

Single cell analysis of M. tuberculosis phenotype and macrophage lineages in the infected lung.

In this study, we detail a novel approach that combines bacterial fitness fluorescent reporter strains with scRNA-seq to simultaneously acquire the host transcriptome, surface marker expression, and bacterial phenotype for each infected cell. This approach facilitates the dissection of the functional heterogeneity of M. tuberculosis-infected alveolar (AMs) and interstitial macrophages (IMs) in vivo. We identify clusters of pro-inflammatory AMs associated with stressed bacteria, in addition to three different populations of IMs with heterogeneous bacterial phenotypes. Finally, we show that the main macrophage populations in the lung are epigenetically constrained in their response to infection, while inter-species comparison reveals that most AMs subsets are conserved between mice and humans. This conceptual approach is readily transferable to other infectious disease agents with the potential for an increased understanding of the roles that different host cell populations play during the course of an infection.

New management approaches to tuberculosis in people living with HIV.

PURPOSE OF REVIEW: People living with HIV (PLWH) are commonly coinfected with Mycobacterium tuberculosis, particularly in high-transmission resource-limited regions. Despite expanded access to antiretroviral therapy and tuberculosis (TB) treatment, TB remains the leading cause of death among PLWH. This review discusses recent advances in the management of TB in PLWH and examines emerging therapeutic approaches to improve outcomes of HIV-associated TB. RECENT FINDINGS: Three recent key developments have transformed the management of HIV-associated TB. First, the scaling-up of rapid point-of-care urine-based tests for screening and diagnosis of TB in PLWH has facilitated early case detection and treatment. Second, increasing the availability of potent new and repurposed drugs to treat drug-resistant TB has generated optimism about the treatment and outcome of multidrug-resistant and extensively drug-resistant TB. Third, expanded access to the integrase inhibitor dolutegravir to treat HIV in resource-limited regions has simplified the management of TB/HIV coinfected patients and minimized serious adverse events. SUMMARY: While it is unequivocal that substantial progress has been made in early detection and treatment of HIV-associated TB, significant therapeutic challenges persist. To optimize the management and outcomes of TB in HIV, therapeutic approaches that target the pathogen as well as enhance the host response should be explored.

Kinetics of Mycobacterium tuberculosis-specific IFN-γ responses and sputum bacillary clearance in HIV-infected adults during treatment of pulmonary tuberculosis.

In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings.