NOD2 stimulation reduces Cryptosporidium parvum level of infection in neonates by promoting intestinal epithelial production of antimicrobial peptides and cell renewing

Abstract

At birth, the mucosal immune system of neonates is not fully developed, making them more susceptible to respiratory and intestinal diseases. Previously described host-directed therapies using TLR activation-based strategies have proven effective in controlling neonatal diseases, including cryptosporidiosis. In this study, we investigated the effect of NOD receptor stimulation on the control of enteric infection by the protozoan Cryptosporidium parvum in neonatal mice. NOD2 stimulation by intraperitoneal injection of MDP resulted in a rapid reduction in the parasite burden. The protective effect was associated with increased proinflammatory cytokine and antimicrobial peptide gene expression and a rapid influx of neutrophils to the site of infection, whereas NOD1 stimulation did not show a protective effect. The protective mechanism did not involve microbiota participation but involved IFN-{gamma} and IL-22 cytokines and was associated with increased intestinal epithelium renewal in infected neonates. Our findings, demonstrated in neonatal mice, elucidate how the stimulation of NOD2 with the bacterial ligand MDP actively contributes to the non-specific clearance of a parasitic infection within the intestinal epithelial cells. Author SummaryNewborns are particularly vulnerable to intestinal infections due to their immature immune systems. Developing strategies to enhance their ability to fight infections is crucial for improving neonatal health. In this study, we investigated how stimulation of a specific immune receptor, NOD2, can help neonatal mice control an intestinal infection caused by the protozoan Cryptosporidium parvum. We found that intraperitoneally administration of a bacterial molecule called MDP, which activates the NOD2 receptor, led to a rapid reduction in the parasite burden. This protection was associated with increased production of inflammatory molecules, antimicrobial peptides, and a significant influx of neutrophils to the site of infection. Importantly, the protective effect did not depend on the gut microbiota but involved specific immune signals, such as IFN-{gamma} and IL-22, and enhanced the renewal of intestinal epithelial cells. These findings highlight how targeting NOD2 can boost neonatal innate immunity, offering a potential host-directed strategy to combat severe intestinal infections, limit long-term intestinal damage and reduce the risk of fatal outcomes.