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Solving a Flu Mystery, in Time for Flu Season

October 24, 2013 | Matthew Tontonoz

The sniffles and sneezes, aches and pains that besiege us every year from October through February—otherwise known as flu season—are one of the principal banes of winter. Most people recover from a bout of flu in about a week, but for some vulnerable populations—children and the elderly especially—flu can be deadly. Flu kills anywhere from 250,000 and 500,000 people annually, and that’s not even considering the supercharged flu strains that cause periodic worldwide pandemics, like the 2009 “swine flu.”

Stephanie Dougan is a CRI-funded postdoc in the lab of Hidde Ploegh at the Whitehead Institute for Biomedical Research at MIT.

To help protect against flu, doctors recommend that people get a flu shot every year. But even then, we’re not 100% protected.

Thanks to a new report published in the journal Nature, scientists have a clearer understanding of why that is. According to CRI postdoctoral fellow and lead author Stephanie Dougan, the flu virus has evolved an especially sneaky and insidious method for gaining a foothold in our bodies.

First, some background: Flu virus enters the body through cells in the respiratory tract, including the lungs. When someone sneezes, the virus becomes aerosolized and can pass from person to person. To protect us against flu (and other previously encountered viral enemies), the lungs contain a population of “memory” B cells that are primed to respond to these invaders by churning out antibodies, which function like heat-seeking missiles. These memory B cells represent a crucial first line of defense from infection, and flu vaccines work in part by stimulating production of memory cells loaded with a stockpile of antibodies specific for that year’s flu strain. 

Flu virus particles. Antibodies bind to protein "spikes" that make up the viral capsid, or exterior.

Here’s where the virus gets sneaky. In order for flu virus to infect B cells, Dougan and colleagues have found, the virus needs to bind to a receptor on B cells. But not just any B cells—only those B cells with a receptor specific for one of flu’s identifying proteins. Once it finds those B cells, the virus maneuvers inside and disables the B cell’s antibody-making machinery. A few hours later, the infected B cells die. By quickly and efficiently dispatching the very cells that are capable of mounting a frontline attack, the virus steals precious time with which to spread unchecked in the lungs. 

“This is how the virus gains a foothold,” says Dougan. "The virus targets memory cells in the lung, which allows infection to be established—even if the immune system has seen this flu before."

The discovery is easy enough to explain, but the technological maneuvers that were necessary to conduct the experiments were quite a bit more complicated. In order to study how flu interacts with a specific population of flu-specific B cells, which are normally very rare in the lungs, the researchers had to first create a transgenic mouse whose B cells all displayed a flu-specific B cell receptor. They did this by taking the DNA-containing nucleus out of one such B cell, implanting it into a mouse cell whose nucleus had been removed, then coaxing that one cell to develop into a full-grown mouse. Called somatic cell nuclear transfer, this is the same technique that researchers used back in 1997 to clone Dolly the sheep. It’s a painstaking process, but once successful it means you have an endless supply of just the particular flavor of immune cell you want to study. 

Dougan says the technique has broad potential application to the field of immunology and cancer immunology. In fact, Dougan published another paper earlier this year in Cancer Immunology Research showing how the technique could be used to generate T cells specific for particular tumor antigens—an extremely useful population of cells to have. T cells, of course, are the main adaptive immune cells that seek out and destroy cancer cells. Being able to produce designer T cell specific for different types of cancer antigens has great potential to push the field forward.

Flu can be deadly. Above, a hospital ward at Camp Funston in Kansas during the "Spanish flu" pandemic of 1918, which killed 3-5% of the world population.

"For cancer," says Dougan, "the most important part of this paper is that it highlights the transnuclear mouse technology, which we are hoping will become widely accepted among immunologists as the best way to model antigen-specific T and B cell responses."

What about tips for avoiding or preventing flu—does this research offer any? Unfortunately, the main takeaway lesson of Dougan’s paper, which features CRI postdoctoral fellow Chunguang Guo as a co-author, is that it’s hard to fully protect oneself against flu. A flu shot can certainly help (and many doctors stress you are wise to get one) but the virus has some pretty clever means of usurping our best defenses. No wonder it’s so hard to beat.

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