Dr. Davey is interested in understanding how viruses like Ebola virus penetrate the cell membrane and establish infection. In addition, the Davey laboratory has developed safe, efficient, high-throughput screening techniques for Ebola virus and performs contract work on testing drugs and compounds against Ebola virus infection in the BSL-4 maximum containment laboratory. This work has resulted in exciting findings towards potential drug candidates to combat Ebola virus. Dr. Davey has been working with:
- Filoviruses: Ebola virus, Marburg virus
- Lassa fever virus
- Bunyaviruses: Crimean-Congo hemorrhagic fever virus
Dr. Davey contributes more than 25 years of expertise in virology and has been studying Ebola virus since 2006; his recent work has been published in high-impact journals that include PLoS Pathogens, PNAS and a cover feature in Science.
In The Lab
Drug screening. Ebola virus outbreaks, such as the 2014 epidemic in West Africa, are episodic and deadly, and filovirus antivirals are currently not clinically available. With our team well trained in ABSL-4 procedures, our lab performs contract work on testing drugs and compounds for the inhibition of Ebola virus infection; we also collaborate with several groups on the study of pathogenic viruses, with a main focus on Ebola virus. Our lab applies sophisticated molecular and cell biology techniques, including high throughput screening techniques for Ebola viruses. Using industry standard 384-well plates, we can screen thousands of small molecules for those that have potential as therapies. Combined with customized computer software to automatically identify infected cells and determine drug efficacy, our semi-automated approach drastically reduces the time to find effective drugs by 90% over traditional methods.
Our lab is using this platform to perform drug testing for NIH, private drug companies as well as academic scientists. The hits from this work are then analyzed for how they work. Using this approach, tetrandrine is showing promise for use against Ebola virus and genistein appears broadly active against Lassa fever virus as well as Ebola virus.
Cellular factors important for establishing infection. Another aspect of our research is the identification of cellular factors important for establishing infection by filoviruses and bunyaviruses. Our studies have allowed a deeper understanding of the entry and cell signaling pathways used by each virus to penetrate the cell membrane and establish infection. We were the first to demonstrate that PI3 kinase is a trigger for Ebola virus uptake and that macropinocytosis is the major pathway for productive infection. Most recently, we demonstrated that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs), and that TPC proteins play a key role in Ebola virus infection and may constitute effective targets for antiviral therapy. Similarly, we were the first to show that Crimean Congo virus uses specialized sorting organelles called multivesicular bodies to enter into the cell cytoplasm; blocking access to these organelles prevents infection.
Treatment options. We found that the FDA-approved drug interferon gamma may serve as a novel and effective prophylactic or treatment option. Using mouse-adapted Ebola virus, we found that giving the innate immune response a kick-start using interferon gamma, animals were protected from disease and reduced morbidity and serum virus titers. We think this works by priming macrophages so that they more aggressively attack virus-infected cells and making themselves inherently resistant to infection.
Immunodiagnostics. The ongoing evolution of Ebola viruses poses significant challenges to the development of immunodiagnostics for detecting emergent viral variants, showing a critical need for the discovery of monoclonal antibodies with distinct affinities and specificities for different Ebola viruses. We developed an efficient technology for the rapid discovery of antigen-specific monoclonal antibodies from immunized animals by mining the VH:VL paired antibody repertoire encoded by highly expanded B cells in the draining popliteal lymph node (PLN). This approach requires neither screening nor selection for antigen-binding. This collaborative effort with UT Austin scientists will aid in development of better vaccines and is also currently being developed as a potential new rapid diagnostic platform.
Main Technologies And Methods Used
- High throughput screening techniques
- Cell biology techniques including microscopy and siRNA suppression of gene expression
- Computer assisted image analysis
- Efficacy of treatments by in vitro and in vivo disease models