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Biomedicine

Taking On the Common Cold

Colds researchers deleted the word “cure” from their lexicons in the early 1960s when they discovered that some 200 different viruses can cause colds-far too many to conquer with a vaccine, the conventional method of defeating an infectious disease. With the discovery of each new family of cold virus-rhinovirus, coronavirus, Coxsackie virus, adenovirus, respiratory syncytial virus, to name a few-researchers sank into a deeper funk. And as funding for common-cold research by the National Institutes of Health dwindled to its current level of $2 million per year, a mere 0.02 percent of its total budget, most researchers moved on to study influenza, herpes, AIDS, or other viral diseases.

But after years of low-profile research, biologists who remained dedicated to fighting the common cold believe they have homed in on a strategy both to stop cold viruses from replicating and to dampen the immune response that produces symptoms-together, the closest thing yet to a cure.

This optimistic scenario evolved in parallel with the gradual scientific unraveling of how the immune system reacts-or, more precisely, overreacts-when it encounters a cold virus. In fact, although cold viruses infect only about 1 percent of the epithelial cells that line the nasal passages (a mere pinprick compared with most other infectious viruses), they induce the immune system to launch a full-fledged attack that can result in the all-too-familiar congestion, runny nose, aches, and pains.

No one is sure why the immune system reacts so vigorously or why the resulting symptoms make us feel so lousy. But research shows that this aggressive response is present in vertebrates and invertebrates, suggesting that as humans evolved, the benefits of overkill outweighed the disadvantages.

In any case, viewing the immune system as part of the problem, rather than blaming only the viruses, is “the start of something new,” says Jack M. Gwaltney, Jr., a professor of medicine at the University of Virginia School of Medicine who has pioneered treatments aimed at shutting down the body’s runaway reaction to cold viruses. An important clue led Gwaltney and his colleagues to this novel theory: the knowledge that even though many different viruses cause colds, the body’s reaction is almost the same for each one.

This response begins after virus-laden droplets, often from someone else’s sneeze or cough, come in contact with nasal epithelial cells. In the case of rhinoviruses, a strain that causes most colds, the virus attaches to a receptor that coats the surface of the cells. This receptor, called intercellular adhesion molecule-1, or ICAM-1, is as slippery as silk to most of the natural world but is like Velcro to a rhinovirus.

Once the virus invades the nasal cells, the cholinergic nervous system-an early line of defense, so named because its signals are transmitted by a neurotransmitter molecule called acetylcholine-responds by triggering the secretion of a thin watery fluid through the mucous membranes to try to flush out the virus. When this happens, most people immediately sense they are coming down with something.

A molecular biologist would need a couple of hours, a large blackboard, and several colors of chalk to diagram what happens next as cells infected by the virus tap into the body’s equivalent of the Internet-a complex set of immune reactions, some of which help repel or destroy the virus, but which also may make people miserable.

First, the epithelial cells release histamine, a protein hormone (or cytokine) that dilates nearby blood vessels and floods the region with fluid, exacerbating an already runny nose. At the same time, infection-fighting white blood cells that are pulsing along arteries near the infection recognize a beacon generated by cytokines from the stressed epithelial cells and slither out of the swollen blood vessels to reach the infected tissue.

Once they arrive, the white cells release cytokines of their own, including interferon-alpha2, which signals nearby cells to make enzymes that interfere with viral replication. They also signal the infected tissue to release prostaglandin, a hormonelike compound that increases dilation of nearby blood vessels, raises body temperature to slow virus replication, and initiates the production of neutralizing antibodies. A physician would call the end result “inflammation” since the affected nasal tissue appears reddened, warm, swollen, and tender, but most people would just call it a bad cold.

Gwaltney and others hoped that colds might be cured when interferons were discovered. But human trials proved that these antiviral cytokines did virtually nothing to reduce cold symptoms. Unfortunately, traditional anti-inflammatory drug treatments alone didn’t work either. As Gwaltney explains, it’s still essential to deplete the virus, not because it is so dangerous-it isn’t-but because it will prolong the powerful immune response, much like the burr under the saddle of a horse will make a horse keep bucking uncontrollably.

Gwaltney wondered what would happen if a combination of anti-inflammatory and antiviral drugs would be effective. So in 1992, he gave human volunteers deliberately infected with cold viruses a nasal spray containing three drugs: Ipratroprium, an FDA-approved anticholinergic drug that competes at nerve receptors with acetylcholine (to dampen the cholinergic nervous systemcaused runny nose); Naproxen, an FDA-approved anti-inflammatory drug that interferes with prostaglandin synthesis (to reduce dilation of blood vessels, pain, and fever); and the antiviral cytokine, interferon-alpha2b (to inhibit replication of rhinoviruses). He found that the drug combination reduced symptoms from rhinovirus infections but was ineffective against other cold viruses.

Gwaltney, who has a patent on the drug therapy, hopes that it will reduce symptoms in the 50 percent of colds caused by rhinoviruses. He is currently seeking a pharmaceutical company to package and sell his treatment.

In the search for agents that would be effective against all cold viruses, researchers have since discovered other cytokines in the fluid of tissue infected with cold viruses. Ronald Turner, director of the Division of Pediatric Infectious Diseases and Clinical Immunology at the Medical University of South Carolina, says that one of these, interleukin-8 (IL-8), is found in virtually all cold patients’ nasal fluids, while cytokines that are involved in other kinds of infections are present only some of the time.

That evidence has led him and others to propose that an effective IL-8 blocker, if one could be developed, might short-circuit the inflammatory process in all colds. In fact, the pursuit of safe and effective cytokine blockers, including an IL-8 blocker, is now one of the hottest areas of research in a number of pharmaceutical companies-not only for the treatment of viral diseases but also often fatal bacterial infections.

Antiviral Agents

Researchers at Agouron Pharmaceuticals in La Jolla, Calif., claim to have discovered other compounds that attack cold viruses, including one that inhibits 3C protease, an enzyme essential for rhinovirus replication. The enzyme, which is shaped like a doughnut, slips down the long viral protein and cuts the strand in just the right places prior to replication. Agouron is developing chemicals that it says can plug the doughnut hole and immobilize the enzyme.

On another front, Bayer Corp. is testing a spray that keeps rhinoviruses from attaching to the ICAM-1 receptors on nasal epithelial cells. The spray, which contains soluble ICAM-1, has reduced the occurrence of colds in chimpanzees. The company plans to test the spray on human volunteers who will be given the spray a few times a day during the cold season to determine if it will reduce their incidence of colds.

If such antiviral compounds prove successful, they could be used prophylactically to prevent a cold from occurring in the first place, thus obviating the need for anti-inflammatory drugs. But according to David Proud, a biochemist and professor of medicine at Johns Hopkins who is also engaged in colds research, such a product might not find much of a market unless it is accompanied by an anti-inflammatory agent. “Obviously, you’d like to block cold viruses as early as you can in the pathway,” he says. “But the fact is that most patients won’t be willing to spend money until they get infected.”

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