Host vs. Microbe: Disarming the Bad Bugs

BY MARK SHWARTZ

WINTER 2006 -- We tend to think of germs as solitary pests that occasionally invade our immune system and cause infections. In truth, the human body is home to trillions of bacteria, viruses, and other microorganisms -- some virulent, some benign.

"We're covered with microbes, inside and out," says Packard immunologist Alan M. Krensky, MD, the Shelagh Galligan Professor in the Stanford School of Medicine. "That's a little scary, especially because there are a lot of organisms that we don’t know anything about."

Understanding how individual pathogens interact with a child's developing immune system is likely to lead to novel treatments for a wide range of infectious and autoimmune diseases, adds Krensky. "It may be that microorganisms can impact childhood diseases in many ways," he says. "For example, diabetes, inflammatory bowel disease, and even multiple sclerosis may be a late response to some kind of underlying infection."

Unraveling the complex biochemical relationship between host and microbe is now a central focus of pediatric research at the Stanford Institute for Immunity, Transplantation and Infection.

To illustrate this pioneering cross-disciplinary effort, Krensky points to the work of Manuel Amieva,MD, PhD, assistant professor of pediatrics and of microbiology and immunology at Stanford.

"In medicine, you look at your patients' symptoms and try to figure out what's going on -- is there an infection, for example," explains Amieva. "When you study microbiology, you start with the microbe and work backwards to uncover what condition it might cause. Our lab is a place where those two different approaches meet."

Amieva became fascinated with microorganisms early in his career. "When you look at the human body through a microscope, you see a landscape inhabited by all kinds of creatures of all sizes and shapes," he says. "We're talking about things that are 10 million times smaller than we are, so for them, our body is like a planet and a single cell becomes a whole city. Disease is really a product of little tricks or tools that these bugs use for survival."

Clever Ploys

Immunologist and microbiologist Manuel Amieva, MD, PhD, is studying how microbes attack cells within the body to better combat infections in children.

Right now, Amieva is studying some of the clever ploys bacteria use to invade a protective layer of cells called the epithelium that lines the gastrointestinal tract. "These very specialized epithelial cells form a barrier that keeps microbes out," he says. "We want to find out how the bugs interact with individual cells to penetrate this barrier, because when they get in, they have the potential of causing very severe disease or killing us."

His lab is focusing on two types of bacteria that are potentially harmful to children: Helicobacter pylori, which is associated with gastric ulcers and cancer of the stomach, and Listeria, a relatively rare but extremely lethal infection, especially in developing fetuses and newborns. "Listeria alone accounts for about 30 percent of all deaths caused by food-borne infections in the U.S., and most of these deaths are in babies," says Amieva.

H. pylori and Listeria invade the body by finding or creating weaknesses in the epithelium. Instead of attacking the cells head-on, the bacteria look for tiny gaps in the glue that holds the cells together.

"The bugs take advantage of this little Achilles heel of epithelium," explains Amieva. "Some of them find places where gaps naturally open, while others actually sit on the cell and with a needle inject proteins that open up a gap from inside. If we interfere with the functions of this little syringe, then perhaps we could alter the outcomes of the infection."

Mixed Signals

Interpreting the intricate signals between bacteria and their host one day could lead to individualized treatments for children, he says: "That's where the dreaming stage comes for me. For example, can we invent our own microbes with syringes that target bad cells, like cancer cells, or that trigger specific host responses?"

Following septic surgery to treat a bone infection in her knee, 3-year-old Mia Luna Ruiz gets a check up from Sharon Chen, MD, at Packard's Infectious Diseases Clinic.

Such groundbreaking therapies are likely to be achieved through multidisciplinary science, adds Amieva, whose current Stanford collaborators include bacteriologist Stanley Falkow, PhD, biochemist Julie Theriot, PhD, and developmental cell biologist W. James Nelson, PhD.

"There may be bacteria that cause other cancers, immune diseases, and skin diseases, so it's important to do research with experts in different fields who might have different perspectives," he says. "The more we understand how these microbes get in, the more sophisticated we can be in combating them."

Translational Research

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A Perfect Place to Heal

Host vs. Microbe:
Disarming the Bad Bugs