Thursday, May 2, 2013

Knocking Out Breakbone Fever: New Mammalian Transmission Model for Dengue Virus


A recent study uses several varieties of knockout mice to develop a dengue fever transmission model. This approach could greatly contribute to knowledge of transmission between vertebrate hosts and the dengue virus vector, the Aedes mosquito. 

         Agonizing muscle and joint pains. Measles-like skin rashes. Sudden-onset high fever. Severe headaches. With symptoms such as these there is little wondering why dengue fever is so feared. Even more concerning is that cases of dengue fever have been spreading into new geographic regions; a result of increased population density, international travel, habitat development, environmental change, and a plethora of other factors. Additionally, with no approved vaccine for dengue virus currently on the market, it has become of utmost importance to gain a better knowledge of the entomological, virological and immunological components of infection establishment and transmission to prevent its spread. 

          Dengue fever and the more severe conditions it can cause –like dengue shock syndrome and dengue hemorrhagic fever - are a result of infection by dengue virus, a single positive-stranded RNA flavivirus. It is the most common arboviral (viruses that are transmitted by arthropods) infection of humans. The dengue virus vector - the organism that transmits the virus to another organism - is the mosquito Aedes aegypti, a species that originated in Africa. However, the range of this vector has dramatically spread over the past few decades and can now be found in most tropical and sub-tropical regions. The ability of this vector to move into new regions is one of the primary reasons that dengue fever epidemics are now regularly occurring in southeast Asia, India, the western Pacific and much of South America. 

         Even with dengue fever becoming a severe global threat, the study of the disease has been neglected. This is partially a result because of how difficult dengue virus is to study, as result of the lack of a good vertebrate transmission model. While it has been found that mice can get infected in lab settings, they don't get sick in any way which limits the usefulness of mouse models to the study of dengue virus replication. As a result, much research into dengue vaccines has been limited as few are willing to jump into clinical trials with a product that has yet to be animal tested. 

         However, a lab at the Louisiana State University in Baton Rouge might have found the solution to this problem. Using an array of genetic technologies it is possible to target and "knock out" specific mouse genes, allowing researchers to replace existing genes with altered versions. Using this technique, several varieties of knockout mice deficient in type I and II interferon receptors have been developed. By decreasing the response of interferons, the proteins that drive transcription to activate an antiviral response, researchers suspected that they could increase the permissiveness of cells to dengue fever and allow for increased virus transmission. The knock-out mice were inoculated with a non-mouse adapted dengue virus and tested for viral load and cytokine production daily. In addition, the mice were exposed to mosquitoes that were fed the same virus strain via an artificial membrane feeder. Finally, uninfected mosquitos were allowed to forage on dengue virus infected mice to determine if the mosquitos could contract the virus from the mammalian host. 

      It turns out that the researchers were correct, with both needle inoculation and infectious mosquito bites resulting in 100% infection. The most significant result of the project was the confirmation that the transmission cycle (mouse-to mosquito-to mouse) could be completed using the IRF3/7 -/- -/- knock-out mouse that the researchers had developed. As a result, this genetically modified mouse model can serve as an essential tool for studying the transmission dynamics between the virus host and vector. 
     Despite the many obstacles that dengue virus researchers face, great strides – such as the development of new animal models and the production of weakened dengue virus in cell cultures – have been made. These contributions to the field of virology and immunology will no doubt assist in combatting the ever-increasing threat of this emerging disease. 

For general information on Dengue virus, see: http://www.cdc.gov/dengue/ 
For recent map of dengue cases, see : http://www.healthmap.org/dengue/index.php 
For a background on the mouse as a model organism, see: http://www.genome.gov/10005834 


Primary Source: 

1.Christofferson RC, McCracken MK, Johnson AM, Chisenhall DM, Mores CN. (2013) Development of a transmission model for dengue virus. J Gen Virol. 10:127 http://www.virologyj.com/content/pdf/1743-422X-10-127.pdf 

Secondary Sources: 

2. Gubler D.J.(2002) Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends in Microbiology 10: 100 - 103 


3. Zompi S, Harris E (2012) Animal models of dengue virus infection. Viruses 4:62-82 


4. Clarke T (2002) Dengue virus: break-bone fever. Nature. http://www.nature.com/news/2002/020415/full/news020415-10.html (April 18 2002) 

5. Knowlton K, Solomon G, Ellman MR (2009) Mosquito-born dengue fever threat spreading in the Americas. NRDC Issue Paper. http://www.nrdc.org/health/dengue/files/dengue.pdf 

Image From: Lowe, Chan. (2010) Chan Lowe: Dengue fever in Florida. http://blogs.trb.com/news/opinion/chanlowe/blog/2010/07/chan_lowe_dengue_fever_in_flor.html (July 16 2010)

1 comment:

  1. You said that it had been difficult to make a vaccine for Dengue fever, but have any positive steps been taken to actually make the vaccine?