Animal model for dengue research

Aug 28 2007

A mosquito-borne disease often known as "break-bone fever" has found a new enemy in a unique type of mouse.

The first animal model to test potential treatments for the dengue fever virus – an immuno-suppressed mouse that has been transplanted with human cord blood cells – was developed last year by Dr. Rebeca Rico-Hesse at Southwest Foundation for Biomedical Research. Now, with a new $111,000 pilot study grant from the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, Dr. Rico-Hesse will strive to enhance the model so it can be used to test candidate vaccines and help researchers learn more about immune factors that contribute to varying disease severity among individuals.

The research holds great promise, potentially removing one of the biggest hurdles in the race to find the first effective treatment or vaccine for a disease that has periodic outbreaks along the Texas-Mexico border, is increasing in the severity of illness it causes, and threatens to move farther north at any time.

“Until now, there has never been an animal model for dengue research, because only humans are susceptible to the virus,” said Rico-Hesse. “This has been a huge obstacle, because it's meant that candidate vaccines and drug treatments could only be tested on cells in a Petri dish. Those kinds of tests tell you nothing about how a therapy or vaccine will work in a living animal or how it will interact with the immune system. So pharmaceutical companies have been waiting for an animal model to become available so they can proceed to preclinical trials of potential new drugs they've developed.”

In May 2006, in the journal Drug Discovery Today: Disease Models, Rico-Hesse published her success in developing the model for testing drug therapies. The paper chronicled how she had taken some mice that had been bred to have no immune system and given them transplants of human umbilical cord blood cells. “Cord blood contains a type of stem cell that eventually forms white blood cells called dendritic cells, which are the type of cells you need to be able to contract dengue,” Rico-Hesse explained.

When these unique mice were exposed to the dengue virus, they developed a fever, rash and other dengue symptoms, indicating that, for the first time, another species besides humans could contract the disease. “And if we can give a mouse dengue, we can use that model to test potential drug therapies for treating the disease,” Rico-Hesse said.

With this success, Rico-Hesse and her research team will use the new Kleberg Foundation funding in an attempt to make this one-of-a-kind animal model even more valuable. In their next round of studies, they will transplant the human cord blood cells into immuno-compromised mice that are still newborns, rather than adults, since other groups have shown that the newborns can go on to develop a full human immune system.

“If this work is successful, the animal model should be useful for testing candidate vaccines as well, because it should have adaptive immunity,” said Rico-Hesse. “In other words, a successful vaccine would be able to stimulate an immune response, including the production of antibodies, that would protect the animal from infection when challenged with the virus.”

She said this model also would be valuable to research on immune factors that influence the varying degrees of disease severity among individuals.

Every year, 50 million to 100 million people around the world contract dengue fever. The disease is prevalent throughout Mexico, which averages hundreds of thousands of cases each year, including 5,000 to 10,000 severe cases. During the last couple of centuries, the United States had periodic outbreaks in Baltimore, Washington D.C., New Orleans, Houston and Galveston. During this century, dengue outbreaks have occurred periodically in South Texas border cities.

In its mild form, dengue causes what's dubbed “break-bone fever” because of its severe flu-like symptoms, including body aches that can make a person feel as though his bones are breaking. “It's self-limiting. You recover, but it feels as though you have a bad flu for two to three weeks,” Rico-Hesse said.

After a person has contracted a second infection with the virus, or as Rico-Hesse's research has shown, even one infection with the most virulent of its strains, he is susceptible to dengue hemorrhagic fever, which also causes massive internal bleeding that can sometimes lead to death. With no drug therapy available, treatment for dengue typically includes rest, drinking plenty of fluids, and use of pain relievers that do not include aspirin.

Rico-Hesse has been monitoring one of the more virulent strains as it's moved around the globe, and it first appeared in Texas in 2005 with a small outbreak in Brownsville. “That's bad news, because our research has shown that the more virulent strain replicates at 10 times the rate of the other strains, and mosquitoes transmit it [to humans] at 65 times the rate of the other strains. That means we can expect to see more severe disease in South Texas, and we can expect dengue to spread more quickly.

“And unfortunately, San Antonio is a perfect port of entry into Central and North Texas and other parts of the United States, because we have the type of mosquito that can carry dengue – Aedes aegypti, recognized by the white stripes on its legs and body – ideal weather for breeding it, and commerce from Texas border cities and Mexico traveling up Interstate 35 on a daily basis.”

So Rico-Hesse is grateful for the Kleberg Foundation grant that is furthering her groundbreaking research with this new animal model. “It's our hope and expectation that this will prove to be a major advancement in the fight against dengue, speeding up efforts to get potential vaccines and treatments approved for human use,” she said.

Southwest Foundation for Biomedical Research is one of the leading independent biomedical research institutions in the United States, dedicated to advancing human health through innovative biomedical research. It is recognized within scientific and academic communities worldwide for the quality of its basic research into the nature, causes, preventions, and treatments for disease. SFBR's staff of more than 75 doctoral-level scientists conducts nearly 200 major research projects, with marked success in the areas of genetics, neonatal development, metabolic disorders and infectious diseases.