Cathelicidin antimicrobial peptide

Antimicrobial peptides (AMPs) is a large family of compounds serving as natural antibiotics, widely distributed across the organism, mainly in mucus layers. They are designed to prevent pathogens from colonization. Among them, defensins and cathelicidins could be found. LL-37, the sole human cathelicidin draws particular attention because of its outstanding abilities. In addition to being a broad spectrum antibiotic, LL-37 has potent chemotactic and immunomodulatory properties. In this review, we discussed the potency of LL-37 as a therapeutic agent in four systems: immunological, respiratory, gastrointestinal and in the skin. We analyzed the main molecular pathways dependent on human cathelicidin and related them to specific diseases. We conclude that LL-37 shows a great potential to be further investigated and developed as a drug with clinical use.

The incorporation of the innate immune system into humans is essential for survival and health due to the rapid replication of invading microbes and the delayed action of the adaptive immune system. Antimicrobial peptides are important components of human innate immunity. Over 100 such peptides have been identified in various human tissues. Human cathelicidin LL-37 is best studied, and there has been a growing interest in designing new peptides based on LL-37. This chapter describes the alternative processing of the human cathelicidin precursor, protease digestion, and lab cutting of LL-37. Both a synthetic peptide library and structure-based design are utilized to identify the active regions. Although challenging, the determination of the 3D structure of LL-37 enabled the identification of the core antimicrobial region. The minimal region of LL-37 can be function-dependent. We discuss the design and potential applications of LL-37 into antibacterial, antibiofilm, antiviral, antifungal, immune modulating, and anticancer peptides. LL-37 has been engineered into 17BIPHE2, a stable, selective, and potent antimicrobial, antibiofilm, and anticancer peptide. Both 17BIPHE2 and SAAP-148 can eliminate the ESKAPE pathogens and show topical in vivo antibiofilm efficacy. Also discussed are other application strategies, including peptide formulation, antimicrobial implants, and peptide-inducing factors such as vitamin D and sunlight. Finally, we summarize what we learned from peptide design based on human LL-37.

Background & aims: Alteration of the gut microbiota is implicated in the development of autoimmune type 1 diabetes (T1D), as shown in humans and the nonobese diabetic (NOD) mouse model. However, how gut dysbiosis arises and promotes the autoimmune response remains an open question. We investigated whether early events affecting the intestinal homeostasis in newborn NOD mice may explain the development of the autoimmune response in the adult pancreas. Methods: We profiled the transcriptome and the microbiota in the colon between newborn NOD mice and nonautoimmune strains. We identified a seminal defect in the intestinal homeostasis of newborn NOD mice and deciphered the mechanism linking this defect to the diabetogenic response in the adult. Results: We determined that the cathelicidin-related antimicrobial peptide (CRAMP) expression was defective in the colon of newborn NOD mice, allowing inducing dysbiosis. Dysbiosis stimulated the colonic epithelial cells to produce type I interferons that pathologically imprinted the local neonatal immune system. This pathological immune imprinting later promoted the pancreatic autoimmune response in the adult and the development of diabetes. Increasing colonic CRAMP expression in newborn NOD mice by means of local CRAMP treatment or CRAMP-expressing probiotic restored colonic homeostasis and halted the diabetogenic response, preventing autoimmune diabetes. Conclusions: We identified whether a defective colonic expression in the CRAMP antimicrobial peptide induces dysbiosis, contributing to autoimmunity in the pancreas. Hence, the manipulation of intestinal antimicrobial peptides may be considered a relevant therapeutic approach to prevent autoimmune diabetes in at-risk children.