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Oct 21, 2013

Flu Invaders Seize Beachhead by Killing B Cell Sentinels

  • B cells studded with high-affinity, virus-specific receptors are uniquely equipped to halt those viruses for which its receptors are a match. It turns out, however, that such B cells may also be uniquely vulnerable. In the case of the flu virus, and possibly other kinds of viruses, the very specificity of the B cell receptors may be exploited. As demonstrated by scientists centered at the Whitehead Institute for Biomedical Research, the flu virus uses these receptors to ease their entry to the B cells, disrupting their antibody production and ultimately killing them.

    The scientists presented their findings in Nature on October 20, in a paper entitled “Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus.” In this paper, they propose that “influenza targets and kills influenza-specific B cells in the lung, thus allowing the virus to gain purchase before the initiation of an effective adaptive response.”

    “We can now add this to the growing list of ways that the flu virus has to establish infection,” said Joseph Ashour, a co-author of the Nature paper and a postdoctoral researcher in the lab of MIT professor and Whitehead member Hidde L. Ploegh, Ph.D.

    “This is how the virus gains a foothold,” adds Ploegh lab postdoc Stephanie Dougan, also a co-author of the study. “The virus targets memory cells in the lung, which allows infection to be established—even if the immune system has seen this flu before.”

    To track the interactions between live virus, flu antigens, and the primary B cells specific for them, the scientists needed to overcome serious difficulties—virus-specific B cells occur in low numbers and are hard to isolate.

    The scientists began by using a protein-labeling technology to attach a fluorescent label to influenza virus, thus identifying flu-specific B cells by their interaction with fluorescent flu micelles. (This step was essential because no flu protein can be tagged in the conventional manner with green fluorescent protein in the context of an infectious virus.) Then the B cells’ nuclei were introduced into enucleated mouse egg cells via somatic cell nuclear transfer. This generated a line of mice that harbored B cells with receptors specific for the hemagglutinin of influenza A/WSN/33 virus.

    These mice, called FluBI mice, secrete an immunoglobulin gabba 2b that neutralizes infectious virus. “Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of hemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the hemagglutinin-specific B cells,” noted the scientists. “Mere binding of virus is not sufficient for infection of B cells: this requires interactions of the BCR with hemagglutinin.”

    Besides generating an interesting result about the way influenza works, the scientists have a model that is likely to prove useful in further studies. Indeed, the scientists note that they are aware of no other mouse model that harbors B cells of known pathogen specificity or whose primary B cells produce IgG2b.

    "We can now make highly effective immunological models for a variety of pathogens,” said Dr. Dougan. “This is actually a perfect model for studying memory immune cells.”



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