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Científicos patrocinados por los NIH resuelven código genético del gusano que causa elefantiasis

NIH-Funded Scientists Solve Genetic Code of Parasitic Worm that Causes Elephantiasis

More than 150 million people worldwide are infected with filarial parasites — long, thread-like worms that can live for years inside the human body and cause severe, debilitating diseases such as elephantiasis. Mosquitoes spread the larvae of these parasitic nematodes from human to human, placing at risk more than a billion people who live in places in Africa, Asia and Latin America where filarial parasites thrive.
Now, a team of researchers funded by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), has revealed the genetic secrets of one of these parasites. In the September 21, 2007 issue of Science, the researchers report solving the complete genome of Brugia malayi, one of the worms that causes the often debilitating disease elephantiasis. The World Health Organization (WHO) estimates that more than 40 million people around the world are seriously incapacitated and disfigured by elephantiasis. The WHO also estimates that about half a million people around the world have lost their vision due to onchocerciasis, or river blindness, which is caused by another type of filarial parasite.

The life cycle of Brugia malayi, the causal agent of Filariasis.
Credit: Courtesy of CDC/Alexander J. da Silva/Melanie Moser.

“Filarial diseases are treatable, but the current treatments were discovered decades ago,” says NIAID Director Anthony S. Fauci, M.D. “There is an urgent need for new discoveries in this area because of the limitations of the current drugs, including toxicities and the development of resistance.”

The B. malayi genome reveals dozens of potential new targets for drugs or vaccines and should provide new opportunities for understanding, treating and preventing elephantiasis and similar diseases.

“Having a complete genetic blueprint gives us a better understanding of what genes are important for different processes so you can target them more specifically,” says Elodie Ghedin, Ph.D., who led the sequencing project while at the Institute for Genomic Research, now part of the J. Craig Venter Institute, a not-for-profit research organization based in Rockville, Md. Dr. Ghedin is now a professor at the University of Pittsburgh School of Medicine.

When a mosquito bites someone infected with B. malayi, it ingests microscopic worms that develop into infectious larvae. These larvae are then deposited onto the skin of the next person bitten. Once the parasites penetrate the skin, they wend their way to the body’s lymphatic system — a network of fine vessels and organs that drains fluid from the body’s tissues and plays a key role in coordinating the immune response by concentrating immune cells in the lymph nodes. Male and female worms cluster, intertwining in the draining vessels just below the lymph nodes, and mate. A fertile female may produce 1,000 or more larvae a day and grow to be three or four inches long.

This filarial union can cause severe disease. Because they most often position themselves in front of vessels draining liquid from the lymph nodes, the worms can effectively obstruct the drainage. This causes the surrounding tissues to fill with fluid and swell to elephantine proportions.

As the disease progresses, tissues in the swelling arms, legs or scrotum can die or become infected, turning black and oozing puss. Making matters worse, the fluid accumulation can lead to permanent disfigurement over time as the swollen limbs become solid masses with connective tissue, blood vessels and nerve endings. Reducing the bulbous tissue may require major surgery.

Female B. malayi worms can live up to eight years in the human body. This longevity complicates elephantiasis treatment because existing drugs for treating the disease target the larvae only and do not completely kill the adult worms. The drugs often must be taken for years, and the worms can cause massive immune reactions when they die, releasing foreign molecules in the body.

The worm’s longevity is curious because it lives for years in the shadow of the lymph node, where immune cells meant to clear the body of infections congregate. One way the worm survives is by releasing chemicals that dampen the human immune response. B. malayi is so good at this that most people who are infected have no symptoms: The worms can live in their bodies for years without their even knowing it.

Understanding how this particular parasite has adapted to humans may yield medical benefits far beyond those places where elephantiasis is common, according to collaborator Alan L. Scott, Ph.D., of the Bloomberg School of Public Health at Johns Hopkins University. Worms can be viewed as foreign tissue transplanted into the human body. But unlike baboon hearts or pig kidneys, which the immune system quickly rejects, worms can survive for years in the body. Discovering how they do so may someday benefit transplant surgery, according to Dr. Scott.

Along with NIAID, J. Craig Venter Institute, and Johns Hopkins, collaborators on the project included researchers from the University of Edinburgh; New England Biolabs; the University of California, Davis Genome Center; Smith College; Imperial College, London; the University of Dundee; Divergence, Inc; Washington University; Lyon College; The Australian National University; the University of Toledo; the New York Blood Center; the Hospital for Sick Children in Toronto; the University of Göttingen; and the University of Alabama.

Since 1998, NIAID has supported the sequencing of many genomes of pathogenic microorganisms, including those considered emerging and re-emerging as well as potential agents of bioterrorism. For more information about NIAID’s large-scale sequencing efforts, see: http://www.niaid.nih.gov/dmid/genomes/mscs/.

For more information about filarial parasite biology and research, visit the NIAID/NIH Filariasis Research Reagent Repository Center (FR3) at: http://www.filariasiscenter.org/.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Reference: E Ghedin et al. Draft genome of the filarial nematode parasite Brugia malayi. Science DOI: 10.1126/science.1145406 (2007).

Credits: National Institutes of Health

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