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Those interfering scientists

Members of the Vector-Borne Disease Research Group at Virginia Tech are looking inside the mosquito, the pathogen, and the victim and at the environment for places to interrupt transmission of disease.

Jianyong Li, associate professor of biochemistry, is part of an international group that has determined the structure of a protein that is responsible for the production of xanthurenic acid (XA) in Anopheles gambiae, the malaria carrying mosquitoes. XA plays a key role in the sexual reproduction of the malaria parasite, Plasmodium falciparum, in A. gambiae. Interfering with the formation of XA could be an avenue for development of anti-malarial agents. (Proceedings of the National Academy of Science (PNAS) April 11, 2006).

Jake Tu, associate professor of biochemistry, was among 100 researchers who collaborated to sequence the genome of the malaria mosquito, A. gambiae (Science, Oct. 4, 2002). His was one of the labs that characterized the transposable elements (TEs) that make up 16 percent of the A. gambiae genome. Five years later, as part of a collaboration of 24 institutions, Tu’s lab led the efforts of five labs in three countries that annotated the TEs that make up half of the genome of Aedes aegypti mosquito, which carries the yellow fever and dengue fever viruses (Science, June 22, 2007). “We discovered that a significant number of elements have potentially active TE copies, indicating that they may be developed as tools for genetic studies of mosquitoes,” Tu says.

Jinsong Zhu, assistant professor of biochemistry, was a member of the team that sequenced the genome of the yellow fever/dengue fever mosquito. He is involved in research that has validated most of the 15,419 predicted protein coding genes in Ae. aegypti (Science, June 22, 2007). He explains, “An important part of this project is gene annotation, which predicts numbers and locations of mosquito genes in the genome. In parallel to sequencing DNA in chromosomes, scientists have also sequenced large amounts of messenger RNAs collected from different mosquito tissues at distinct developmental stages.” This unprecedented insight into mosquito physiology and mosquito- parasite interaction greatly facilitates the development of novel strategies to control mosquito-transmitted diseases, he says.

It is not enough to engineer mosquitoes that are unable to support virus replication, which can now be done by feeding the dengue-carrying mosquito an antivirus gene as part of a blood meal (PNAS, March 14, 2006). We also want her children to inherit that resistance. Zach Adelman, assistant professor of entomology, and colleagues at the University of California at Irvine and Colorado State University have figured out how to use TEs from a housefly to copy and carry the man-made antivirus gene into the female germline so it is passed to all her progeny. (PNAS, June 17, 2007)

Kevin Myles, assistant professor of entomology, is developing novel methods for controlling arthropod-borne viruses (arboviruses) based on understanding at the molecular level the virus-vector interactions occurring in the mosquito. Current research seeks to identify genetic factors influencing mosquito innate immune responses to arboviral pathogens.

To develop novel strategies for malaria control, Igor Sharakhov, assistant professor of entomology, and his group are researching the ecological and physiological adaptations related to malaria transmission associated with chromosomal inversions, or genome rearrangements that result from flipping a chromosomal segment in the mosquito genome. The breakpoints of one of the chromosomal arrangements, namely 2La, have been identified (PNAS, April 18, 2006). A recent collaboration with colleagues at the University of Minnesota, Harvard Medical School, University of California at Davis, and Imperial College London has identified a major malaria-control locus near the 2La inversion breakpoint in East African mosquitoes. (Malaria Journal, July 6, 2007)

Michael Klemba, assistant professor of biochemistry, and his colleagues are studying the breakdown of hemoglobin by the human malaria parasite Plasmodium falciparum. This process is necessary for reproduction of the parasite within the host’s red blood cells. Klemba’s group has identified and characterized several enzymes that are responsible for breaking hemoglobin down into its building blocks, amino acids. They are aiming to better understand these enzymes in order to develop inhibitors that have anti-malarial properties. (Journal of Biological Chemistry, 2004

Dharmendar Rathore, assistant professor with the Virginia Bioinformatics Institute, is working to develop drugs to treat malaria. Pathological symptoms of malaria include high fever, chills, and anemia and are due to the rapid multiplication of the parasite inside the host red blood cells. The parasite cannibalizes vast amounts of hemoglobin present in the cell. This degradation releases heme, which is extremely toxic to the parasite. To protect itself, the parasite detoxifies heme into hemozoin, a crystalline solid. Rathore’s research group has identified the protein that plays a critical role in this detoxification. Blocking the activity of this protein could inhibit parasite development in the host cells. Rathore’s group has screened 80,000 drug-like molecules and identified several compounds that block the interaction of this protein with heme and show potent anti-malarial activity on P. falciparum parasites in culture.

Jeffrey Bloomquist, professor of entomology, and colleagues from across campus, the International Centre for Insect Physiology and Ecology, and Molsoft, aim to develop an insecticide for use on bed nets that is safe for humans but deadly to the malaria mosquito, Anopheles gambiae. The strategy is to use the enzyme acetylcholinesterase as a scaffold for synthesizing its own chemical inhibitor. Acetylcholinesterase is involved in the process of neural transmission. The insect would pick up two inactive molecules from the net that would bind to the enzyme, react, and disable it within the mosquito, which is called click chemistry. The researchers have identified a number of promising chemistries, which were synthesized in Paul Carlier’s laboratory.

Paul Carlier, professor of chemistry, leads a large group of postdoctoral associates and graduate students in the synthesis of species-specific enzyme inhibitors and receptor ligands. Since human and insect proteins of identical physiological function often share only 50 percent identity in their amino acid composition, it is possible to design compounds that dramatically interfere with the function of insect proteins while leaving human proteins largely unaffected. A number of techniques are used in the design of these compounds, including structure-based drug design, click chemistry, and traditional lead optimization. In collaboration with Jeffrey Bloomquist and Sally Paulson, and colleagues at Molsoft, Carlier has prepared highly effective contact poisons for A. gambiae that show 100-fold selectivity for mosquito acetylcholinesterase over the human enzyme.

Sally Paulson, associate professor of entomology, is doing research directed at the La Crosse (LAC) encephalitis virus, the most common and important endemic mosquito-borne disease of children in the United States. Her group is looking at the role of newly introduced mosquito species, Aedes albopictus and Ochlerotatus japonicus, in the transmission of disease, specifically in Southwest Virginia (Journal of the American Mosquito Control Association, 2007). She is also studying the bionomics, or relationship to the environment, in Southwest Virginia of the Culex mosquito, which carries West Nile virus. (Journal of the American Mosquito Control Association, 2006)

Understanding the spatiotemporal dynamics of a vector and the disease it transmits is critical for controlling these organisms. Carlyle Brewster, associate professor of entomology, uses satellite remote sensing, geographic information systems (GIS), and spatial analyses to study vector population dynamics and the ecological determinants of disease transmission by the vectors. His efforts have included studies of vector populations throughout regional landscapes in relation to environmental variables with the aim of developing targeted surveillance programs. Brewster, Paulson, and others have been looking at the incidence of canine infection with LAC to determine whether dogs might be used as sentinels for LAC virus activity and transmission risk to humans.

 

Biochemistry Associate Professor Jianyong Li applies a protein sample for the purification of a human aminotransferase II that will be used for crystallization and structural characterization. Photo by John McCormick.

Biochemistry Ph.D. candidate Praju V. Mehere checks the purity of an isolated protein on an SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) gel. Photo by John McCormick.