PotM - September 2026
Scarpa E., Oliveri D., Rondelli D., et al., Nature Communications 2026
Brief Summary
We started from a very simple question: What happens to an innate immune cell that hosts a pathogen for a long time? While chronic infections are tipically studied from the side of the bacterium, we decided to focus our looking glass on the host cell instead.Using Mycobacterium abscessus as a model pathogen, as it hides and replicates inside alveolar macrophages for long time while resisting most antibiotics, we found that prolonged intracellular infection pushes macrophages into senescence. The cells stay alive and start secreting a strong inflammatory cocktail (SASP). We were able to find the original molecular event triggering the senescence process in the DNA damage, caused by the live bacteria inside the cell. The secreted SASP spreads senescence to nearby healthy macrophages, making them more infection-permissive. We think the pathogen exploits this to create a protective niche for proliferation. We then used the senolytic drug navitoclax to remove these host cells instead of antibiotics, leading to a significant reduction in bacterial burden in cell models and infected mice. This offers a new approach to treating chronic intracellular infections, which matters in a time of rising antimicrobial resistance.
Interview to the corresponding authors Dr . Edoardo Scarpa (University of Milan, INGM) & Prof Loris Rizzello (University of Milan, INGM)
What is the potential impact of this work?
Loris Rizzello, senior author: Mycobacterium abscessus is one of the most difficult pathogens to treat today. It is intrinsically resistant to most antibiotics, and it has a second line of defence that is often underestimated. It lives inside host cells, and many antibiotics do not reach an intracellular compartment at useful concentrations. The bacterium survives because it is protected by both its own intrinsic resistance and by the cell hosting it. The consequences are most severe for people with cystic fibrosis, where a chronic M. abscessus infection can be a reason to be excluded from lung transplantation. For these patients there is no reliable option at the moment.The high impact of this work is that it removes that second layer of protection. Instead of trying to reach a bacterium that hides inside a cell, we directly eliminate the cell itself. From the point of view of the pathogen there is no escape, because the strategy does not depend on drug penetration and it is not affected by antibiotic resistance, which is a property of the bacterium and not of the host. It could also be combined with existing antibiotics rather than replacing them, and be useful precisely in the situations where antibiotic therapy alone does not clear the infection.More generally, this opens a line of research on chronic intracellular infections that respond poorly to antimicrobial therapy. Several other pathogens survive inside host cells for long periods, and the same principle could be tested there. In a context of increasing antimicrobial resistance, a strategy that does not depend on the pathogen itself is a real advantage.
What question does this paper open for the future?
The first question is about the biological meaning of cell senescence during an infection. It is not clear whether we are looking at a host response that the pathogen tolerates, or at a state that the pathogen actively induces for its own benefit. This is not trivial as it will give an answer whether senescence should be either prevented, exploited or eradicated (and timing also could play a role on the decision making process).The second question is whether senescent macrophages are more permissive to infection. In that case the pathogen may shape the tissue in a way that favours its persistence. Chronic inflammation and senescence would then be part of a more complex strategy for infection. The third question is more general. Several other pathogens persist inside host cells for long periods. It will be extremely interesting to test whether what we observed is a conserved mechanism/behaviour. If so, senescence would represent a common “background” of many chronic intracellular infections.Finally, there is the clinical question. Senolytic drugs were developed for ageing and cancer, and moving them into infectious disease raises practical problems of timing, dosing and safety. When to treat, for how long, and in which patients are all unresolved. The link with ageing is also worth pursuing, since senescent cells accumulate over time and may contribute to the higher susceptibility to infection that we see in older people.
What does ICSA represent to you, and how does this paper connect with the ICSA community?
Edoardo Scarpa: To us, ICSA represents an open and generous scientific community. We came to senescence from infection biology and felt welcomed from the very beginning, when this project was still just an idea. What stood out was the willingness to share ideas, tools and expertise, and to support researchers approaching senescence from a different field. The community’s shared criteria and guidelines helped us build confidence that what we were observing in our macrophages was indeed senescence. Our paper reflects that exchange: it brings senescence into chronic bacterial infection, a context where its role has been relatively unexplored, and shows how concepts developed in ageing and cancer can help us understand persistent infections. People from the ICSA community offered advice and encouragement throughout this journey. For us, that is what makes ICSA special: a willingness to collaborate across disciplines and give new ideas room to grow, however unconventional they may initially seem.
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