Janet L. Douglas
"It takes all the running you can do, to keep in the same place."
-From the Red Queen's race in Lewis Carroll's Through the Looking Glass
The Red Queen hypothesis suggests that viruses and their hosts are in a constant evolutionary arms race to survive. Studying this intricate battle provides us with important insights into anti-viral immunity and reveals new targets for developing anti-viral therapies. My research focuses on the interplay between the host's defense mechanism that prevents viral release from cells, and the various viral countermeasures that have co-evolved.
A major aspect of our work involves a characterization of the mechanism whereby the HIV-1 protein Vpu counteracts the host restriction factor BST-2/Tetherin to allow efficient viral egress. We are specifically investigating how Vpu and BST-2 interact and how Vpu uses the host's own ubiquitin system to eliminate the obstacle to egress presented by BST-2. In addition, the lab is employing various screening methodologies to identify a) additional host factors that may be necessary for BST-2 function and/or b), adaptors important for Vpu's ability to downmodulate BST-2.
The viral release restriction imposed by BST-2 is not limited to HIV, but may represent an innate immune mechanism that functions to limit the spread of many, if not all, enveloped viruses. Like HIV, the egress of Ebola and Marburg viruses is inhibited by BST-2. These filoviruses are enveloped, negative strand RNA viruses that encode only seven ORFs. Despite their simplicity, human infection results in highly transmissible hemorrhagic fevers with mortality rates approaching 90%. Currently there are no treatments or vaccines for Ebola virus. Interestingly, Ebola virus appears to encode a BST-2 countermeasure, and this function has been mapped to the viral envelope glycoprotein GP. Therefore, we are extending our studies to determine how Ebola virus GP is able to overcome the BST-2 restriction. The GP/BST-2 interaction has the potential to be a new target for the design of effective anti-Ebola strategies.
BST-2's ability to prevent the egress of some enveloped viruses remains untested. For example, the flaviviruses acquire their envelopes in a fundamentally different manner than that of HIV and Ebola, and so the flaviviruses may avoid BST-2 restriction altogether. The dengue flavivirus is the most common cause of mosquito-born infections in humans and is the causative agent of dengue fever and dengue hemorrhagic fever. Incidents and spread of dengue infections are on the rise and are a major public health concern. Therefore, another interest of the lab is to determine whether Dengue is restricted by BST-2. If so, like HIV-1 and Ebola, Dengue may also encode a means to overcome BST-2. In contrast, if Dengue is able to completely avoid the BST-2 restriction, we will use this virus to uncover novel egress co-factors and host restriction factors.
Biography
Janet attended graduate school at the University of Tennessee in Memphis where she received her Ph.D. in 1995 for her work characterizing the immortalizing and transforming potential of the Adenovirus E1A gene. As a postdoctoral fellow in Dr. Victor Garcia's laboratory at St. Jude Children's Hospital in Memphis, TN, she developed an HIV-based lentiviral gene delivery system for the transduction of non-dividing human lymphocytes and hematopoietic stem cells. Her expertise in this emerging technology led her to a position at the biotechnology company Systemix in Palo Alto, CA, where she extended her work on gene therapy to include a humanized mouse model for assessing the efficacy of lentiviral vectors. She left the field of gene therapy in 2001 and began working in antiviral drug discovery for Gilead Sciences in Foster City, CA. There, she participated in a multi-disciplinary team of scientists attempting to identify novel small molecule inhibitors of respiratory syncytial virus (RSV) fusion and HIV-1 reverse transcriptase. In 2004 Janet returned to academic science and began working with Dr. Ashlee Moses at the Vaccine and Gene Therapy Institute (VGTI) at OHSU, where they a) investigated the cellular transformation mechanisms induced by KSHV/HHV-8 infection and b), determined how the HIV-1 accessory protein Vpu functions to enhance the release of viral particles by counteracting the host immunomodulatory protein BST-2. Currently an assistant scientist at the VGTI, Janet continues her research on the host's restriction of HIV-1 viral egress and she has extended these studies to other viruses.
Key Publications
Mansouri M., J. Douglas, P. P. Rose, K. Gouveia, G. Thomas, R. E. Means, A. V. Moses and K. Früh. 2006. Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood. 108:1932-1940.
Douglas J. L., J. K. Gustin, B. Dezube, J. L. Pantanowitz, and A. V. Moses. 2007. Kaposi's sarcoma: a model of both malignancy and chronic inflammation. Panminerva Med. 49:119-138.
Douglas J. L., J. G. Whitford, and A. V. Moses. 2009. Characterization of c-Kit expression and activation in KSHV-infected endothelial cells. Virology. 390:174-185.
Douglas J. L., K. Viswanathan, M. N. McCarroll, J. K. Gustin, K. Früh, and A. V. Moses. 2009. Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. J. Virol. 83:7931-7947.
Mansouri M., K. Viswanathan, J. L. Douglas, J. Hines, J. Gustin, A. V. Moses, and K. Früh. 2009. Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. J Virol. 83:9672-9681.
Douglas J. L., J. K. Gustin, K. Viswanathan, M. Mansouri, A. V. Moses, and K. Früh. 2010. The Great Escape: Viral Strategies to Counter BST-2/Tetherin. PLoS Path. 6: e1000913.
Douglas J. L., J. K. Gustin, A. V. Moses, B. J. Dezube, and L Pantanowitz. 2010. Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis, and Chronic Inflammation. Translational Biomedicine. 1:1-15.
Gustin J. K., A. V. Moses, K. Fruh, and J. L. Douglas. 2011. Viral takeover of the host ubiquitin system. Front. Microbiol. 2:1-24.
