Dr. Kylene Kehn-Hall, Associate Professor, came to George Mason University (GMU) in 2009 and is a member of the National Center for Biodefense and Infectious Diseases and the School of Systems Biology. Dr. Kehn-Hall holds a B.S. in Biology and Chemistry (cum laude) from Virginia Commonwealth University, a M.S. from The George Washington University (GWU), and a Ph.D. in Biochemistry and Molecular Biology from GWU. She did her post-doctoral research at the FBI Counterterrorism and Forensic Science Research Lab, focusing on application based science and assay development. In 2007 she took a Research Scientist position within Dr. Sina Bavari’s laboratory at the US Army Medical Research Institute of Infectious Disease, where she worked towards high throughput assay development and the identification of novel therapeutics for hemorrhagic fever viruses. Prior to coming to GMU, Dr. Kehn-Hall was an Assistant Research Professor in the Department of Microbiology, Immunology, and Tropical Medicine at GWU, where she continued her work on HIV and HTLV-1 studying the host response to viral infection. Dr. Kehn-Hall has served as a principal investigator on grants from the National Institute of Health, National Center for Foreign Animal and Zoonotic Disease Defense, Commonwealth Health Research Board, and Defense Threat Reduction Agency. She has authored 75 peer-reviewed publications and serves as an academic editor for PLoS ONE. Dr. Kehn-Hall received the 2013 Mason Emerging/Researcher/Scholar/Creator Award and the 2013 George Mason University College of Science Impact Award.
Emerging Infectious Diseases (Bunyaviruses, Alphaviruses, Influenza viruses), Host-Pathogen Interactions, Small Molecule Inhibitors for Therapeutics, Cell Cycle Alterations, Transcriptional Regulation, RNAi Modulation, Novel Diagnostic Platforms
Research in my laboratory is centered on Rift Valley fever virus (RVFV) and encephalitic alphaviruses [Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV), and Western equine encephalitis virus (WEEV)]. These viruses cause emerging infectious diseases and are classified as “biodefense viruses”. Among the priority threats, RVFV, VEEV, and EEEV rank high in their potential for having a large health and economic impact. There are also periodic naturally occurring outbreaks, with a few to sometimes hundreds of people infected. RVFV is endemic to Africa, but has the potential of being introduced into the United States and becoming established in the mosquito population, very much like what happened in the case of West Nile virus. VEEV, EEEV, and WEEV are also transmitted by mosquitoes and periodic cases occur in the United States.
Despite being recognized as emerging threats, relatively little is known about the virulence mechanisms of these viruses and there are currently no FDA licensed vaccines or therapeutics available. In addition, diagnostic assays are limited for these agents. My laboratory is focused on 1) identifying critical host factors that are necessary for viral replication and/or pathogenesis, 2) evaluating small molecule inhibitors that target essential host-based events for their therapeutic potential and 3) developing novel diagnostic tools to enable the early detection of viral infections.
Elucidating the role of RVFV NSs protein. NSs, the main virulence factor of RVFV, is a potent interferon antagonist and its expression results in a robust transcription inhibition at least partially through modulating chromatin remodeling proteins and degrading the general transcription factor TFIIH p62 subunit. Ongoing studies are aimed at identifying and characterizing NSs-dependent events that contribute to RVFV pathogenesis. We have found that a number of signaling pathways are altered following RVFV infection in an NSs dependent manner (Baer et al., 2012; Austin et al., 2012). We have also identified an interaction between a ΩXaV motif in NSs and the p62 subunit of TFIIH (Cyr et al., 2015). This motif in NSs is similar to ΩXaV motifs found in nucleotide excision repair (NER) factors and transcription factors known to interact with p62. Structural and biophysical studies demonstrated that NSs binds to p62 in a similar manner as these other factors. Functional studies in RVFV-infected cells show that the ΩXaV motif is required for both nuclear filament formation and degradation of p62. These results demonstrate that p62 binding to NSs through the ΩXaV motif is essential for degrading p62, forming nuclear filaments and enhancing RVFV virulence. These studies should provide critical mechanistic information about this interaction as well as knowledge on how to therapeutically target this interaction.
Transcriptomic analysis of alphavirus infected cells. Relatively little is known about the virulence mechanisms of the encephalitic alphaviruses. Next generation RNA sequencing is being utilized to elucidate pathways that are important for viral replication and/or virulence. This work is in collaboration with Dr. Jonathan Jacobs (MRIGlobal) and Dr. Jonathan Dinman (University of Maryland). Recent transcriptomic studies by our group demonstrated a significant and dramatic upregulation of the transcription factor early growth response 1 (EGR1) in VEEV-TrD infected human astrocytoma cells (Baer et al., Accepted). EGR1 upregulation was dependent on the activation of the unfolded protein response pathway. Loss of EGR1 resulted in lower susceptibility to VEEV induced cell death. The influence of EGR1 on cell death is of great importance as neuronal damage can lead to long-term sequelae in individuals who have survived VEEV infection. These studies are being extended to determine which specific altered genes are dependent on EGR1 expression and if they contribute to VEEV induced apoptosis. Transcriptomic analysis of EEEV and WEEV infected cells is ongoing.
Molecular pathogenesis of RVFV, VEEV, Junin virus and their live attenuated vaccine derivatives. A combinatorial proteomics and transcriptomics analysis pipeline is being used to identify cellular factors important for the infectivity and replication of RVFV, VEEV, and Junin virus. This project is in collaboration with Dr. Connie Schmaljohn’s laboratory (USAMRIID) and Dr. Catherine Campbell (DCE consulting). The primary goals of this work are threefold: (1) to perform comparative analyses of host transcriptome and proteome changes following infection with either Select Agent viruses or their attenuated vaccine counterparts, (2) to produce a bioinformatic model of host-pathogen relationships and (3) to validate the model in vitro and ex vivo using a combination of reverse genetics, modulation of host cell function, and biochemical analyses of archival tissues. This integrated analysis of viral molecular biology will yield insights into the molecular pathogenesis of hemorrhagic fever and encephalitic viral infections as well as identify molecular events indicative of these diseases. The production of virus-host interaction maps will also open avenues for targeted therapeutic design, ultimately contributing to development of novel diagnostics and therapeutics.
Targeting host proteins important for viral replication. Targeting host responses to invading viruses has been the focus of recent antiviral research. This line of investigation is a natural complement to our studies on identification of host factors required for viral replication. My lab has been studying 3 different classes of inhibitors: 1) nuclear import and export inhibitors (Lundberg et al., 2013), 2) RNAi inhibitors (Madsen et al., 2014), and 3) kinase and phosphatase inhibitors (Kehn-Hall et al., 2012; Benedict et al., 2015; Baer et al., 2015). The ultimate goal of these studies is to find suitable host targets, which disruption of would minimally, if at all, affect cell function but greatly impact the virus. An ideal candidate would also be capable of inhibiting more than one virus, thus demonstrating broad spectrum utility.
The use of Nanotrap particles to enhance diagnostic assays. We are studying the use of hydrogel nanoparticles as a novel technology platform to improve diagnostics through enrichment and protection of diagnostically important targets for emerging infectious diseases. These studies are in collaboration with Ceres Nanosciences. We have demonstrated that Nanotrap particles can capture RVFV nucleoprotein, RNA, as well as virions (Shafagati et al., 2013; Shafagati et al., 2015). Our results are the first to show that Nanotrap particles can capture live infectious virus. We have shown that Nanotrap particle capture resulted in a hundred-fold enrichment of virus at low viral titers when other diagnostics assays may produce false negatives. Capture of RVFV with Nanotrap particles also protects viral RNA from degradation and increases viral stability as demonstrated through preservation of infectivity at elevated temperatures. The viral protection provided by the Nanotrap particles allows time for unknown samples to be taken from patients in the clinic or cases from the field and transferred to the laboratory for further investigation without the need to utilized cold chain transport. We have extended these studies to include mixed infections scenarios (HIV and RVFV) as well the capture of additional viruses including HIV, VEEV, EEEV, WEEV, influenza A virus, influenza B virus, respiratory syncytial virus, adenovirus, and human coronavirus (Shafagati et al., 2013; Shafagati et al., 2014; unpublished data). These results demonstrate the broad applicability of Nanotrap particles for viral diagnostics.
Selected Publications (out of 75)
- Baer A, Shafagati N, Benedict A, Ammosova T, Ivanov A, Hakami RM, Terasaki K, Makino S, Nekhai S, Kehn-Hall K. Protein Phosphatase-1 Regulates Rift Valley Fever Virus Replication. Antiviral Research. Accepted.
- Baer A, Lundberg L, Swales D, Waybright N, Pinkham C, Dinman JD, Jacobs JL, Kehn-Hall K. Venezuelan Equine Encephalitis Virus Induces Apoptosis through the Unfolded Protein Response Activation of EGR1. Journal of Virology.
- Benedict A BN, Senina S, Hooper I, Lundberg L, de la Fuente C. Narayanan A, Gutting B, Kehn-Hall K. Repurposing FDA-approved drugs as therapeutics to treat Rift Valley fever virus infection. Front Microbiol. 2015 Jul 8;6:676.
- Shafagati N, Lundberg L, Baer A, Patanarut A, Fite K, Lepene B, Kehn-Hall K. The use of nanotrap particles in the enhanced detection of rift valley fever virus nucleoprotein. PLoS One. 2015 May 28;10(5):e0128215.
- Cyr N, de la Fuente C, Lecoq L, Guendel I, Chabot PR, Kehn-Hall K, Omichinski JG. A ΩXaV motif in the Rift Valley fever virus NSs protein is essential for degrading p62, forming nuclear filaments and virulence. Proc Natl Acad Sci U S A. 2015 May 12;112(19):6021-6.
- Guendel I, Meltzer BW, Baer A, Dever SM, Valerie K, Guo J, Wu Y, Kehn-Hall K. BRCA1 functions as a novel transcriptional cofactor in HIV-1 infection. Virology Journal. Virol J. 2015 Mar 6;12(1):40.
- Madsen C, Hooper I, Lundberg L, Shafagati N, Johnson A, Senina S, de la Fuente C, Hoover LI, Fredricksen BL, Dinman J, Jacobs JL, Kehn-Hall Small molecule inhibitors of Ago2 decrease Venezuelan equine encephalitis virus replication. Antiviral Res. 2014 Dec;112:26-37. Epub 2014 Oct 18.
- Baer A, Kehn-Hall Viral concentration determination through plaque assays: using traditional and novel overlay systems. J Vis Exp. 2014 Nov 4;(93):e52065.
- Shafagati N, Patanarut A, Luchini A, Lundberg L, Bailey C, Petricoin E 3rd, Liotta L, Narayanan A, Lepene B, Kehn-Hall The Use of Nanotrap Particles for Biodefense and Emerging Infectious Disease Diagnostics. 2014. Pathog Dis. Jul;71(2):164-76.
- Lundberg L, Pinkham C, Baer A, Amaya, M, Narayanan A, Wagstaff K, Jans D, Kehn-Hall K. Nuclear Import Inhibitors Reduce Venezuelan Equine Encephalitis Virus Replication and Alter Capsid Protein Distribution in Mammalian Cells. Antiviral Res. 2013 Dec;100(3):662-72.
- Shafagati N, Narayanan N, Baer A, Fite K, Pinkham C, Bailey C, Kashanchi F, Lepene B, Kehn-Hall K. The Use of NanoTrap Particles as a Sample Enrichment Method to Enhance the Detection of Rift Valley Fever Virus. PLoS Negl Trop Dis. 2013 Jul 4;7(7):e2296.
- Austin D, Baer A, Lundberg L, Shafagati N, Schoonmaker A, Narayanan A, Popova T, Panthier JJ, Kashanchi F, Bailey C, Kehn-Hall K. p53 Activation Following Rift Valley Fever Virus Infection Contributes to Cell Death and Viral Production. PLoS ONE. 2012; 7(5):e36327.
- Kehn-Hall K, Narayanan A, Lundberg L, Sampey G, Pinkham C, Guendel I, Van Duyne R, Senina S, Schultz K, Stavale E, Aman MJ, Bailey C, Kashanchi F. Modulation of GSK3-b Activity in Venezuelan Equine Encephalitis Virus Infection. PLoS ONE. 2012; 7(4):e34761.
- Baer A, Austin D, Narayanan A, Popova T, Kainulainen M, Bailey C, Kashanchi F, Weber F, Kehn-Hall K. Induction of DNA Damage Signaling upon Rift Valley Fever Virus Infection Results in Cell Cycle Arrest and Increased Viral Replication. J Biol Chem. 2012 287(10):7399-410.
- Narayanan A, Popova T, Turell T, Kidd J, Chertow J, Popov S, Bailey C, Kashanchi F, Kehn-Hall K. Alteration in superoxide dismutase 1 causes oxidative stress and p38 MAPK activation following RVFV infection. PLoS ONE. 2011; 6(5):e20354.
- Narayanan A, Bailey C, Kashanchi F, Kehn-Hall K. Developments in antivirals against influenza, smallpox and hemorrhagic fever viruses. Expert Opin Investig Drugs. 2011 Feb;20(2):239-54
Complete List of Published Work in MyBibliography: http://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/
- Dr. Kehn-Hall received the George Mason University Emerging Researcher, Scholar, Creator Award in October, 2013. The awards, which carry a $3,000 stipend, recognize faculty members who are within 10 years of receiving a terminal degree and have growing national and international recognition for their work. http://newsdesk.gmu.edu/2013/11/emerging-researcher-scholar-creator-awards-announced/
- Dr. Kehn-Hall and Dr. Narayanan (Co-PI, GMU) have received a three year NIH R15 grant entitled “Induction of DNA Damage Signaling Cascade upon RVFV Infection”. This grant is aimed at determining the mechanism by which RVFV NSs induces DNA damage signaling and how this signaling aids in viral replication in vitro and in vivo.
- Dr. Kehn-Hall and Dr. Jonathan Jacobs (Co-PI, MRIGlobal) have received a three year grant from DTRA entitled “Interactions of Alphaviruses with the Host MicroRNA Processing Machinery”. This project also involves a collaboration with Dr. Jonathan Dinman’s laboratory at University of Maryland. The objective of this grant is to determine the importance and mechanism of specific miRNAs in alphavirus replication, thereby understanding their potential as a host based therapeutic target.
- Dr. Kehn-Hall and Dr. Carpenter have received a contract from Unither Virology entitled “Animal Modeling Development and Therapeutic Testing”. This contract will focus on the development of an aerosol exposure mouse model of Venezuelan Equine Encephalitis Virus.
- Dr. Kehn-Hall has received a subcontract from Ceres Nanosciences to facilitate work on a DARPA project entitled “Universal Nanotrap-enabled Biofluid Sample Preparation and Storage Toolset”. This is a two year grant that is focused on testing whole virus capture and preservation with NanoTrap particles both in liquid and on filter paper for RVFV, Influenza, and HIV.
- Dr. Kehn-Hall and Dr. Narayanan (Co-PI, GMU) have received a five year grant from DTRA entitled “Molecular Pathogenesis of Select Agent Viruses and their Attenuated Vaccine Derivatives”. This project is in collaboration with Dr. Connie Schmaljohn’s laboratory at USAMRIID. The objectives of this grant are (1) to identify significant differences at the host response level to Select Agent viruses versus attenuated vaccine counterparts through comparative analyses of host transcriptome and proteome changes, (2) to produce bioinformatic models of host-pathogen relationships and (3) to validate these models using reverse genetic systems and siRNA approaches.