The tips of an antibody’s two arms usually constitute the antibody’s “business end,” but sometimes the antibody’s tail matters, too. Both arm tips and the tail, it turns out, may engage the flu virus at once, so long as the antibody in question is immunoglobulin A. This discovery, recently announced by scientists based at the University of Zurich, suggests that a new front may be opened in the fight against the flu. To date, flu vaccines have focused on stimulating the production of immunoglobulin G, rather than the dual-acting immunoglobulin A (IgA).

Influenza A and other viruses that use sialic acid as a receptor may be vulnerable to dual-acting immunoglobulin A (IgA), which binds to the viruses via its variable arms and its glycosylated tail. This video shows IgA1 antibodies binding to the influenza A virus antigen hemagglutinin. [TSRI/UZH]

IgA is known to protect our mucosal surfaces from viral infection, to manage commensal bacterial flora, and to extend maternal immunity via breast feeding. Although IgAs are notoriously hard to work with, they may figure more prominently in vaccine and drug research, now that they have been found to have an additional function. According to the University of Zurich-led team, “the C-terminal tail unique to IgA molecules interferes with cell-surface attachment of influenza A and other enveloped viruses that use sialic acid as a receptor.”

Details appeared April 3 in the journal Cell Reports, in an article entitled “Glycosylation of Human IgA Directly Inhibits Influenza A and Other Sialic-Acid-Binding Viruses.” This article indicates that the IgA1 antibody works through two kinds of immune activity—first, through acquired immunity, which is traditionally associated with antibodies that specifically recognize pathogens, and second, through innate immunity via the sialic acids at the other end of the molecule, which is more of a nonspecific, broad-ranging attack. Essentially, IgA antibodies attach themselves to flu viruses in two places at once.

“This innate antiviral activity is mediated by sialic acid found in the complex N-linked glycans at position 459,” the article’s authors reported. “Antiviral activity was observed even in the absence of classical antibody binding via the antigen binding sites.”

The scientists were also able to demonstrate that bird flu viruses are significantly more vulnerable to such a broad-ranging attack. “It's certainly possible that this tail is one of the reasons why we're not that easily infected with bird flu viruses,” noted Lars Hangartner, Ph.D., former professor at the Institute of Medical Virology of UZH. Dr. Harngartner, who headed the IgA current study, now works at The Scripps Research Institute.

“This was a completely unexpected and unforeseen finding,” he continued. “We found that antibodies called IgAs, which are commonly found on mucosal surfaces, can actually protect us from infections in two different ways.”

According to Dr. Hangartner, the study’s findings could help improve the effectiveness of flu vaccinations and drugs. The researcher believes future research should focus on developing IgA antibodies that are easier to produce and can be tested in mice. His idea is to graft the tail of the IgA1 onto an IgG-type antibody, which is much easier to handle.

“It would combine the best of both worlds and give us a molecule that's more effective and hardy, and that ultimately may be very useful when it comes to fighting the flu,” he suggested. Thanks to the strength with which the antibodies attach themselves to the virus, even small amounts would be enough to provide effective protection.

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