Lessons from a Blood Meal

Usually a mere nuisance, a tick or an insect can turn serious or even deadly when its bite introduces a disease-causing microbe into the blood of its quarry. To avoid disease, humans and other vertebrates fight this intrusion with a host of chemical weapons, some of which hinder the bug's ability to enjoy a leisurely meal. The bugs in turn fight back with chemicals of their own that hide their approach or disarm their prey's defenses. These battles have raged over thousands of years, and both humans and bugs have evolved multiple measures and countermeasures in an attempt to trump one another. According to Dr. Ribeiro, head of the medical entomology section in NIAID's Laboratory of Parasitic Diseases, studying this ongoing conflict offers much potential for understanding these diseases and the body's response to infection. His laboratory identifies biologically active proteins from disease-causing ticks and insects in an effort to understand more about arthropod-borne disease transmission and to devise potential new targets for treatment or control. Many of these proteins are also promising agents for treating other illnesses, such as strokes or blood clots, making Dr. Ribeiro's research relevant to a range of human diseases.

In the battle between humans and bugs, it hasn't historically been a fair fight. From an evolutionary standpoint, arthropods have the advantage. Ticks and insects have been around since long before humans appeared on the planet, but began adding human blood to their diets as soon as it became available. Just as land animals occupy different ecological niches - some live on the prairie, others thrive deep in the woods - blood-feeding bugs are uniquely adapted to their hosts, from which they derive food, shelter, or a place to reproduce. According to Dr. Ribeiro, the earth holds 16,000 species of blood-feeding bugs, compared to 19,000 land vertebrates like reptiles, birds and mammals. In short, there are sufficient species of ticks, mosquitoes, and their kin to go around.

With the abundance of animals on which to feed, different bug species possess unique physical and biochemical properties to enable them to get the most from their chosen meal. Some have biting mouthparts, while some drink blood through a tiny straw-like proboscis. Some drink quickly and take off, while others latch on for an extended drink. Some feed on multiple individuals, while others return to the same host many times for follow-up snacks. As Dr. Ribeiro studies the host of chemical compounds that enable these organisms to fend off the body's defenses and satisfy their need for blood, he finds that each new discovery usually fits into one of three strategies used by the blood-feeder: preventing clot formation, countering the defense, and avoiding the swat.

Stopping the Clot

In two recent reports, Dr. Ribeiro and colleagues describe blood clot inhibitors from the saliva of several bug species. Each inhibitor, however, works in a unique way, illustrating how different feeding strategies require different chemical agents. In one study, the researchers looked at the saliva from the blood-sucking kissing bug, Rhodnius prolixus. This creature looks like many other bugs except for its menacing, needle-like proboscis that thrusts through the skin to draw blood from the underlying blood vessels. Dr. Ribeiro's team discovered a salivary protein that, when injected into the blood by the insect, prevents platelets from clustering together and forming a clot. This allows Rhodnius to get a good drink without a clot blocking his efforts. Doctors use similar platelet aggregation inhibitors to prevent strokes and heart attacks, but the Rhodnius protein works through a different chemical process, suggesting a potential new class of drugs.

In black fly saliva, Dr. Ribeiro's team isolated another protein. This enzyme, hyaluronidase, signals other anti-clotting factors to spread throughout the bite site and also causes small blood vessels near the skin to leak. Black flies have biting mouthparts and lack the imposing feeing tube of Rhodnius, and therefore feed by lapping at a pool of blood located just under the skin, rather than tapping directly into the blood vessels. Hyaluronidase may be critical for drawing the blood through the vessel walls and into these pools while simultaneously directing anti-clotting activities.

Countering the Defense

When studying a species of deer tick that carries the Lyme disease-causing bacteria in the Eastern United States, Dr. Ribeiro's team isolated an immunity-blocking protein from the tick's saliva. A common blood protein, complement, normally drills holes in invading bacteria, marks them for destruction by roving cells called phagocytes, and plays an important role in rejecting ticks. Because ticks feed very slowly, they must spend a lot of time on their host, and complement is an obstacle to a long, leisurely meal. Once again, the bug has a solution. The researchers discovered an anti-complement protein the tick presumably releases during feeding, temporarily halting the body's attempts to reject the bug from its meal site. If the tick's saliva contains a harmful bacterium, such as the one responsible for Lyme disease, this protein also may benefit the microbe by turning off the body's defenses long enough for the bacteria to begin the infectious process.

But stopping the immune response isn't always desired by those who seek a good blood meal. In the sand fly, Dr. Ribeiro and colleagues have studied salivary proteins that cause a special type of allergic skin response called delayed-type hypersensitivity, or DTH. When the researchers compared feeding at DTH sites to normal skin, the sand flies fed to completion twice as quickly at the DTH sites. This is probably because of increased blood flow and pooling associated with DTH. "It appears that the flies can manipulate the immune response of their host, specifically stimulating DTH, to get a better meal," explains Dr. Ribeiro.

Stopping the Swat

In addition to these features, some arthropods might also be anesthesiologists, using chemical components of their saliva to reduce discomfort in their selected targets. Dr. Ribeiro and other scientists have located several proteins in tick saliva that might block pain locally. By preventing the feel of a bite, the tick buys more time on the host.

"The saliva of blood-eating bugs contains a complex and advanced pharmacy that can teach us much about human skin, blood, and the immune system," explains Dr. Ribeiro. For example, the anti-complement agent in deer ticks is the smallest such compound identified, making it a potentially useful tool for dissecting how complement proteins work; and researchers are using the mosquito proboscis as a model for new mechanisms of painless drug delivery. In addition, Dr. Ribeiro's laboratory will continue to catalogue the biologically active proteins from disease-causing ticks and insects in an effort to understand more about disease transmission and to devise potential new targets for treatment or control.

"There's a moral of humility here," notes Dr. Ribeiro, "They've been working at understanding our vascular physiology far longer than we have, and it shows. The goal of my lab is to try and catch up."