Research Abstract:
The research in the Diamond laboratory focuses on the interface between viral pathogenesis and the host immune response. For several years, we have been primarily focused on two globally important mosquito-borne human pathogens West Nile virus and Dengue virus. Both are single-stranded positive-sense RNA viruses of the same genus (Flavivirus) that cause severe encephalitis and hemorrhagic fever, respectively, in humans and related to a group of viruses that cause human disease worldwide. Recently, we have begun to study another member of the same virus family, hepatitis C, which causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Investigations with hepatitis C virus are aimed at generating a novel mouse model and understanding the epitope specificity of protective antibodies against this virus. To date, studies with West Nile and Dengue viruses have focused on investigating their pathogenesis and the immune system response that controls infection. Using in vitro models of infection in primary neurons, macrophages, and dendtitic cells, we are studying the mechanisms by which West Nile virus causes direct injury to specific cell types, and how the host responds to limit viral replication. Using a mouse model we have defined critical roles for interferon, antibody, complement, CD4+, and CD8+ cell in the control and eradication of West Nile virus infection. We have begun to study the structural and molecular basis of antibody-mediated protection of West Nile and Dengue virus. By combining our structural and pathogenesis data, we have developed a single monoclonal antibody that has strong therapeutic activity against WNV even after the virus has disseminated into the central nervous system. A humanized form of this antibody is currently in human clinical trials for the treatment of acute West Nile virus. This data is also being applied to the development of novel strategies for vaccine development. New directions in the Diamond laboratory include understanding how the immune response restricts West Nile virus diversity and fitness, the role of microRNA in regulating flavivirus infection, mechanisms of immune evasion by Dengue and West Nile virus. In addition, our most recent studies with the complement opsonin C1q suggest new insight into understanding the conditions in which antibodies enhance Dengue virus replication during secondary infection.
Selected Publications:
Shrestha B, Zhang B, Purtha WE, Klein RS, and Diamond MS. Tumor necrosis factor-α protects against lethal West Nile virus infection by promoting trafficking of mononuclear leukocytes into the central nervous system. J. Virology 2008 (In Press).
Daffis S, Samuel MA, Suthar M, Keller BC, Gale M, and Diamond MS. Interferon regulatory factor (IRF)-7 protects against lethal West Nile virus infection by specifically inducing an antiviral interferon (IFN)-α response. J.Virology 2008 (In Press).
Mehlhop, E, Ansarah-Sobrino, C, Johnson, S, Engle, M, Fremont, DH, Pierson TC, and Diamond MS. C1q inhibits antibody-dependent enhancement of flavivirus infection in vitro and in vivo in an IgG subclass specific manner. Cell Host and Microbe. 2007 2(6):417-26.
Avirutnan, P, Zhang, L, Punyadee, N, Manuyakorn, A, Puttikhunt, C, Kasinrerk, W, Malasit, P, Atkinson, JP, and Diamond MS. Secreted non-structural protein NS1 of Dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E.PLOS Pathogens 2007 3(11):e183.
Samuel, MA, Wang, H, Siddhartha, V, Morrey, JD, and Diamond MS. Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis. PNAS 2007 104(43):17140-5.
Last Updated: 08/01/2008 |