Dengue virus, a mosquito-borne, flu-like illness can be deadly.  It occurs sporadically, often as a sudden epidemic, and was previously confined to topical and subtropical climates.  But in recent years dengue fever has become a concern, if not a major threat, to industrial countries, due in part to increased international travel and global warming. The source is now literally in our backyards.  And yet, it is a disease that is largely unknown to most Americans.

Sujan Shresta, Ph.D., is determined to prevent the deadly potential of dengue fever from becoming a real threat.  "I'm trying to understand how the immune system controls this virus infection and what aspects of the virus are essential--how does the virus cause the disease? I use the mouse model to learn the key aspects of human disease in mice, both the virology and immunology of this virus infection."

"Viruses that cause yellow fever and the Japanese, West Nile, and St. Louis encephalitides are all related. Currently there are no vaccines and anti-virals," explained Shresta.

Dengue (pronounced "DENG-ee") is caused by any of four related viruses, dengue serotype-1, -2, -3, and -4, transmitted to humans by certain types of mosquitoes.  According to the National Institute of Allergy and Infectious Diseases (NIAID) News, the Aedes albopictus (nicknamed "Asian tiger mosquito") and Aedes aegypti were first seen in the U.S. in 1985, and one or the other has since been found in 36 states.  Wherever the mosquitoes are found, the virus can follow.  

The virus is complex to study because the immune system appears to play both protective and pathogenic roles.  Making a vaccine for Dengue is a tremendous challenge because existing dogma support a role for pre-existing immunity in severe disease manifestations.  For instance, if you are infected with Dengue serotype-1, you will develop a lifelong immunity to Dengue serotype-1, and you will be protected from reinfection with this serotype.  But, if your secondary infection is with Dengue serotype-2, -3, or -4, you might come up with dengue hemorrhagic fever and dengue shock syndrome, the severe forms of the disease.  In fact, secondary infection is the single greatest risk factor for developing dengue hemorrhagic fever and dengue shock syndrome,

"In terms of what this means for a vaccine, it's horrendous," said Shresta.  "The vaccinated people could come up with severe disease.  Therefore, we're trying to figure out why that may happen.  We're developing mouse models for primary and secondary Dengue virus infections, trying to mimic what may be happening in the human population--for example, we infect mice first with Dengue serotype-1, then a few weeks to months later, we challenge these mice with Dengue serotype-2.  Using this kind of mouse model, we are trying to understand what are the risks associated with dengue-specific vaccines, and if there are risks, try to intervene and come up with alternatives."

Shresta's lab has been developing new mouse models for Dengue disease, which was the first priority for studying the disease according to NIAID's 2007 Dengue research program. "There is no good animal model because the natural hosts of this virus are mosquitoes and humans. Not even primates get the disease.  So, developing a mouse model has been extremely challenging," said Shresta.  

"When I first started the work everyone thought I was crazy," said Shresta.  "Many said, ‘you're never going to be able to create a mouse model of dengue disease because you're not going to get any infection in mice.' I think they're right--the mouse is not a human and can never recapitulate the human disease perfectly, there is no perfect model--but we can mimic aspects of the human disease in the mouse and understand and translate that knowledge into humans later on," Shresta explained.   

Shresta is in collaboration with Novartis in Singapore, as well as AVI Biopharma, and is the primary researcher in the field making mouse models.  "We have the best mouse model for Dengue disease, so these companies are using our mouse model to test their anti-viral candidate drugs," she said.  

"In contrast, the Gates Foundation is supporting efforts towards development of Dengue-specific vaccines.  Therefore, more basic research is now needed to examine the risk associated with the vaccines," said Shresta.  By using her mouse model to understand the basic virology/immunology of Dengue, Shresta is teasing out the good vaccine candidates, those with minimal risks or possible interventions. "We are generating new data suggesting how the vaccines may pose considerable risks, so we're desperately trying to move that story forward and make it available to the scientific community" she said.

"Everything we're finding out about this virus is so interesting, it's nothing that's ‘as-written' in the textbook.  It's always doing something different than you expect," said Shresta.  

Dengue viruses provide a new lens through which to examine the basic virology of this group of medically relevant viruses (yellow fever, West Nile virus etc) and the immune system.  For example, immunologic studies with our mouse models may shed insights into heterologous immunity, which at present is poorly understood and is controversial topic among immunologists.