Alphadefensins

Alphadefensins, commonly referred to as alpha-defensins, are a family of short, cationic antimicrobial peptides that form part of the innate immune system. They are typically 29–34 amino acids long and contain three intramolecular disulfide bonds formed by six conserved cysteine residues, giving them a compact, stable structure capable of withstanding physiological conditions.

In humans, alpha-defensins are produced by two main cell lineages: neutrophils and intestinal Paneth cells. Neutrophils release HNP-1 through HNP-4 during degranulation, while Paneth cells secrete HD-5 and HD-6 into the gut lumen. The genes encoding human alpha-defensins are clustered on chromosome 8 (DEFA1–DEFA4 and related genes such as DEFA5–DEFA6).

Mechanistically, alphadefensins exert antimicrobial effects by permeabilizing microbial membranes and by binding to microbial components such as LPS, which can modulate inflammatory signaling. They kill a broad spectrum of bacteria and fungi and can also exhibit antiviral activity against certain enveloped viruses. Beyond direct killing, they modulate immune responses by acting as chemoattractants for neutrophils, monocytes, and T cells, and by influencing cytokine production.

Biologically, alphadefensins contribute to mucosal defense, shaping the composition of the gut microbiota and the airway surface liquid. Dysregulation of defensin expression has been linked to inflammatory bowel disease, cystic fibrosis, and other inflammatory or infectious conditions. Gene copy number variation of defensin loci can influence expression levels and susceptibility to infections.

Because of their broad-spectrum activity and stability, alphadefensins are studied as templates for antimicrobial therapeutics and as biomarkers of mucosal immune status, though translating this into clinical therapies remains challenging due to potential toxicity and host interactions.