Cathelicidin-related antimicrobial peptide (CRAMP) is toxic during neonatal murine influenza virus infection.

Document Type

Article

Publication Date

3-18-2025

Abstract

Respiratory viral infections are a major contributor to mortality in children under 5 years of age, and disproportionately affect preterm neonates. Previously, using our established 3-day-old neonatal murine model of influenza virus infection, we demonstrated that treatment of neonatal mice with intranasal Lactobacillus rhamnosus GG (LGG) prior to influenza viral infection improved survival. Transcriptional analysis revealed expression of the mouse cathelicidin-related antimicrobial peptide (CRAMP, encoded by CRAMP) was downregulated in LGG-treated neonates. Mouse CRAMP is a key effector protein secreted by infected epithelial cells and resident and infiltrating immune cells, but the role of CRAMP in neonatal defense to respiratory viruses is unknown. Neonatal mice with a deleted CRAMP gene (CRAMP-/-) were intranasally infected with influenza virus. CRAMP-/- neonates had improved survival over C57BL/6 neonates after influenza viral infection (75% vs. 14%, p < 0.05). Next, immune cell recruitment to the lung of infected neonates was determined. Surprisingly, at 3-days postinfection, there was increased recruitment of neutrophils, inflammatory monocytes, and alveolar macrophages, coupled with increased proinflammatory cytokine and chemokine production in CRAMP-/- compared to C57BL/6 neonates. However, this changed over the first week of infection. C57BL/6 neonatal mice increased CRAMP production significantly, in direct contrast to their adult counterparts. Inflammatory cytokine production increased that indicated CRAMP amplified the innate immune response later in the infection. Furthermore, we identified pulmonary nonimmune cells as an important source of increased CRAMP levels as the infection progressed and CRAMP production drove mortality. These insights emphasize the age-specific role of CRAMP in influenza viral pathogenesis.

Publication Title

Journal of immunology (Baltimore, Md. : 1950)

Comments

online ahead of print

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