Role of Immunity and the Microbiota in Enteropathogenic E. coli Eradication

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ABSTRACT Enteric and diarrheal diseases caused by pathogens are important causes of childhood death worldwide. These diseases are estimated to cause near 1 million deaths per year in children under 5 years old worldwide, ranking second as the cause of death in this age group. This is largely due to their increased susceptibility of neonates and young children to enteric infections. In the healthy adult gut, the microbiota provides “colonization resistance”, forming a barrier against invading pathogens. The increased susceptibility to infections has been generally ascribed to immaturity of the immune system; however, additional factors may play an important role because immune responses to different stimuli are highly variable among neonates. Recent studies in our laboratory showed that the microbiota of neonatal mice is impaired in mediating colonization resistance against Salmonella and Citrobacter rodentium, a bacterium that models infection by enteropathogenic E. coli (EPEC), the most common cause of diarrheal deaths by bacteria worldwide. The lack of colonization resistance was caused by the absence of Clostridiales in the neonatal microbiota. We also found that IgG, but not IgA, induced after infection recognized surface C. rodentium virulence factors and bound virulent bacteria within the intestinal lumen leading to their opsonization and engulfment by neutrophils, while phenotypically avirulent pathogens remained in the intestinal lumen and are out-competed by the microbiota. Thus, the immune system and the microbiota play cooperative and essential roles in C. rodentium eradication. In this proposal, we proposed three specific Aims (i) to identify mechanisms by which Clostridia species mediate inhibition of enteric pathogen in the gut; (ii) understand the mechanisms that promote the colonization of protective Clostridiales in the neonatal intestine and (iii) determine the mechanism by which intestinal IgG against C. rodentium virulence factors protects neonates from infection. The proposed studies have the potential for a major impact on human health and in particular on that of infants and children.