A senolytic drug already in clinical development for oncology sharply reduced bacterial burden in preclinical models of notoriously treatment-resistant Mycobacterium abscessus infection by eliminating senescent host macrophages rather than targeting the pathogen directly, according to research published August 18 in Nature Communications. The findings identify cellular senescence as a disease-promoting host response in chronic intracellular infection and raise the prospect of host-directed therapies that operate independently of conventional antimicrobial resistance mechanisms.
The work was led by corresponding authors Edoardo Scarpa and Loris Rizzello at the National Institute of Molecular Genetics "Romeo and Enrica Invernizzi" (INGM) and the University of Milan's Department of Pharmaceutical Sciences, in collaboration with the Emerging Bacterial Pathogens Unit at IRCCS San Raffaele Scientific Institute and other Italian institutions.
Senescence as a bacterial refuge
Mycobacterium abscessus (Mab), a nontuberculous mycobacterium that causes chronic pulmonary disease, is intrinsically resistant to many antibiotics and notoriously difficult to eradicate. The researchers found that chronic intracellular Mab infection drives murine alveolar-like macrophages into a stable senescent state through pathogen-induced DNA damage.
The effect required live, replicating bacteria: propiolactone-fixed Mab failed to induce comparable markers of DNA double-strand breaks. Bulk RNA sequencing and reanalysis of spatial transcriptomics data from infected mouse lung tissue further showed transcriptome-wide upregulation of senescence-associated gene programs and their spatial enrichment in infected regions.
Infected senescent macrophages also developed a senescence-associated secretory phenotype (SASP), characterized by factors including TNF-α, IL-6, IL-1α, and matrix metalloproteinases. Conditioned-media experiments showed that these secreted factors were sufficient to induce senescence in naïve, uninfected neighboring cells.
The effect was also evident spatially: approximately 85.7% of uninfected cells within 60 µm of Mab-positive cells were positive for senescence-associated β-galactosidase (SA-β-gal). The resulting SASP environment increased the permissiveness of neighboring cells to subsequent Mab infection, suggesting that infection-induced senescence may help create and expand a cellular niche favorable to bacterial persistence. Key findings were also validated in human monocyte-derived macrophages from healthy donors.
Senolytic treatment reduces bacterial burden
The researchers next tested navitoclax (ABT-263), an inhibitor of the anti-apoptotic proteins BCL-2, BCL-XL, and BCL-W with established senolytic activity. Senescent cells can become dependent on these survival pathways, making them particularly susceptible to apoptosis following navitoclax treatment.
In chronically infected macrophages, navitoclax produced an approximately 2.3 log10 reduction in intracellular colony-forming units (CFUs) across at least seven biological replicates, an effect comparable in magnitude to the standard-of-care antibiotic clarithromycin. Importantly, navitoclax did not increase extracellular bacterial counts, suggesting that apoptotic elimination of infected senescent cells did not simply release viable Mab into the surrounding environment.
The effect extended to an in vivo model. In C57BL/6N mice with chronic respiratory Mab infection, oral navitoclax at 50 mg/kg/day reduced pulmonary bacterial burden compared with vehicle control, with the experiment independently repeated twice.