Umbilical cord-derived mesenchymal stromal cells prime monocytes to enhance eosinophils-mediated defense against Klebsiella pneumoniae

The increasing prevalence of antibiotic-resistant Klebsiella pneumoniae (KP) necessitates novel preventive strategies. Although human mesenchymal stromal cells (MSCs) exhibit immunomodulatory and antimicrobial properties, their clinical utility against bacterial infection remains limited. Here, we examined the protective efficacy and underlying mechanism of prophylaxis using human umbilical cord-derived MSCs (hUC-MSCs) in a murine model of KP lung infection. Pretreatment with hUC-MSCs significantly protected both young and aged mice from KP pneumonia, as evidenced by improved survival, reduced pulmonary bacterial loads, and attenuated lung injury. Mechanistically, hUC-MSCs reprogrammed monocytes toward an immunoregulatory phenotype that enhanced bacterial clearance and drove CCL24-dependent recruitment of eosinophils (EOS) to infected lungs. EOS were subsequently activated by epithelial-derived IL-33 and exhibited potent antimicrobial activity. Disruption of the monocyte-EOS axis abolished hUC-MSC-mediated protection. Clinically, higher circulating EOS level was associated with better clinical outcomes in KP-infected patients. Thus, we identify a novel hUC-MSC-monocyte-EOS protective axis that balances anti-inflammatory and antimicrobial responses, providing a mechanistic basis for hUC-MSC-based prophylaxis against severe bacterial pneumonia.