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    California Pacific Currents 2000

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    Researchers Strive to Unlock the Secrets of a Major Threat to AIDS Patients

    Luiz E. Bermudez, M.D., Lowell S. Young, M.D.

    If you're not infected with HIV or not immunocompromised in some other way, you have little to fear from Mycobacterium avium. But if your immune system is seriously weakened, you may be at risk from this common microscopic organism, which can deliver a life-threatening wallop.

    Mycobacterium avium is a species of bacterium related to Mycobacterium tuberculosis, the pathogen that causes TB. Unlike M. tuberculosis though, which lives only a matter of hours outside the human body, M. avium is everywhere in the environment, including soil, food, and water. Almost everyone has the bacteria in their body, but a normally functioning immune system protects them from infection.

    Not so with AIDS patients. M. avium can disseminate throughout their bodies, often infecting the lungs, intestines, bone marrow, liver, and spleen. An estimated 50% of people with AIDS develop M. avium disease, called Mycobacterium Avium Complex (MAC), especially if their T-cell count is below 50. It is the third most common opportunistic infection among AIDS patients, and the result can be blood infections, hepatitis, pneumonia, and other serious conditions.

    Starting at Ground Zero
    In response to the problem, investigators at California Pacific Medical Center Research Institute's Kuzell Institute for Arthritis and Infectious Diseases have set themselves an ambitious task. “We strive to be the leader both in understanding how MAC develops as well as how to treat it,” says Lowell S. Young, MD, Kuzell Institute director, who was also chief of the Division of Infectious Diseases at the medical center from 1985 to 1999. “Before we began work on M. avium in 1985, nobody knew much about it. We started from ground zero and are working our way through.”

    Antibiotics inactivate or kill bacteria, a well-known fact. Then why is it so difficult to thwart M. avium when the world's pharmacopoeias are full of antibiotics? For one thing, the bacterium mutates with alarming speed; in some cases, developing resistance to an antibiotic in a matter of months. For another, M. avium was little studied before the AIDS epidemic, so there was scant knowledge about how the pathogen infects human macrophages, the principal cell M. avium targets. Without this understanding, anticipating which antibiotics might be effective was difficult.

    “When I came here in 1985, Dr. Young already had a contract with the National Institutes of Health to discover new therapies for MAC,” says Luiz E. Bermudez, MD, a senior research scientist at the Kuzell Institute. The contract is ongoing, and over the years researchers at the institute have found several drugs that effectively treat disseminated MAC disease.

    Searching for New Treatments
    To discover new pharmaceutical treatments for an indication relies on massive screening of drugs — old and new,” says Dr. Bermudez. This is a time-consuming process requiring each drug candidate to be tested in vitro (not in the body but in a petri dish or test tube) against cultures of M. avium. Sounds straightforward, but there's a hitch. “A lot of times a drug is very active against M. avium in vitro, but when you put the bacterium in an environment that more closely resembles that of the host cell, the drug becomes less active,” says Bermudez. This is a recurring theme with M. avium — it exhibits complex and variable behavior that is difficult to predict and sometimes even to understand.

    Testing at the Kuzell Institute, however, was crucial in discovering two antibiotics that have become the mainstay of anti-MAC therapy: clarithromycin and azithromycin, both belonging to an antibiotic group called macrolides. The drugs are extraordinarily effective against the pathogen, except that M. avium mutates, develops resistance to macrolides over time, and the patient is once again defenseless.

    “The normal thing is to develop resistance to a macrolide, and then you continue the macrolide and add other drugs,” says Dr. Bermudez. “But we're trying to come up with an oral regimen that does not contain macrolides at all.” And they have. Recent research at the institute has uncovered two more drugs, moxifloxacin and mefloquine, the latter a drug used against malaria. Interestingly, these drugs also show effect against drug-resistant tuberculosis.

    It's not enough to show that a drug works against M. avium, however. “We need to know why,” says Dr. Bermudez. Understanding the activity of a drug against the pathogen at a molecular level can lead to the creation of new drugs based on a similar principle. “Once you know where the drug is acting, you can design rational therapies or improve a drug such as mefloquine to eliminate side effects,” he adds.

    Understanding the Pathogen
    Along with efforts to understand drug activity against M. avium, Kuzell Institute researchers are working to tease out the most basic mechanisms of the organism: How it gains access to the host cell (the macrophage), disables its normal functions, reproduces in the host, and how its bacterial offspring go on to infect subsequent macrophages.

    Macrophages (literally, “large eater” cells) are scavenging cells of the immune system that engulf, digest, and remove microorganisms and cellular debris from the body. This presents a conundrum: How is it that M. avium hijacks the very cells designed to eliminate it?

    As seen with screening of drugs for activity against the microorganism, M. avium exhibits different behavior in live hosts versus in vitro experiments. Not only that. Its activity varies in the live host, too, depending on whether it is the initial M. avium bacterium to invade a macrophage or a daughter bacterial cell produced in the macrophage by the infection. These daughter cells are released from the macrophage and go on to infect other macrophages.

    Kuzell Institute researchers are using advanced molecular and genomic techniques to explore the organism's protean nature. These methods enable, for example, detection of the macrophage receptors the bacterium binds to when entering the host. The initial M. avium-infecting cell uses one type of receptor; the daughter cells use another. "Now we know the receptors,” says Bermudez, “and we're trying to learn more.” Like, how does the bacterium bind to the receptors? How does this modify the natural life of the bacterium in the macrophage? How does the intracellular environment of the macrophages infected by the daughter cells differ from that of the macrophages infected by the parent bacteria?

    Pursuing More Leads
    Another mystery is how the mycobacterium gets past the natural barriers of the stomach's acidity and the intestinal mucosa to infect the body. Most disseminated MAC infections result from food or water intake, so the organism must pass through the digestive system first. Recent published studies by Bermudez and colleagues reveal that, unlike many bacteria, M. avium is resistant to the acid conditions of the stomach.

    Once in the intestine, M. avium infects the intestinal mucosa, seemingly inhibiting or delaying the production of cytokines and chemokines, which are chemicals produced by the body to aid the immune response. How this happens is also subject for future study and more evidence that M. avium is indeed a cunning microorganism.

    Stepping up to TB
    Another challenging agent is M. tuberculosis, the current primary focus of Dr. Young. As with M. avium, the Kuzell Institute is working with the National Institutes of Health to screen drugs for efficacy against tuberculosis, especially drug-resistant TB. “The TB patients most in need of new drugs don't live in the Bay Area,” he says. “They live in Africa, Asia, and South America. There are only 20,000 cases of TB in the U.S. in comparison to 2 to 4 million cases worldwide. There's a tremendous need for new treatments.”

    Dr. Young travels the world in pursuit of new knowledge of the disease and to present the institute's latest research. “If you look at the former Soviet Union, a lot of their medical problems are with drug-resistant tuberculosis. Really horrendous is the only way to describe the epidemic.”

    What's in the future for the Kuzell Institute? More research on M. avium and an increasing involvement in tuberculosis research, says Dr. Young. “We have a lot of interesting ideas that we hope will prove fertile.”