How Flu Virus Attacks Immune System to Establish Infection

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VirusBcellShedding light on influenza’s insidious nature, scientists from the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts have discovered how the flu virus is able to quickly infect its host by first targeting and then killing off special cells of the immune system that are actually best equipped to neutralize the virus.

Confronted with a harmful virus, the immune system generates B cells capable of producing antibodies perfectly suited to bind to, and disarm, viral invaders. These virus-specific B cells proliferate and secrete antibodies that slow and eventually eradicate the virus. After exposure to a virus a population of these immune cells retains the information needed to neutralize the virus and takes up residence in the lung to ward off secondary infection from re-exposure to the virus via inhalation.

On the surface of these so-called memory B cells are receptors that bind to virus particles to reduce viral spread. While such cells normally serve at the body’s first line of defense, it turns out that the flu virus exploits these receptors to gain entry, allowing the virus to disrupt antibody production and ultimately kill the cells. By dispatching its enemies in this fashion, the virus is able to replicate efficiently before the immune system can mount a second wave of defense. This counter-intuitive pathway to infection is described this week in the journal Nature.

“We can now add this to the growing list of ways that the flu virus has to establish infection,” says Joseph Ashour, co-author of the Nature paper.

“This is how the virus gains a foothold,” adds 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.”

Discovering this dynamic of the virus was no small task, in part because virus-specific B cells are found in exceedingly small numbers and are extremely difficult to isolate. To overcome these challenges the researchers attached a fluorescent label to influenza viruses, thus identifying flu-specific B cells by their interaction with fluorescent flu micelles. The B cells’ nuclei was next enucleated into mouse egg cells via somatic cell nuclear transfer (SCNT) to generate a line of mice with virus-specific B cells and cell receptors.

Though complicated, the generation of mice with B cells specific for a known pathogen allowed Dougan and Ashour to track the virus’s interactions with the cells in unprecedented fashion. Because the infectious process they discovered is likely not exclusive to influenza virus, these scientists believe their approach could have implications for other viruses as well.

The study was supported by the Cancer Research Institute, the Pancreatic Cancer Action Network, the Human Frontiers Science Program, and the National Institutes of Health.

Source: Stephanie K. Dougan, Joseph Ashour, Roos A. Karssemeijer, Maximilian W. Popp, Ana M. Avalos, Marta Barisa, Arwen F. Altenburg, Jessica R. Ingram, Juan Jose Cragnolini, Chunguang Guo, Frederick W. Alt, Rudolf Jaenisch, Hidde L. Ploegh. Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virusNature, 2013; DOI: 10.1038/nature12637