Elimination of senescent cells with senolytic 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 {gamma}H2A.X, senescence-associated {beta}-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 activation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb-infected B6.Sst1S macrophages. As senescent cells are long-lived, non-dividing cells that release tissue-damaging SASP, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Senolytic drug treatment 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 senescence markers. These findings indicate that (1) Mtb infection may induce lung myeloid cells to enter a senescent state and that these cells play a causal role in disease progression, and (2) Senolytics merit consideration for human clinical trials against tuberculosis (TB).