Cell senescence emerges as a hallmark and therapeutic target of chronic intracellular infection.

Abstract

Intracellular pathogens are ideal candidates for modelling the pathophysiology of chronic infection, as they hide within host cells and avoid immune clearance by reshaping cellular fate. This study unveils how the intracellular pathogen Mycobacterium abscessus (Mab) reprograms alveolar macrophages towards a senescent state -a multifaced phenotype marked by proliferative arrest, distinctive morphological shifts, activation of DNA damage signalling cascade, and secretion of senescence-associated secretory phenotype (SASP) factors. Mab-induced DNA damage emerged as the primary driver of senescence, while SASP secretion acts as a molecular broadcaster, propagating secondary senescence in neighbouring, uninfected cells through paracrine signalling. This cascading wave of amplified senescence undermines the tissue microenvironment, turning it into a chronic inflammatory niche that facilitates Mab persistence and immune evasion. By leveraging evidence of chronic infection-induced senescence, we prototyped a therapeutic approach where the senolytic drug Navitoclax selectively eradicated senescent cells and significantly reduced bacterial burden, similarly to antibiotics.