Malaria is the world's most devastating parasitic disease, killing 1 million people per year, mostly children under the age of five in sub-Saharan Africa. Malaria is transmitted through mosquitoes;hence targeting malaria within mosquitoes (vector control) is central to controlling this disease. This project concerns a protein called thioester-containing protein 1 (TEP1) that is the major factor in the mosquitoes own immune response to malaria infection.
The aim i s to identify other mosquito proteins that interact with TEP1 and characterize those interactions at the molecular level. The outcome of this project shall be a specific set of protein- protein interactions that are necessary for the proper function of TEP1 in parasite killing. These interactions can then be manipulated either genetically or pharmacologically to develop new methods for malaria control. For instance new insecticides may be developed that kill only mosquitoes infected with malaria, or even compounds that increase the immune response of mosquitoes to malaria infection;in effect curing mosquitoes of malaria. This research shall be conducted by Dr. Richard Baxter, an Australian citizen and US permanent resident, who has resided in the US since 1998 when he commenced his Ph.D. at the University of Chicago. Dr. Baxter received scholarship and fellowship support throughout his graduate training, demonstrating his unique skills and abilities as a researcher. Dr. Baxter's doctoral degree is in the field of chemistry, but his research involves the purification and crystallization of proteins, therefore he has both the rigorous physical training and the appropriate laboratory skills to determine the structure and function of proteins at the molecular level. Dr. Baxter's research shall initially be conducted at University of Texas Southwestern Medical Center, one of the premier biomedical research institutes in the nation. UT Southwestern boasts world-class research facilities, 18 members of the prestigious National Academy of Sciences and four Nobel Prize winners, including Dr. Baxter's mentor Prof. Johann Deisenhofer, a world authority in the field of protein crystallography. Dr. Baxter's research shall be performed in collaboration with Dr. Elena Levashina at the University of Strasbourg, France, a specialist in the immune response of mosquitoes to malaria, under Prof. Jules Hoffmann, an internationally recognized pioneer in the field of insect immunity. The collaboration between these two laboratories shall combine complementary specialties in protein purification and structure determination with cell biology studies in vivo. Dr. Baxter shall continue his collaboration with Dr. Levashina upon obtaining a tenure-track position at a US academic institution, where he shall develop a robust research program incorporating proteomics, structural biology and high throughput screening to understand host immune responses and host-pathogen interactions bearing on emergent and re-emergent arthropod-borne diseases.

Public Health Relevance

Thioester-containing protein 1 (TEP1) is a central component of the immune response of mosquitoes to malaria infection. A fundamental understanding of molecular structure and protein-protein interactions involving TEP1 are necessary to understand how it kills malaria parasites. This knowledge shall then lead to the discovery of new ways to control and possibly eradicate malaria.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K22)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Costero, Adriana
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Le, Binh V; Nguyen, Jennifer B; Logarajah, Shankar et al. (2013) Characterization of Anopheles gambiae transglutaminase 3 (AgTG3) and its native substrate Plugin. J Biol Chem 288:4844-53
Le, Binh V; Williams, Marni; Logarajah, Shankar et al. (2012) Molecular basis for genetic resistance of Anopheles gambiae to Plasmodium: structural analysis of TEP1 susceptible and resistant alleles. PLoS Pathog 8:e1002958