Paul Bates, Ph.D.

Associate Professor of Microbiology

Office Address:
University of Pennsylvania School of Medicine
303A Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104-6076

TEL 215-573-3509
LAB 215-573-3508
FAX 215-573-9068
pbates@mail.med.upenn.edu

RESEARCH SUMMARY

Our lab analyzes 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 studied include retroviruses, Ebola virus, and the Severe Acute Respiratory Syndrome 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:

1. Retroviral envelope-receptor protein interactions - cell biology of viral entry.
2. Analysis of glycoprotein function and identification of the host receptor for emerging, pathogenic human viruses such as Ebola and SARS CoV.
3. Identification and characterization of host factors involved in retroviral and SARS CoV assembly.
4. 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 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 and inhibitors that block membrane fusion. We use a combination of molecular 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 pseudotype systems to analyze infection mediated by the Ebola or SARS viral glycoproteins, allowing study of the glycoproteins of these highly pathogenic viruses outside high level containment. We used these pseudotypes 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 Ebola infection. We recently demonstrated that the dendritic cell surface protein, DC-SIGN, interacts with the Ebola glycoproteins suggesting that Ebola might utilize the viral glycoproteins to target these cells during the early stages of infection in vivo and to affect dendritic cell function and host immune responses. Analysis of the spike glycoproteins of SARS CoV revealed that this virus utilizes the cellular receptor ACE2 and an endocytic pathway to infect host cells. Currently, we are utilizing the SARS CoV S pseudotypes to develop a rapid high throughput screen for inhibitors of infection.

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 that 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. In addition, we are analyzing the M and E proteins from SARS CoV to determine if they interact with similar host machinery during coronavirus assembly.