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 as well as an emerging alphavirus, Chikungunya virus. Investigations with hepatitis C and Chikungunya viruses are aimed at understanding the epitope specificity of protective neutralizing antibodies against these viruses. To date, studies with West Nile and Dengue viruses have focused on investigating their pathogenesis and the immune system response that control infection. Using in vitro models of infection in primary neurons, macrophages, and dendtitic cells, we are also 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 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, mechanisms of immune evasion by Dengue and West Nile virus, and novel antiviral effector pathways that restrict infection downstream of type I interferon.
Selected Publications:
Szretter KJ, Samuel MA, Gilfillan S, Fuchs A, Colonna M, Diamond MS. The immune adaptor SARM modulates TNF-alpha production and microglial activation in the brainstem and restricts West Nile virus pathogenesis. J. Virol. 2009 (In Press).
Mehlhop E, Fuchs A, Engle M, Diamond MS. Complement modulates pathogenesis and antibody-dependent neutralization of West Nile virus infection through a C5-independent mechanism. Virology 2009 (In press).
Vogt MR, Moesker B, Goudsmit J, Jongeneeien M, Austin SK, Oliphant T, Nelson S, Pierson TC, Wilschut J, Throsby M and Diamond MS. Human Monoclonal Antibodies Induced by Natural Infection Against West Nile Virus Neutralize at a Post-Attachment Step. J Virol. 2009 83:6494-6507.
Thompson BS, Moesker B, Smit JM, Wilschut J, Diamond MS and Fremont DH. A Therapeutic Antibody against West Nile Virus Neutralizes Infection by blocking Fusion within Endosomes. PLoS Pathog. 2009 5(5):e1000453.
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.Virol. 2008 82:8456-8475.
Last Updated: 08/11/2009 |