By contrast, that the longer isoform is highly susceptible to Vpu mediated antagonism. Consequently s-Tetherin is a very potent HIV-1 restriction factor. Although both protein isoforms act as antiviral factors to retain budding virions, the shorter Tetherin isoform is significantly more resistant to HIV Vpu-mediated antagonism and degradation. Additionally, we recently identified two species of the Tetherin protein generated by alternative translation initiation that display dramatically different biologic activities. However, the mechanism by which ebolavirus impedes Tetherin function is unknown and is one of the areas under active investigation in our lab. Moreover we found that the ebolavirus glycoprotein (GP) antagonized the antiviral effect of human and murine Tetherin and facilitated viral budding. Our lab demonstrated that Tetherin functions as a broadly acting antiviral factor by showing that both human and murine Tetherin potently inhibit the release of the filovirus, ebolavirus, from the surface of cells. Tetherin, also known as Bst2 or CD317, is an interferon-induced, cellular response factor that was initially found to block release of HIV-1 and other retroviruses from infected cells. Mammalian cells employ numerous innate cellular mechanisms to inhibit viral replication and spread. Finally, the proposed steric shielding model for surface protein down-regulation by ebolavirus represents a novel mechanism for a viral glycoprotein affecting host cell function and may also be informative for cellular mucin proteins involved in metastatic cancer. In addition, these studies are likely to suggest new therapeutic or prophylactic strategies to combat ebolavirus infection. First, what are the cellular factors required for ebolavirus entry? Second, how does ebolavirus GP antagonize the function of the cellular antiviral factor Tetherin? Third, what is the impact of ebolavirus GP's novel mechanism of surface protein down-modulation via steric occlusion on immune recognition? Answers to these questions will provide important new information about how ebolavirus interacts with the host. The ongoing research in my lab addresses three important questions regarding ebolavirus glycoprotein (GP) interactions with the host. Bunyaviruses include many important human pathogens such as Crimean Congo Hemorrhagic Fever Virus, Hantaan Virus, Rift Valley Fever Virus, Andes virus and Sin Nombre Virus.Įbolavirus infection is associated with a high mortality rate and there are no effective treatments for Ebola infection. Currently our focus for this line of research are members of the Bunyaviridae family. Cells resistant to infection by these recombinant viruses contain inactivating mutations in host factors needed for infection that can be readily identified using massively parallel deep sequencing technology. We have developed a gene-trap lentiviral vector that act as an insertional mutagen and produced a library of >200 million haploid human cells bearing insertions and are interrogating this library by employing novel replication-competent, recombinant viruses. The recent availability of haploid mammalian cells makes possible the use of this technology to identify host factors that interact with viruses and promote infection. Interrogation of insertionally mutagenized haploid cells is a powerful technology to identify genes important for a specific function. Current research is examining whether Tetherin is a new innate immune pattern recognition receptor. We recently initiated research on the intrinsic antiviral factor, Tetherin, that we showed is a broadly acting antiviral factor capable of activating NFkB. Although we work with a number of different viral systems, current projects concentrate on several pathogenic viruses including filoviruses (ebolavirus and Marburgvirus) and bunyaviruses (Hantaan, Andes, Sin Nombre, La Crosse). Generally, research in the Bates lab focuses on viral glycoproteins and host factors that facilitate infection.
Key words: Virus entry, glycoproteins, Tetherin, ebolavirus, hantavirus, SARS, retrovirus We use a combination of molecular, cell biological, and genetic tools to understand how viruses invade host cells and evade host defenses with recent emphasis on emerging viral pathogens. The Bates lab is interested in the interactions between viruses and their host cells.
Description of Research Expertise Research Interests
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