Elimination of senescent cells with senolytic 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 necrotic granuloma lesions unique tocharacteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers including cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-Galactosidase activity, and senescence-associated secretory phenotype (SASP) proteins. These same 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 TNFα- treated and Mtb- infected B6.Sst1S BMDMs. As senescent cells have been postulated shown to be long-lived, non-dividing cells which release tissue damaging signaling molecules, 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)Senolytics should be tested in human clinical trials against TB.