Marsupial cathelicidin peptides provide potent immune defense and protect against sepsis in mouse models

Sugar glider cathelicidins reside in two genomic clusters, are highly expressed in neonatal neutrophils, have potent antibacterial activity, modulate immune responses, and provide sufficient protection against sepsis in a mouse model. Marsupials and monotremes uniquely retain both genomic clusters among tetrapods.

Genomic analysis of cathelicidin gene clusters, gene expression profiling in developing neutrophils, functional antibacterial and immunomodulatory assays, and in vivo sepsis protection testing in a mouse model using sugar glider (Petaurus breviceps).

Cathelicidins are a crucial family of antimicrobial peptides shared across mammals, including humans (LL-37). Discovering that marsupials have an expanded repertoire with proven sepsis protection could inspire novel peptide-based anti-infective therapies and reveal new biology about how these peptides evolved to meet different immune challenges.

This study reveals that evolution has produced diverse solutions to immune defense through antimicrobial peptide expansion. The marsupial cathelicidin repertoire—selected over millions of years for neonates born without a mature immune system—may contain peptides with therapeutic properties not found in the single human cathelicidin (LL-37).

Primary focus on marsupial biology limits direct human clinical translation. Mouse sepsis model provides proof of concept but is not equivalent to human infection. Specific peptide sequences with greatest therapeutic potential were not individually characterized. Evolutionary focus may limit practical application.