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Attaching/Effacing (A/E) bacteria include human pathogens enteropathogenic  Escherichia coli  (EPEC), enterohemorrhagic  E .  coli  (EHEC), and their murine equivalent  Citrobacter rodentium  (CR), of which EPEC and EHEC are important causative agents of foodborne diseases worldwide. While A/E pathogen infections cause mild symptoms in the immunocompetent hosts, an increasing number of studies show that they produce more severe morbidity and mortality in immunocompromised and/or immunodeficient hosts. However, the pathogenic mechanisms and crucial host-pathogen interactions during A/E pathogen infections under immunocompromised conditions remain elusive. We performed a functional screening by infecting interleukin-22 (IL-22) knockout ( Il22   -/-  ) mice with a library of randomly mutated CR strains. Our screen reveals that interruption of the  espF  gene, which encodes the Type III Secretion System effector EspF ( E .  coli  secreted protein F) conserved among A/E pathogens, completely abolishes the high mortality rates in CR-infected  Il22   -/-   mice. Chromosomal deletion of  espF  in CR recapitulates the avirulent phenotype without impacting colonization and proliferation of CR, and EspF complement in  ΔespF  strain fully restores the virulence in mice. Moreover, the expression levels of the  espF  gene are elevated during CR infection and CR induces disruption of the tight junction (TJ) strands in colonic epithelium in an EspF-dependent manner. Distinct from EspF, chromosomal deletion of other known TJ-damaging effector genes  espG  and  map  failed to impede CR virulence in  Il22   -/-   mice. Hence our findings unveil a critical pathophysiological function for EspF during CR infection in the immunocompromised host and provide new insights into the complex pathogenic mechanisms of A/E pathogens.

EspF is crucial for Citrobacter rodentium-induced tight junction disruption and lethality in immunocompromised animals