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

Abstract

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.