Defensins are lectin-like antimicrobial peptides that are produced by cells in both plants and animals. They are critical for innate host defence, although the precise details of their mode of action has remained unsolved. Now, a new report published in Nature Immunology reveals a general mechanism of action for how defensins block influenza-virus infection.

Leikina and colleagues initially focused on the θ-defensin retrocyclin 2 (RC2), which, along with many of the other multivalent lectins found in the innate immune system, has broad-spectrum antiviral properties. Their results demonstrated that, rather than affecting later stages of infection, RC2 in fact inhibited viral entry into the cell. The authors were able to rule out both viral binding and endocytosis as the stages of viral entry at which RC2 had an effect, leaving the final stage, membrane fusion, as the probable target.

Haemagglutinin (HA) is the receptor-binding and membrane-fusion glycoprotein of influenza virus, and is a target for neutralizing antibodies. HA undergoes conformational changes upon activation, which triggers membrane fusion. Leikina et al. were next able to demonstrate that, although RC2 did not prevent conformational changes in HA, it did block at least one of the other processes involved in HA-mediated membrane fusion, thereby preventing viral entry. In addition, the authors showed that RC2 is not specific to HA, but can inhibit fusion mediated by other viral proteins.

RC2, like other lectins, binds cell-surface carbohydrates (glycans). To determine if this quality contributed to the fusion inhibition, the authors examined whether deglycosylation could abolish RC2's antiviral effect. Their positive results confirmed that RC2 interacts with carbohydrates at the cell surface, and further investigation showed that RC2 immobilized the movement of membrane glycoproteins. This led to the conclusion that RC2 crosslinks those surface proteins in order to inhibit fusion. Supporting these findings, Leikina et al. also demonstrated that two other lectin components of the innate immune system, mannan-binding lectin and human β-defensin 3, similarly inhibited the step that precedes viral entry.

Many of the antimicrobial peptides of the innate immune system possess a broad spectrum of antiviral activity; this novel mechanism of blocking viral fusion by crosslinking and immobilizing surface glycoproteins might help to explain this phenomenon, and further investigation could ultimately point to new therapeutic strategies for preventing viral illness.