Defensins versus pathogens: an unfolding story

Bacteria are one of the major factors shaping the evolutionary landscape of all eukaryotic organisms including humans. Bacterial epidemics, which have taken hundreds of millions of human lives in the observable history, are arguably some of the most vivid and cruel manifestations of natural selection. The history of co-evolution of eukaryotic and prokaryotic organisms is ingrained in their organization as the immune system from one side, and effector molecules supremely tuned to manipulate the essential pathways and cascades (e.g. toxins) from the other. Bacterial proteinacious toxins are the deadliest compounds on our planet. Given the outstanding killing efficiency of toxins, eukaryotes had no choice but to develop mechanisms of their effective neutralization. The adaptive immune system does so by producing highly specific and potent neutralizing antibodies. However, 5-7 days required to produce antibody is too long to protect from immediate threats. Innate immunity, in contrast, acts promptly by recognizing molecular patterns of pathogens (i.e. characteristic and essential microbial traits: lipid A of LPS, as well as bacterial flagellin, lipoproteins, and DNA) and exerting prominent cellular and humoral response towards their sources. But how can innate immunity recognize and protect from toxic bacterial proteins, which are plentiful and diverse? A decade ago, a group of antimicrobial effector peptides called defensins was reported to efficiently neutralize anthrax toxin both in vitro and in an animal model [1]. Human defensins are produced primarily by either neutrophils and intestinal Paneth cells (α-defensins) or various epithelial cells (β-defensins). The anti-toxin potential of defensins long remained hidden in the shadow of their other antimicrobial potentials-the immune-modulating abilities as well as the ability to kill microbes via disintegration of bacterial membranes, assisting in formation of neutrophil extracellular traps (NETs), and self-assembled nanonets [2]. In the years following the discovery of defensins' ability to neutralize anthrax toxin, many other toxins were recognized as defensins' targets. Six conserved cysteine residues connected by three characteristic disulfide bonds, several cationic and hydrophobic amino acids, as well as the ability to form dimers and/or higher order oligomers were all identified as parameters essential for toxin inactivation by these peptides [3]. Surprisingly, most of the affected toxins do not share common mechanisms of toxicity and belong to different enzymatic and non-enzymatic groups of toxins with little to no sequential or structural similarity. Given that human defensins represent a small structurally conserved group of antimicrobial peptides with limited variability, their ability to target a …