Wenqing Xu, Ph.D., 2003 Investigator in Pathogenesis of Infectious Disease
2005 - When 17th century poet John Donne penned the oft quoted verse, “never send to know for whom the bell tolls, it tolls for thee,” he was referring to the ravages of the plague—a deadly infection and the scourge of humans from time immemorial. Death from the plague and many other infections is due to septic shock, a condition in which the body’s immune system shuts down the organ systems in response to systemic bacterial infection. Septic shock is the ultimate result of an immune system’s failure to keep pace with a pathogen’s advance through the host’s body. But septic shock is relatively rare. What about the vast majority of bacterial infection, which is caught by the oldest and most conserved part of our defense system, the innate immune system, and destroyed before we even know we are infected?
Until recently, few researchers were able to address this kind of question. But in the past several years, experiments that started with fruit flies and now extend into humans have revealed the existence of a network of so-called “toll-like” receptors that may finally solve the mystery of innate immunity.
“Innate immunity is essential for quick response to bacterial infections,” says Wenqing Xu, a 2003 BWF Investigator in Pathogenesis of Infectious Disease and an associate professor of structural biology at the University of Washington School of Medicine. “Innate immunity has to have certain pathogen-recognition ability encoded in the genome, ready and waiting all the time to attack. It is our first line of defense. We are very interested to learn how it does this.”
Dr. Xu is one of a growing cadre of researchers working to understand how the innate immune system’s front line, a small family of 10 toll-like receptors, can effectively recognize and dispose of a huge variety of infectious organisms. As the first line of immune defense, the toll-like receptors recognize the molecular signatures associated with potential pathogens and then send signals to recruit the white blood cells, including the macrophages that engulf the invader, while simultaneously signaling adaptive immunity, the body’s later-evolved and more specific immune response, to gear up for a fight.
The structure of the toll-like receptor proteins is a particularly interesting question for Dr. Xu, because as an X-ray crystallographer, he possesses the research tools and experience that can help him visualize the precise protein-protein interactions that trigger the various signaling components of the innate immune response. He has a few clues to help him get started. Scientists working with the fruit fly first discovered the toll receptor as a developmental protein that is necessary for proper formation of the insect’s basic body plan. Only later did they find that it can trigger production of anti-microbial agents to fight infection. Additional studies showed toll-like receptors served a similar function in humans.
“We know that the toll-like receptors contain leucine-rich repeat regions that recognize, for example, bacterial lipopolysaccharide, a unique component in gram negative bacteria, not present in human cells,” says Dr. Xu. “The big question is how can these receptors, which are all structurally similar, recognize so many different pathogen components.”
Dr. Xu has experience in determining the structures of medically important proteins, having been part of the team at the Massachusetts Institute of Technology that crystallized the key signaling protein SRC. When he set up his own lab at the University of Washington, he wanted to choose “something medically important, something closely tied to infectious disease,” he recalls.
He is currently working on determining the X-ray crystal structure of TLR2, a toll-like receptor that plays a role in peptidoglycan signaling. Other projects in his lab include determining the crystal structure of a complex between a lipopolysaccharide-recognizing toll-like receptor, TLR4, and an accessory protein, MD-2, that helps it signal the body to trigger inflammation. TLR4 is important, he says, because it plays a role in the series of events that lead to septic shock, the nearly always fatal result of the immune system overreaction to the presence of bacteria in the bloodstream. Dr. Xu says he is hopeful that “our structural studies will help to design inhibitors of the TLR4 pathway that can be useful for the treatment of septic shock and other infectious disease.”
The next time the death bells tolls, researchers like Dr. Xu are working to make sure it tolls for bacteria and not for thee.