Mechanisms of tissue-specific disease tolerance in genotoxigenic bacterial infection

Disease tolerance, defined as limiting tissue damage without influencing pathogen load, is a component of the innate host response to infection.

However, knowledge about the host mechanisms and the role of pathogen virulence factors inducing disease tolerance is very limited.We demonstrated that Salmonella enterica, expressing the genotoxin known as typhoid toxin, suppresses intestinal inflammation without influencing the bacterial load, despite the induction of DNA fragmentation.

Conversely, the bacterium induces a strong inflammation in the liver.

Thus, comparison of the response upon infection with the genotoxigenic Salmonella in different tissues provides a powerful model to dissect the molecular mechanisms of disease tolerance and in which condition it is maintained.

Using in situ, ex vivo single-cell analysis, and 3D models we will address:How tissue-specific microenvironment influences disease tolerance induced by the genotoxigenic SalmonellaWhether the toxin hijacks the default intestinal response to DNA damageThis novel project addresses the molecular mechanism of a poorly characterized aspect in response to microbial infections, expanding our basic knowledge of infection biology.

Understanding the principles of disease tolerance may further offer new and complementing therapeutic approaches in pathologies related to overresponse of the immune system (COVID-19) or high-morbidity co-infections (e.g. severe bacterial-induced lung infections following influenza).