Description of Research Expertise

Research Interests
Research in the Bates lab focuses on viral glycoproteins and their interactions with the host in viral entry and pathogenesis with recent emphasis on emerging viral pathogens.

Key words: Ebola, Virus entry, glycoproteins, viral assembly, SARS, retrovirus, gene therapy

Description of Research
Our lab studies the interactions of viral glycoproteins with the host in viral entry and pathogenesis. Additionally, we are interested in the cell biology of viral-host membrane fusion during both viral entry (infection) and viral assembly (budding). Viruses that are currently studies include retroviruses, Ebola virus, and more recently SARS associated coronavirus (SARS CoV). Within our studies of viral entry, we are also addressing methods to target infection of viral vectors for gene therapy. Specific projects currently underway include:

-Retroviral envelope-receptor protein interactions - cell biology of viral entry.
-Analysis of glycoprotein function and identification of the host receptor for emerging, pathogenic human viruses such as Ebola and SARS CoV.
-Identification and characterization of host factors involved in viral assembly.
-Targeted viral infection in vivo for gene delivery with application to gene therapy.

All enveloped viruses enter cells via the specific interaction of the viral glycoproteins with a receptor on the cell surface. Our lab uses Rous sarcoma virus as a model system to analyze the interactions of host receptor proteins and retroviral glycoproteins that lead to activation of the viral glycoprotein and entry into the host. Using this unique model, we have recently demonstrated that receptor protein binding directly induces major conformational changes in the viral glycoproteins resulting in activation of their fusogenic potential. To refine this model for receptor-triggered retroviral entry, we are currently analyzing mutations in the retroviral glycoproteins and the host receptor that affect entry at various stages. We use a combination of molecular biological and cellular biological techniques to probe these structure/function questions with the ultimate goal of using knowledge gained from these studies to derive therapeutics targeted to viral entry.

Our lab also works on glycoproteins from emerging viral pathogens Ebola and SARS associated coronavirus (SARS CoV). We established a pseudotype system to analyze infection mediated by the Ebola viral glycoproteins, allowing study of the glycoproteins of this highly pathogenic virus outside P4 containment. We used this system to define the host range of Ebola, to analyze host immune response to Ebola, and to functionally characterize the Ebola glycoproteins. Studies are underway to identify the cellular receptor for Ebola virus and host proteins that interact with the abundant soluble viral glycoprotein produced during infection. We recently demonstrated that an important dendritic cell surface protein, DC-SIGN, interacts with the Ebola glycoproteins suggesting that Ebola might utilize the viral glycoproteins to affect dendritic cell function and host immune responses. A second project in collaboration with Dr. Hao Shen involves analysis of host immune responses to the Ebola proteins and identification of strongly neutralizing monoclonal antibodies using retroviral vectors pseudotyped with the Ebola glycoproteins. Similar studies analyzing the glycoproteins of the very recently emerged and highly pathogenic virus associated with Severe Acute Respiratory Syndrome.

In related projects, our lab is attempting to use the knowledge gained about viral glycoprotein function to develop a system for targeted viral infection. Toward this end, we have employed mutants of the influenza hemagglutinin protein as tools to direct infection of specific cells. We have incorporated HA and a targeting ligand into retroviral vectors and demonstrated that these foreign proteins can re-direct viral infection to specific target cells. Current efforts are underway to develop unique methods for including different ligands into these targetable vectors and to apply these vectors to gene therapy.

Finally, our interests in viral-host membrane fusion prompted us to begin investigating the late events in viral assembly when the budding virion wraps itself in host membrane and is released from the cell. We have recently demonstrated that the retrovirus equine infection anemia virus utilizes the host multivessicular body machinery which normally is involved in late endosome vesicle budding to facilitate membrane fusion during virus release. Currently we are using unique chimeric viral-host proteins to identify additional host factors involved in this process and to define functional regions in known factors.

Rotation Projects for 2006-2007
-Host factors associated with Ebola soluble glycoprotein.
-Analysis of SARS corona viral glycoproteins
-Characterization of host factors required for retroviral assembly.
-Requirements for receptor-triggered activation retroviral glycoproteins.