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

<title>Abstract</title> Intracellular pathogens are ideal candidates for modelling the pathophysiology of chronic infection, as they hide within host cells and avoid conventional immune clearance through a controlled reshaping of cellular fate. This study unveils how the emerging intracellular pathogen Mycobacterium abscessus (Mab) reprograms alveolar macrophages towards a senescent state -a complex 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 underscores a detrimental effect on the tissue microenvironment, potentially turning it into a chronic inflammatory niche that facilitates Mab persistence and immune evasion. By leveraging on the evidence of chronic infection-induced senescence, we prototyped a therapeutic approach where senolytic drugs selectively eradicated senescent cells and significantly reduced bacterial burden, similarly to antibiotics. This work molecularly dissects a previously overlooked axis of chronic infection-triggered senescence, wherein pathogen-induced DNA damage serves as the initiating event for starting the senescence program in host immune cells. More importantly, the results presented here demonstrate that eliminating infected senescent cells constitutes an unprecedented and effective host-directed therapy that can enhance treatment outcomes while bypassing the limitations imposed by rising antimicrobial resistance.