Chronic mycobacteria infection triggers macrophage senescence

Abstract

Chronic infections with intracellular pathogens such as Mycobacterium abscessus (Mab) pose significant health challenges due to their capacity to persist within host cells and evade immune responses. This study investigates the cellular responses to chronic Mab infection in macrophages, particularly focusing on cellular senescence. Using an in vitro model of chronic infection in murine alveolar-like macrophages, we found that Mab induces a senescent phenotype characterised by decreased proliferation, altered morphology, DNA damage signalling activation, and upregulation of senescence markers such as p21 and SA-{beta}-galactosidase. Intriguingly, senescent macrophages secreted pro-inflammatory cytokines, consistent with a senescence-associated secretory phenotype (SASP), which promoted secondary senescence in neighbouring uninfected cells. This paracrine transmission of senescence underscores a potentially deleterious effect of Mab-induced SASP on tissue microenvironments, fostering a pro-inflammatory niche that may contribute to pathogen persistence. These findings highlight Mab-induced senescence as a key factor in chronic infection pathology, suggesting that targeting senescent cells and SASP-related pathways could enhance treatment outcomes in chronic bacterial infections.