Cathelicidin antimicrobial peptides mediate immune protection in marsupial neonates

Marsupial neonates are born with immature immune systems, making them vulnerable to pathogens. While neonates receive maternal protection, they can also independently combat pathogens, although the mechanisms remain unknown. Using the sugar glider (<i>Petaurus breviceps</i>) as a model, we investigated immunological defense strategies of marsupial neonates. Cathelicidins-a family of antimicrobial peptides expanded in the genomes of marsupials-are highly expressed in developing neutrophils. Sugar glider cathelicidins reside in two genomic clusters, and their coordinated expression is achieved by enhancer sharing within clusters and long-range physical interactions between clusters. Functionally, cathelicidins modulate immune responses and have potent antibacterial effects, sufficient to provide protection in a mouse model of sepsis. Evolutionarily, cathelicidins have a complex history, with marsupials and monotremes uniquely retaining both clusters among tetrapods. Thus, cathelicidins are critical mediators of marsupial immunity, and their evolution may reflect the life history-specific immunological needs of these animals.