Tissue damage control in disease tolerance

•Disease tolerance protects the host from infection without targeting pathogens.•Tissue damage control is a central underlying mechanism of disease tolerance.•Tissue damage control is regulated by conserved stress and damage responses.•These present therapeutic targets for treating infectious and inflammatory diseases.

Immune-driven resistance mechanisms are the prevailing host defense strategy against infection. By contrast, disease tolerance mechanisms limit disease severity by preventing tissue damage or ameliorating tissue function without interfering with pathogen load. We propose here that tissue damage control underlies many of the protective effects of disease tolerance. We explore the mechanisms of cellular adaptation that underlie tissue damage control in response to infection as well as sterile inflammation, integrating both stress and damage responses. Finally, we discuss the potential impact of targeting these mechanisms in the treatment of disease.