Why Salmonella Typhimurium?

S. Typhimurium (abbreviation for Salmonella enterica subspecies 1 serovar Typhimurium) is an important foodborne pathogen that causes numerous diarrheal infections in Switzerland, Europe and worldwide (external pagesee and external pagesee also). In fact, recent epidemiologic surveys indicate that 10% of the European population may get exposed to this pathogen every year (external pageMølbak et al., Clin Infect Dis. 2014). In most cases, exposure seems to cause benign symptoms and the infection is only detected because the exposed person develops an antibody response ("serum conversion"). However, some patients go on to develop the well-known "Salmonella diarrhea", characterized by fever, abdominal cramps and excessive watery stool. It remains poorly understood why people respond so differently to the pathogen. Solving this puzzle would be an important step towards strategies for cure or prevention.

This pathogen offers unique technical advantages for the discovery of novel concepts of general importance in infection biology. Contemporary studies of S. Typhimurium benefit from unsurpassed genetics tools, genome-wide mutant libraries, fluorescent reporters, an extensive knowledge-base of bacterial gene function and physiology, elaborate tissue culture infection models, and superb collections of clinically relevant strain isolates at national reference centres. The Hardt lab has complemented this experimental arsenal with automated fluorescence microscopy assays and a versatile mouse model for studies of the diarrheal disease in genetically tractable mammalian hosts (external pageBarthel et al., Infect Immun. 2003; external pageKaiser et al., Immunol Rev. 2012). Intravital microscopy allows monitoring all steps of the disease from bacterial arrival in the gut lumen, epithelial invasion, translocation into the lamina propria to the mounting of an inflammatory mucosal response by 8-12h of infection (external pageMüller et al., Cell Host Microbe. 2012; external pageSellin et al., Cell Host Microbe. 2014). Importantly, the use of fluorescent reporters has led to the discovery of heterogeneity in S. Typhimurium virulence factor expression and allowed us to demonstrate the importance of bacterial subpopulations expressing different phenotypes for the infection process and the evolution of the virulent genotype (external pageAckermann et al., Nature. 2008; external pageSturm et al., PLoS Pathog. 2011; external pageDiard et al., Nature. 2013). Combined, this has established S. Typhimurium gut infection as a paradigm for deciphering general features of pathogen biology, microbiota functions in fostering or preventing gut infection and mucosal immune responses at the molecular, cellular and organismal level.

Finally, there is a wealth of information on the key virulence factors of S. Typhimurium. This provides an excellent basis for mechanistic studies of pathogen-host cell and pathogen-microbiota interactions. We are particularly interested in the type III secretion system 1 (TTSS-1), a syringe-like organelle that allows S. Typhimurium to manipulate and invade into gut epithelial cells (Fig. 1). TTSS-1 injects a cocktail of about 14 different toxins ("effector proteins") into the host cell. Four effector proteins, i.e. SopB, SopE, SopE2 and SipA, are particularly potent in triggering actin cytoskeleton rearrangements ("ruffling") and thereby facilitate host cell invasion. Moreover, several host cell targets manipulated by S. Typhimurium effectors have been identified. This enables advanced studies of the complex networks of molecular interactions that determine the outcome of the infection.

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