Xiao-Qiang (Sean) Yu is looking for a way to cure disease, though he has never been to medical school. His diagnoses take place under a microscope, not on an examination table, and his primary patients don’t talk much—instead, they buzz. “The research in my lab actually uses insects as a model to study immune systems,” Yu explains. “We know that some infectious diseases, like malaria, dengue fever, yellow fever, and West Nile fever, are caused by viruses or parasites but are transmitted by insects like mosquitoes or ticks. We try to understand why insects can kill pathogens, but why they cannot kill these viruses and parasites that cause disease [in humans].”
Insect defenses are not the same as human immune systems, but understanding how insects fight infection has implications for the treatment of people. Yu observes that “there are molecules in insects that can recognize and trigger immune responses. Insects don’t have lymphocytes, but they do have blood cells that can phagocytose,” or eat unwelcome cells. He is trying to understand how those molecules recognize invaders, and what they do to signal a defensive response.
Though mosquitoes lack white blood cells or antibodies, they share a surprising amount of immunological common ground with humans. “There are two major branches of systems: the specific immune system that requires the T-cells and the B-cells, the lymphocytes,” Yu notes. “The other we call the innate immune system, which comes with you.” The specific (or adaptive) immune system learns new ways to fight disease, such as the chicken pox. Vaccines introduce weakened or dead viruses or bacteria for the immune system to fight, so that the body will not be compromised by that same invader again. The innate immune system does not change or learn after encountering a pathogen, however; it remains the same from birth to death.
Both the adaptive and innate immune systems fight disease in the same basic ways. In invertebrates, including insects, and plants, the recognition proteins found in innate systems function similarly to human antibodies, which bind to pathogens and alert killer T-cells to destroy the bound bacteria or viruses. B-cells in adaptive immune systems generate antibodies for each new invader they encounter; in insects, different recognition proteins do the job. “One set of proteins may recognize bacteria, another set may recognize viruses, and another may recognize parasites,” Yu explains.
The next step in an innate immune system comes in the form of small peptides, amino acid combinations that respond to microbes once recognition proteins have spotted an attacker. “Most insects produce similar antimicrobial peptides, but some are species-specific,” Yu notes. This makes some insects vulnerable to certain microbes, but resistant to others.
Yu has a special interest in these peptides because they may have the most direct effect on human immunology. Modern medicine relies heavily on antibiotics, synthetic compounds that have side effects. “Peptides are small proteins made of natural amino acid,” says Yu, “so they don’t have side effects.” Insects use antimicrobial peptides as the first line of resistance against viruses, parasites, and fungi, as well as bacteria—“they could be a good candidate to eliminate pathogens in insects, if we increase their activity,” he speculates. “We may do some modifications to see whether we can just increase [the peptides’] potency or activity.” Eliminating diseases like malaria in insects would have a positive effect on public health, but Yu’s work may reach even farther: antimicrobial peptides produced by insects could be used against human infections. Scientists at Dalhousie University in Nova Scotia have observed the peptides destroying bacteria, viruses, and even cancerous cells, all without creating resistance to treatment as antibiotics do.
Innate immune systems are effective: “If you manually introduce bacteria into the insects, about 95% can be cleared from open circulation in insects and eliminated in about two hours,” says Yu. But not all pathogens are cleared: some that cause disease in insects remain, as do those that affect humans. Yu suggests that this phenomenon is related to the co-evolution of insects and pathogens. That is, pathogens not targeting insects have figured out how to use the creatures for their own devices. Viruses and parasites “take advantage of insect proteins and mask themselves against the host immune system, so that they can escape the surveillance of the insect immune system,” he explains. Why some pathogens adopt this strategy and others do not is still a mystery.
Yu is delving deeper into insect-parasite interactions to solve that mystery. Like any good clinician, he calls on specialists from other departments when he needs more information. “One faculty member in Columbia is working with mosquitoes, and sometimes I get help from her,” he says; “another faculty member works with nematode (roundworm), which I like to use as a parasite.” His own expertise lies in biochemistry and molecular biology, so having a broader perspective on his patients’ environments, behaviors, and susceptibilities assists in his diagnosis.
Applications for this kind of immune system research extend into other areas. Pest insects can cause massive damage to crops, but the methods used against them cause pollution of water and soil sources. Rather than using harmful insecticides, Yu asserts, “the better way would be to use biological control: pest enemies, like wasps.” For this method, we “need to understand insect immune systems and how they respond to biological reagents.”
Every class Yu teaches relates in some way to his basic interests. “I can always introduce some of the research if it is related to the course,” he says, “so that students understand the concepts better. If they are junior or senior students interested in summer research, we always welcome them to come and do some work in the lab.”
The University of Missouri Research Board grant that Yu received in 2004 kept that opportunity for lab research open. Yu says that UMRB funds came at “a critical time” in his project, bridging the time between larger awards, which included two National Institutes of Health (NIH) grants. “If you don’t have any funding to continue your research, even for one year, then it’s difficult to pick up the research again,” he explains. “The UMRB is supporting new investigators when they need this bridge funding.” Most of the funds were used for supplies—though his patients may be tiny, their medical expenses are very substantial.
Seeking additional funds to continue his study, Yu plans to apply for more NIH grants, as well as funds from the National Science Foundation. As a doctor of cell biology, his tool of choice is a microscope rather than a stethoscope—but in this doctor’s hands, that microscope can be a powerful force for good health.