Studie naar de rol van Salmonella biofilm-componenten tijdens gastro-intestinale infectie

Bacteria can adopt two lifeforms: they either exist as free-floating cells or as part of structured communities embedded in a self-produced matrix, known as biofilms. The latter represents the predominant form of microbial life. In the human body, biofilms can be found on medical devices and in tissues, frequently contributing to persistent infections. In the gut, bacterial biofilms have been linked to both health and disease, though the mechanism by which they influence gut homeostasis remains poorly understood. Non-typhoidal Salmonella (NTS) is one of the foodborne pathogens proposed to produce matrix in the intestine. Given that NTS serovars are responsible for over 150 million cases and 50,000 deaths annually, clarifying the role of matrix production in pathogenesis is of major importance. While some studies have examined specific interactions of the matrix with the host, a comprehensive understanding is still lacking. This PhD aimed to close this knowledge gap by investigating Salmonella biofilm formation in different animal models. In the first part of this PhD, a nematode model was used to compare the infection dynamics of biofilm-forming and non-forming Salmonella. Here, Salmonella colonized the intestinal lumen significantly better in the absence of the major biofilm regulator CsgD. This enhanced colonization was not accompanied by increased host morbidity or immune activation. As such, matrix production appeared to impose a fitness cost on the pathogen without affecting host interactions. Salmonella matrix formation thus did not appear important for infection establishment in nematodes. In the second part of this work, the physiologically more relevant murine colitis model was employed. Here, wild-type Salmonella was compared to mutants lacking the major regulator CsgD, or the key matrix components curli and cellulose. While curli and CsgD were dispensable for infection establishment in mice, the absence of cellulose significantly enhanced virulence. Cellulose-deficient strains showed increased epithelial invasion and colonization, accompanied by heightened inflammation. As previously shown in literature, the intestinal inflammation gave Salmonella a competitive advantage compared to the microbiota, enhancing its luminal proliferation. Notably, the pro-inflammatory environment alone did not fully account for the improved colonization of the cellulose-deficient strain, as the wild-type strain could not reach similar levels during coinfection experiments. In contrast, inhibition of flagellar rotation reduced the virulence of the cellulose to the wild-type level, suggesting that cellulose interferes with flagellar mobility. Overall, this research underscores the complex interplay between pathogens and their hosts. The role of the Salmonella biofilm matrix appeared to be context-dependent with matrix formation being dispensable in the nematode model, and cellulose acting as an anti-virulence factor in mice. Whether cellulose similarly attenuates virulence in other animal models and humans, and whether this contributes to chronic or asymptomatic infections, remains to be investigated. Together with future studies, these findings can help in the development of novel therapeutic or diagnostic approaches to combat NTS and possibly other gastrointestinal infections.