Specialized Proresolving Mediators Rescue Infant Mice from Lethal Citrobacter rodentium Infection and Promote Immunity against Reinfection

Abstract

ABSTRACT Infants are generally highly susceptible to oral pathogens. Intestinal infection and the associated diarrhea are significant global causes of morbidity and mortality in infants. Among the enteric pathogens, enteropathogenic Escherichia coli (EPEC) stands out as showing the highest risk for infection-induced death in infants ≤12 months old. We have developed an experimental model of infant infection with EPEC, using the mouse-specific pathogen Citrobacter rodentium . Our murine infant model is similar to EPEC infection in human infants since infant mice are much more susceptible to C. rodentium infection than adult mice; infants infected with 50-fold fewer bacteria than the standard adult dose uniformly succumbed to the infection. Infant infection is characterized by high early and sustained bacterial titers and profound intestinal inflammation associated with extensive necrosis and systemic dissemination of the bacteria. Therefore, it seems likely that infant deaths result from sepsis secondary to intestinal damage. Recently, specialized proresolving mediators (SPM) have been found to exert profound beneficial effects in adult models of infection. Thus, we investigated the actions of two proresolving lipid mediators, resolvin D1 (RvD1) and resolvin D5 (RvD5), on the course of infection in infants. Strikingly, postinfection treatment with RvD1 and RvD5 reduced bacterial loads, mitigated inflammation, and rescued the infants from death. Furthermore, postinfection treatment with RvD1 and RvD5 led to protection from reinfection associated with C. rodentium -specific IgG responses comparable to those in adults. These results indicate that SPM may provide novel therapeutic tools for the treatment of pathological intestinal infections in infants.