Uncovering the Function of Marsupial Cathelicidins: Macrophage Modulation and Direct Antibacterial Defense

Abstract

To counter bacterial threats immediately after birth, marsupial neonates rely on powerful innate immunity factors, as they are incapable of mounting an adaptive immune response. One set of such factors are cathelicidins, peptides which can inhibit bacterial growth and interact with immune cells. Marsupials have high copy numbers of cathelicidins, while most eutherian mammals have relatively few, with humans and mice each having a single cathelicidin gene. Work at the Mallarino and Donia laboratories has previously found putative cathelicidin-coding genes in the sugar glider Petaurus breviceps, whose corresponding peptides have shown antibacterial action. However, the bacterial panel against which these peptides have been tested is limited, and it is unknown whether there are advantages to co-expressing multiple antimicrobial cathelicidins. Additionally, immunomodulation by marsupial cathelicidins has not been investigated. Here, I study the individual and combinatorial antibacterial action of sugar glider cathelicidins and interrogate their effects on inflammation. Using a variety of experimental assays, I demonstrate that these cathelicidins show marked antimicrobial activity against the marsupial pathogen Bordetella bronchiseptica, that they synergize to inhibit bacterial growth, and that they can modulate both LPS-induced and basal secretion of cytokines. These results not only confirm the antimicrobial nature of several sugar glider cathelicidins, but reveal that marsupial cathelicidins show intra-species synergy and have immunomodulatory roles. Furthermore, my work suggests that antimicrobial and immunomodulatory functions are not partitioned between peptides, but that potent antimicrobial cathelicidins moonlight as immunomodulators.