MALTA—Coming down with the flu—and slowly recovering from it—might seem straight forward enough. But a lot of what happens in your body on a molecular level during the time between initial infection and full recovery is still somewhat of a mystery to scientists.

An improved capacity to track the course of an influenza infection could not only help in the development of more effective vaccines to protect against a much broader range of strains than just a few passing seasonal ones as are now included in annual flu shots, but it could also bring new understanding of the immune system as a whole.

We still don't know "what maintains the size of the immune system" and keeps it in homeostasis, Peter Doherty, of the University of Melbourne's Department of Microbiology and Immunology, said September 11, at the European Scientific Working Group on Influenza (ESWI) fourth annual conference in Malta. Among those who spend their careers studying viruses—and how to fend them off—"it's kind of like the big bear in the room," said Doherty, who shared a Nobel Prize in Physiology or Medicine in 1996 for his earlier work on how the immune system recognizes viruses.

The outward symptoms of the flu are familiar enough. And even on a systems level, scientists can predict, to a certain extent, how the immune system is going to respond to an infection. But, Doherty said, "What we need to get down to is what is going on at a molecular level in these cells" in the immune system under attack.

When the body is exposed to a foreign pathogen, the immune system sends out various lines of defense. One of these first lines, the CD8 T cells, Doherty explained, are like Roman soldiers, fighting shoulder to shoulder (with short swords and large shields so as not to get killed themselves) as "lethal, close-range delivery systems." And by seeing how these cells act when confronted with a new invader, researchers are hoping to disarm the enemy far in advance.

Advances in genomics and epigenetics lately have helped research teams follow individual immune cells, allowing a new view of how the cell populations maintain their diversity over time, and adding clues to how the immune system as a whole changes during and after an infection.

As for the flu, good old-fashioned mouse research (in which researchers "prime" mice with small doses of a strain or two of the flu then later give them a different strain to see how their immune cells ramp up over the course of the infection) has supported much of what researchers now understand about how the body recognizes different strains. Unlike mice who had never been exposed to the flu, mice that first got small amounts of H1N1 survived an infection of the much more virulent H7N7 strain, suggesting that their immune systems were ready to attack even a different form of the virus. But those mice that had gotten both H1N1 and an H3N2 primer were much more effective in beating back the infection quickly.

That said, Doherty pointed out, "we're not nice clean organisms like a lab mouse." As humans age, he noted, our immune systems are exposed to all sorts of infections to which our bodies develop specific antigens. And that makes studying immune responses in humans more complicated.

But research done during the 2009 H1N1 outbreak showed that young children followed very much the same time course as lab mice, launching an immune response in about seven days. This finding adds support to the ongoing research in mice to help develop a better understanding of human immune dynamics.

For now, the flu remains unpredictable. And some strains out there, such as H5N5, are extremely deadly and don't seem to be daunted by an equipped, primed immune system. And for strains like these, Doherty noted, "you can prime up absolutely all the T cells in the world, and it won't make any difference. You need something much more powerful." But as researchers still grapple with a better vaccine for more common flu strains, finding a strong prevention for such a virulent one remains an even more daunting challenge.

Image: Rat OX-8 (CD8) expressed in many T-cells in the paracortex of the lymph node, courtesy of National Institute of Allergy and Infectious Diseases