PATHOGENIC MECHANISMS OF CITROBACTER RODENTIUM INFECTION IN IMMUNOCOMPROMISED ANIMALS

Human attaching and effacing (A/E) pathogens enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are the leading causative agents for foodborne diseases, which lead to severe economic burden, morbidity, and mortality worldwide (Collins et al., 2014; Nataro & Kaper, 1998; Tarr & Neill, 2001; Wiles et al., 2004). Their infections in certain susceptible populations, including the elders, young children, and immunocompromised/immunodeficient individuals, suffer from a more severe form of the disease with fatal complications (A, 2012; Linington et al., 2002; Vilchez et al., 2009). Previous infection models, including EPEC/EHEC cell line infection and murine-specific A/E pathogen Citrobacter rodentium (CR) infection in the immunocompetent mice, could not recapitulate the severe infection outcome and explain the critical host-pathogen interactions that account for the severe symptoms. In this study, we utilize CR infection in the immunocompromised Il22-/- mice – these mice suffered from severe morbidity and 100% mortality upon CR infection (Zheng et al., 2008). This model serves to screen for essential virulence factors of CR in the immunocompromised settings. From the functional screening, we have identified three T3SS effectors and further characterized two of these effectors that are crucial for CR-induced severe morbidity and lethality in immunocompromised mice, through distinct pathogenic mechanisms. In chapters 2 and 3 of the study, we identified that EspF is crucial for CR-induced morbidity and mortality in Il22-/- mice. CR infection disrupts tight junction integrity, in particular Claudin family protein, and leads to pathogen systemic spread in an EspF-dependent manner. In chapters 4 and 5 of this study, we have characterized another T3SS effector that is involved in CR proliferation in the expansion phase originated in the host cecum, and it is essential in triggering CR-induced inflammatory response and robust innate immunity in Il22-/- mice. Together, these two essential virulence factors engage in a broad spectrum of pathogenic mechanisms from pathogen colonization to host barrier integrity, inflammation, and immune responses, shedding a light on the crucial host-pathogen interactions during A/E pathogen infection in the immunocompromised settings