Modulation of host immunity with recombinant peptidoglycan hydrolases

PROJECT SUMMARY There exist few preventive or therapeutic modalities for vulnerable hosts against bacterial diarrheal illness. Further, the limited effectiveness of anti-infectives is being compromised by the antimicrobial resistant crisis. In response to this situation, physicians and scientists have investigated the role of probiotics. Despite promising

preliminary data showing benefit in weakened immune hosts and against drug-resistant isolates, probiotic clinical trials have demonstrated inconsistent therapeutic and safety profiles. For these reasons, identifying the molecular mechanisms by which probiotics provide benefit is needed to develop new therapeutics. Notably, the

Hang laboratory has discovered specific Enterococcus peptidoglycan hydrolases can improve intestinal barrier function and confer resistance against enteric infections in mouse models. Furthermore, these peptidoglycan hydrolases genetically engineered into Lactobacillus species were able to recapitulate protective effects. Given

the unclear efficacy of probiotics in humans, we aim to develop orally available recombinant peptidoglycan hydrolases therapeutics that will promote intestinal barrier function to protect against enteric pathogens. We therefore propose to evaluate the activity of recombinant Enterococcus peptidoglycan hydrolase hydrogel

formulations in mouse models of enteric infection (Aim 1) as well as explore peptidoglycan remodeling enzymes from other microbiota species/strains (Aim 2). The work proposed herein should afford new preventive and treatment modalities for vulnerable hosts against enteric infections.