Bakteriell genotoxininducerad cellulär åldrande: en trojanhäst i infektionsbiologi?

Bacterial genotoxins (BTGX) cause DNA damage in the host cells, activating the DNA damage response and promoting senescence, a state associated with secretion of inflammatory mediators.

Under specific circumstances, BTGX-producing bacteria can contribute to tumor development, but the toxins´ biological relevance remains unknown, since it is unlikely that their primary function is to promote cancer.

Using a model based on Salmonella Typhimurium, expressing the BTGX known as typhoid toxin (TT), developed in our laboratory, we will address the following questions:Does the microenvironment promote tissue-specific senescence upon infection with TT-producing bacteria?Do inflammatory and pro-carcinogenic conditions alter the senescence phenotype and the overall outcome of infection?Does TT-induced senescence influence intestinal colonization with polymicrobial communities enriched in the intestinal mucosa of patients suffering from inflammatory or cancer conditions?Do the activities of the multifunctional TT affect the infection’s outcome?This project approaches the role of BTGX in infection from a novel perspective: as modulators of the host immune response.

In a translational setting, we will infer how and when to target BTGX-producing bacteria, facilitating management of intestinal chronic infections and inflammatory conditions.

In a longer perspective, specific senolytic-based therapies may be combined with the more classical therapeutic approaches to treat infection diseases.