Deciphering the mechanism of acute Salmonella Typhimurium gut infection.

Salmonella diarrhoea is a global risk for human and animal health. However, we are lacking curative therapies and efficient vaccines. To identify the pathogen's Achilles' heels and starting points for therapy of prevention, we need a better understanding of the infection biology of non-typhoidal Salmonella (NTS) such as Salmonella Typhimurium. To study the steps of the pathogen-host interaction within the complex environment of a real host, my lab has developed mouse gut infection models, including the classical streptomycin model and food interventions which only mildly disrupt the microbiota. These mouse models have opened the door for studying how microbiota can block S. Typhimurium gut colonization ("colonization resistance"), for identifying the pathogen's virulence factors driving the infection (like the SPI-1 Type III secretion system; T3SS-1) and the host's immune defences (like the NLRC4 inflammasome) which control the pathogen and cause much of the disease symptoms. This work has also identified important gaps in our knowledge. We do not understand why S. Typhimurium infections sometimes begin by invasion into the small and sometimes into the large intestine. Which virulence factors and which target cells are involved? Which NLRC4-controlled defences are relevant for limiting pathogen loads in the gut tissue? And we do not understand how chemotaxis is used by the pathogen to exploit the diseased gut. These questions will be addressed in three distinct subprojects focusing on different stages of the acute infection process: -Why does the nature of the microbiome disturbance affect the site where the initial gut tissue invasion occurs? Is this attributable to alternative sets of T3SS-1 effector proteins, adhesins or altered chemotaxis? And how does this affect gut-luminal pathogen blooms?-How do innate immune defences control pathogen loads in the gut tissue? Here, we will ask how TNF- and NLRC4-mediated defence cooperate to control microbial growth in lamina propria phagocytes and assess the role of Gasdermin C, an effector of the NLRC4 inflammasome.-How does chemotaxis promote S. Typhimurium growth in the infected gut? Here, we will study mutants lacking a chemotaxis receptor (tsr) to assess how S. Typhimurium exploits nutrient niches and avoids elimination by granulocyte-mediated immune defence.Each subproject will be tackled by one PhD student and the work plans include multiple opportunities for the students to collaborate. The students will also profit from complementary knowhow of other lab members, and from our local and international collaboration partners. The data will enhance our understanding of the infection process and the insights might reveal Achilles' heels of the pathogen which might serve as starting points for therapy development.