The innate immune system has the tricky task of foiling all invaders rather than targeting a specific few. Eugenia Leikina, Leonid Chernomordik (NICHHD, Bethesda, MD), and colleagues report that defensin antimicrobial peptides use a unique nonspecific method: they cross-link surface glycoproteins and thus freeze them in place. The resulting web of proteins obstructs the fusion of viral and cell membranes.
Defensins caught Chernomordik's eye because he works on membrane fusion and the defensins have broad specificity. He thought they might interfere with membrane properties, but was disappointed when they accelerated rather than inhibited fusion between protein-free liposomes.
With virus-infected cells, however, things got more interesting. Defensins did not block virus binding or endocytic uptake but did block membrane fusion. Membrane glycoproteins no longer diffused over the membrane surface.
The lack of diffusion may be the key. When a virus binds to a cell there is still a gap of ∼10 nm between the membranes, which can be closed only when proteins in a tiny patch happen, via random diffusion, to get out of the way. With defensins bound, suggests Chernomordik, “the proteins would not move away.”
“This might be the first natural antiviral agent targeting fusion,” says Chernomordik. “The fusion stage targeted is elusive, because if proteins are mobile it is not rate limiting.” He also notes a tantalizing analogy to prokaryotes, which use covalently cross-linked proteoglycans as a barrier, forcing bacteriophages to use injection rather than fusion mechanisms. “For a short time,” he says, “our cells become prokaryotic by erecting these walls.”