Volume 6, Issue 48 November 2009
The First Line of Defense
Gregory Barton is also a faculty member of the Henry Wheeler Center for Emerging and Neglected Diseases (CEND). Photo credit: Laura Lau
The flu shot offers great protection against a major illness. But those walking out of the clinic aren't out of the woods yet. Their adaptive immune systems need about two weeks to amass antibodies against the virus. "That window is where you need another mechanism to keep things in check," says Greg Barton, a Berkeley professor of immunology and pathogenesis.
Barton is an expert in that first line of defense, called the innate immune system. And when cells first come under attack, they rely on the innate immune system to hold down the fort until the adaptive immune system can ride to the rescue.
Many details of this critical part of the body's defenses were only discovered within the last decade. Barton is among the first to study what the innate immune system consists of, how it operates, and what scientists are realizing is a major role in inflammation and autoimmune diseases.
"This is the battleground where all the big decisions are being made. It's going to be decided whether or not I survive this infection over the next four hours based on whether I make interferon or not." Known to fight viruses, interferon is regulated by the innate immune system.
The system's scouts are a group of proteins known as Toll-like receptors, or TLRs. They spot potential pathogens and muster the appropriate defenses. Scientists believe there may be just a dozen or so different TLRs, and a similar number of receptors within the cytosol (intracellular fluid) of the cell, so together they must be able to recognize all potential pathogens.
Viruses are particularly tough to detect. Unlike bacteria, which make many molecules unique to their kind, viruses are little more than floating strands of genetic material once inside a cell. While still a postdoctoral researcher at Yale, Barton studied TLRs capable of recognizing snippets of RNA and DNA. Barton considers this a fail-safe method for spotting viruses. "If you base the recognition just on the presence or absence of RNA or DNA, then there's no way the virus can escape detection—it can't do without its own genetic material," Barton says.
However, this approach has a serious drawback. Those same virus-sensing TLRs can sensitize the immune system to the body's own genetic material. This error causes the life-threatening autoimmune disease lupus. "The whole system has evolved to be very carefully balanced," Barton says.
An innate immune system receptor called TLR9/7 detects viruses by recognizing RNA and DNA floating around the cell. Barton's lab found that enzymes in the endolysosome must cleave these TLRs before they are activated. This minimizes encounters with the body's own DNA. Image credit: Gregory Barton
Barton is now investigating how the body guards against autoimmunity. His laboratory has since discovered several mechanisms that keep TLRs and the body's own genetic material apart.
One is physical separation. Human chromosomes are kept neatly packaged within the nucleus of the cell. The genome of an invading microbe, on the other hand, is likely floating about in the cytosol, or corralled into sacs known as lysosomes. These cellular garbage disposals, Barton's group has found, is where DNA-recognizing TLRs lurk. Lysosomes also seldom swallow human DNA. This means TLRs are not only far from the nuclear DNA they shouldn't see, but are located where evidence of infection is most abundant.
Just last year, Barton and colleagues discovered yet another important autoimmunity safeguard. Just as a trigger safety must be removed before the gun can be fired, TLRs must be clipped before they are activated and able to recognize DNA. And lysosomes are chock full of the protein-snipping proteases needed to arm such TLRs.
"We think requiring the protein be cleaved is an insurance mechanism. It means the receptors can only be activated if they get delivered to the right place," Barton says.
Barton is now trying to understand the clipping system in greater detail. He is probing which proteases are involved in TLR processing, and whether clipping actually prevents autoimmunity. To do this, he has engineered mice to send armed TLRs to the surface of their cells. If his theory proves right, these animals should be predisposed to developing autoimmune disease.
More recently, one of his students has found a TLR that can finger viruses without relying on genetic material. Exactly what the TLR is homing in on isn't known, but Barton is eager to find out. "If there is something like that on viruses, we want to know because it would be a great target for therapeutics," he says. It might lead to new ways of battling infections and optimizing vaccines—making for better flu shots in the future.