# Administration of the NOD2 Agonist MDP Reduces Cryptosporidium parvum Infection in Neonatal Mice Through IL‐22 Involvement

## TL;DR

Giving MDP to newborn mice reduces Cryptosporidium infection by boosting immune responses and renewing intestinal cells.

## Contribution

MDP, a NOD2 agonist, reduces C. parvum infection in neonatal mice via IL-22 and epithelial renewal.

## Key findings

- MDP treatment reduced C. parvum parasite burden in neonatal mice.
- The protective effect involved IL-22, IFN-γ, neutrophil recruitment, and epithelial cell renewal.
- NOD2 stimulation was effective, but NOD1 stimulation had no protective effect.

## 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 toll‐like receptor (TLR) activation‐based strategies have proven effective in controlling neonatal diseases, including cryptosporidiosis. In this study, we investigated the effect of nucleotide‐binding oligomerization domain (NOD) receptors stimulation on the control of enteric infection by the protozoan Cryptosporidium parvum in neonatal mice. NOD2 stimulation by intraperitoneal injection of muramyl dipeptide (MDP) resulted in a rapid reduction in the parasite burden. The protective effect was associated with increased pro‐inflammatory 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‐γ and IL‐22 cytokines and was associated with increased intestinal epithelium renewal in infected neonates. Our findings showed that stimulating neonatal mice with the bacterial ligand MDP, which targets the NOD2 receptor, actively contributes to the nonspecific clearance of C. parvum infection by eliminating or renewing infected epithelial cells.

Neonatal mice infected with C. parvum and treated with MDP, a NOD2 agonist, exhibited reduced intestinal infection. This protective effect was mediated by a local immune response involving neutrophil recruitment, IL‐22 production, antimicrobial peptide expression, and epithelial regeneration in an IFN‐γ‐dependent manner. Therefore, MDP administration enhances host defense mechanisms against C. parvum infection in neonatal mice. Created with BioRender.com.