Professor of Microbiology
Department of Microbiology
Perelman School of Medicine
University of Pennsylvania
303A Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104-6076
Bates Lab Website
The Bates lab is interested in the interactions between viruses and their host cells. We use a combination of molecular, cell biological, and genetic tools to understand how viruses invade host cells and evade host defenses. Generally, we focus on viral glycoproteins and host factors that facilitate infection. 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, Puumula, SFTS). In addition, we study the intrinsic antiviral factor Tetherin to probe its interaction with viral antagonists and explore its signaling properties.
Current areas of interest:
- Forward genetic screens in haploid human cells for discovery of host factors that impact viral infection
- Analysis of the cell intrinsic immune factor Tetherin
- Ebolavirus-host cell interactions
Interrogation of insertionally mutagenized haploid cells is a powerful technology to identify genes important for a specific function. 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. 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. We are interrogating this library by employing novel replication-competent, recombinant vesicular stomatitis viruses bearing on their surface various viral glycoproteins. 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. Currently our focus is on members of the Bunyaviridae family. Bunyaviruses include within the >300 known family members many important human pathogens such as Crimean Congo Hemorrhagic Fever Virus, Hantaan Virus, Rift Valley Fever Virus, and Sin Nombre Virus.
Mammalian cells employ numerous innate cellular mechanisms to inhibit viral replication and spread. 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. 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. Moreover we found that the ebolavirus glycoprotein (GP) antagonized the antiviral effect of human and murine Tetherin and facilitated viral budding. Additionally, ebolavirus GP could substitute for Vpu to promote HIV-1 virion release from Tetherin-expressing cells demonstrating a common cellular target for these divergent viral proteins. The mechanism by which ebolavirus impedes Tetherin function is unknown and is one of the areas under active investigation in our lab. Additionally, we recently identified two isoforms of Tetherin produced by alternative translation initiation. The shorter isoform (s-Tetherin) lacks 12 residues present in the cytoplasmic tail of the longer species (l-Tetherin). Although both act as antiviral factors to retain budding virions, the s-Tetherin isoform is significantly more resistant to HIV Vpu-mediated antagonism and degradation. Consequently s-Tetherin is a very potent HIV-1 restriction factor. By contrast, we demonstrated that the longer isoform, l-Tetherin, is highly susceptible to Vpu mediated antagonism. Importantly, we determined that l-Tetherin (but not s-Tetherin) activates the immune regulatory transcription factor NF-κB. Whether the ratio of the isoforms is controlled in other cell types, under different conditions or by viral antagonists of Tetherin remains unknown and is being investigated. Additionally, we are deciphering the role(s) of the two Tetherin isoforms in the global immune response to viral infection and determining whether Tetherin represents a new type of Pathogen recognition receptor.
Ebolavirus infection is associated with a high mortality rate and the public’s fear of ebolavirus infection makes this virus a bioterror concern. There are no effective treatments for Ebola infection. The ongoing research in my lab addresses three important questions regarding ebolavirus glycoprotein (GP) interactions with the host. 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, does ebolavirus GP employ a novel mechanism of steric occlusion to mediate surface protein down-modulation and what is the effect of GP expression on immune recognition? Answers to these questions will provide important new information about how ebolavirus interacts with the host. In addition, these studies are likely to suggest new therapeutic or prophylactic strategies to combat ebolavirus infection. 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.