Photo of Shirley Luckhart with student Cheick Coulibaly Cheick Coulibaly, a student from the University of Bamako in the West African country of Mali, where malaria is a major human health problem, is working with researcher Shirley Luckhard to find associations between a mosquito's genetic makeup and infection with the malaria paraiste.

From ancient Chinese herbal remedies to fourth-generation antibiotics, humans have a long history of waging war on disease.

Yet today, infectious diseases still kill over 10 million people worldwide each year, second only to cardiovascular disease as the leading cause of death. In the United States alone, infectious diseases send nearly 26 million people to doctors' offices and over 3 million to emergency rooms annually.

As biomedical technology grows ever more sophisticated, UC Davis researchers like Charles Bevins and Shirley Luckhart are using new tools to tackle infectious diseases in ways that are as innovative as they are surprising.

First wave of defense

As a post-doctoral researcher in 1988, Charles Bevins was charged with harvesting eggs from frogs for genetic studies. After each mini abdominal surgery, "we closed the incision with a few sutures then returned the animal to its tank. It was an environment that was anything but sterile," he recalls.

"Once we better understand [defensins], they're going to bring about new approaches in therapeutics."
— Researcher Charles Bevins

Instead of becoming infected and dying, "they healed without any infection or even any signs of inflammation. So the obvious question for us was what could possibly underlie that phenomenon."

Without further ado, Bevins, a professor of medical microbiology and immunology, abandoned genetics to study defensins, a newly discovered class of naturally occurring antimicrobial peptides.

Just three years later, he was among the first to find defensin peptides in mammals – more precisely, in the tracheas of cows. Since then, he and others have found them in humans and in every mammalian organ and tissue they studied.

Wet mucosal surfaces – like the lining of the intestine, or a frog's skin – are particularly adept at churning out defensins.

"Mucosal surfaces are engaged in important physiology, so they're in continuous intimate contact with the outside world, which often includes nasty pathogens," Bevins explains. "Defensins are key to their first wave of defense."

In exploring the role the compounds play in various diseases, Bevins – who's been at UC Davis since 2003 – has teamed up with a host of campus colleagues.

Photo of Charles Bevin and student Hiutung Chu Researcher Charles Bevins, pictured with doctoral student Hiutung Chu, focuses his research on defensins, a newly discovered class of naturally occurring antimicrobial peptides, and has found a growing number of links to common diseases.

He and microbiologist Andreas B.umler are investigating how the antimicrobial peptides may protect against Salmonella, the most common cause of death from food poisoning. Jay Solnick, a professor of internal medicine, is drawing on Bevins' expertise in studies of defensins in Helicobacter pylori infection, the major cause of gastric ulcers.

And neonatologist Mark Underwood, an assistant professor of pediatrics, is working with Bevins to probe their hypothesis that a lack of defensins may underlie the intestinal inflammation that characterizes necrotizing enterocolitis, a devastating disease of premature newborns.

"What we imagine is that the immature guts are not making enough of the peptides to handle the microbes they are confronted with," Bevins says. Consequently, the body is forced to resort to its "second wave" of defense – activation of white blood cells and inflammation.

In 2005, Bevins and his team linked a similar process to another inflammatory disorder of the bowel – Crohn's disease. They found that levels of HD-5 defensin – a peptide normally produced in the small intestine – were abnormally low in patients with a common form of the disease. Bevins says that a biopharmaceutical company may be taking HD-5 into clinical trials for Crohn's disease within a year or two.

It's only been in the last few years that hard links between defensins and common diseases have been established, Bevins points out. "Yet in a few more years, once we better understand these molecules, they're going to bring about new approaches in therapeutics."

Targeting mosquitoes

The numbers can take your breath away. Each year, malaria strikes 350 to 500 million people and kills more than one million, mostly children. The hardest hit regions are usually the poorest: places where families can't afford five dollars for a bed net to ward off the mosquitoes that transmit the malaria parasite, or even 13 cents for the chloroquine tablet that could treat the disease.

That's why Shirley Luckhart, an associate professor in the medical school's Department of Medical Microbiology and Immunology, is working on an international effort to develop a genetically altered mosquito that cannot transmit the parasite.

"The basic aspect of my work is comparative immunology," she says. "That is, looking at what actually occurs when mosquitoes take a blood meal from a human host with malaria. Up until a few years ago, we really didn't appreciate that there are quite a few proteins and factors that come in with blood that can function inside the mosquito."

One of those factors is human insulin. In 2007, Luckhart found that this hormone decreases a mosquito's lifespan. Now she's embarking on a project that could lead to bioengineering mosquitoes that are particularly susceptible to insulin.

"The idea is to create a mosquito that can't live long enough to develop the malaria parasite to maturity," she says. "It takes only three days for a mosquito to complete a batch of eggs, but 12 days for the parasite to mature after the mosquito acquires it during a blood meal."

Working with mosquitoes can be challenging, Luckhart observes. Many of the tools that have been developed to study mammalian cell biology and immunology are not available to her.

"We're constantly pushing to develop new strategies and technologies," she says. "We're using genomics, bioinformatics and proteomics technologies. Mosquitoes don't have the firepower of mouse or human research. I can't just call up my favorite biotech company and order a panel of reagents for screening, say, 50 analytes in mosquito tissue."

On the other hand, pioneering a new field has its own rewards. We're finding out how a mosquito's immune system is similar to ours," Luckhart says. "It's really exciting. There's always a lot of discovery."