Defensins

Defensins are a family of small (2–5 kDa) cationic antimicrobial peptides with a β-sheet core stabilized by three intramolecular disulfide bonds. Humans express alpha-defensins (in neutrophils and intestinal Paneth cells) and beta-defensins (in epithelial surfaces). They constitute a frontline barrier of innate immunity against bacteria, fungi, and enveloped viruses.

Defensins kill microbes primarily by disrupting microbial membranes. Their cationic, amphipathic structure enables electrostatic binding to negatively charged bacterial membranes, followed by insertion and pore formation that causes membrane disruption and leakage of intracellular contents. Beyond direct killing, defensins serve as immunomodulators: they chemoattract dendritic cells, T cells, and mast cells via CCR6 and other receptors, bridging innate and adaptive immunity. Alpha-defensins (HNP-1 to -4) are stored in neutrophil azurophilic granules and released during phagocytosis.

Over 50 human defensin peptides have been characterized. Alpha-defensins HNP-1 to -4 comprise 5–7% of total neutrophil protein. Beta-defensins (HBD-1, -2, -3) are constitutively or inductively expressed on skin and mucosal surfaces. Research has linked defensin deficiency to increased susceptibility to Crohn's disease, atopic dermatitis, and recurrent infections. Therapeutic applications under investigation include topical antimicrobials for wound care, vaginal infections, and oral candidiasis. Retrocyclin (theta-defensin analog) shows HIV-neutralizing activity in vitro.