Elimination of senescent cells with senolytic drugs as adjunctive host-directed therapy reduces tuberculosis progression in mice

By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis (Mtb) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb-infected B6.Sst1S macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Adjunctive senolytic drug treatment in presence of anti-tuberculosis (TB) therapy prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung pathology and senescence markers. These findings indicate that (1) Mtb infection induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against TB. Infection with Mycobacterium tuberculosis can induce lung necrosis. Here, Shee et al. describe a build-up of senescent cells in infected mouse lungs, and show that adjunctive treatment with host-directed senolytic drugs enhances the efficacy of anti-tuberculosis therapy in mice