Gaya K. Amarasinghe, Ph.D.
Pathology and Immunology
Laboratory and Genomic Medicine
Molecular Microbiology and Microbial Pathogenesis Program
interferon, viral infection, structural biology, signaling, biochemistry
Signaling through interferons: Mechanisms and implications for viral pathogenesis and cancer biology
The innate immune system serves as a first line of defense against viral infections. Germline encoded pattern recognition receptors detect pathogens and promote innate immune responses, including activation of type I interferons (IFNs) and stimulation of antiviral genes. In addition to limiting infections, innate immunity is required to activate humoral responses and to develop long-term protection via adaptive immune response. Dysregulation of IFN signaling is detrimental to the host, resulting in events such as cytokine storms during infections or autoimmune disorders.
In my laboratory, we use a multidisciplinary research program that spans length and time scales to address this question by characterizing the molecular mechanisms of initial interactions at the host-pathogen interface. Using this information, we expect to develop a framework to manipulate viruses by modulating virulence (less virulent) in order to gain insight into immune mechanisms that are at play during these critical time points. Our current efforts are aimed toward defining the molecular basis for viral hemorrhagic fever (VHF) at the host-viral interface. VHF is a complex multivariable challenge with contributions from the virus and from the host dictating the outcome. We have begun a series of studies to understand the viral components, host factors and their interactions between each other. Below I briefly describe recent and recently completed studies that provide the experimental framework for us to examine these questions.
Ramanan P, Edwards MR, Shabman RS, Leung DW, Endlich-Frazier AC, Borek DM, Otwinowski Z, Liu G, Hyh J, Basler CF, Amarasinghe GK: Structural basis of Marburg virus VP-35-mediated immune evasion mechanisms. Proc Natl Acad Sci USA 2012;109(50):20661-20666. PMCID: PMC3528546
18. Shabman, RS., Hoenen, T., Groseth, A., Jabado, O., Binning, JM., Amarasinghe, GK., Feldmann, HBasler, CF. An Upstream Open Reading Frame Modulates Ebola Virus Polymerase Translation and Virus Replication. PLOS Pathogens 2013;9(1):e1003147. PMCID: PMC3561295
19. Luthra P, Ramanan P, Mire CE, Weisend C, Tsuda Y, Yen B, Liu G, Leung DW, Geisbert TW, Ebihara H, Amarasinghe GK, Basler CF. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome. Cell Host Microbe. 2013; 14(1):74-84. PMCID: PMC3875338
20. Binning JM, Wang T, Luthra P, Shabman RS, Borek DM, Liu G, Xu W, Leung DW, Basler CF, Amarasinghe GK. Development of RNA aptamers targeting Ebola virus VP35. Biochemistry. 2013;52(47):8406-8419. PMCID: PMC3909728
21. Hyde JL, Gardner CL, Kimura T, White JP, Liu G, Trobaugh DW, Huang C, Tonelli M, Paessler S, Takeda K, Klimstra WB, Amarasinghe GK, and Diamond MS. A viral RNA structural element alters host recognition of non-self RNA. Science 2014;343(6172):783-787. PMCID: PMC4209899
22. Brown CS, Lee, MS, Leunga, DW, Wang,T, Xu, W., Luthra, P., Shabman, RS, Melito, LM, Millan, KS., Borek, DM, Otwinowski, Z, Ramanana, P., Stubbs, AJ, Peterson, DS, Binning, JM, Olson, MS, Ready, JM, Basler CF, Amarasinghe GK. In silico derived small molecules bind the filovirus VP35 protein and inhibit its polymerase co-factor activity. J Mol Biol 2014;426(10):2045-2058. PMCID: PMC4163021
23. Edwards ER, Johnson B, Mire CE, Xu W, Shabman RS, Speller LN, Leung DW, Geisbert TW, Amarasinghe GK, and Basler CF. The Marburg virus VP24 protein interacts with Keap1 to activate the cytoprotective antioxidant response pathway. Cell Reports 2014 Mar 27;6(6):1017-1025. PMCID: PMC3985291
24. Xu W, Edwards MR, Borek DM, Feagins AR, Mittal A, Alinger JB, Berry KN, Yen B, Hamilton J, Brett TJ, Pappu RV, Leung DW, Basler CF, Amarasinghe GK. Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 2014 Aug 13;16(2):187-200 PMCID: PMC4188415
25. Luthra P, Jordan DS, Leung DW, Amarasinghe GK, Basler CF. Ebola Virus VP35 Interaction with Dynein LC8 Regulates Viral RNA Synthesis. J Virol 2015 Mar 1;89(9):5148-5143. PMCID: PMC4403485
26. Korasick DA, Chatterjee S, Tonelli M, Dashti H, Lee SG, Westfall CS, Fulton DB, Andreotti AH, Amarasinghe GK, Strader LC, Jez JM. Defining a Two-Pronged Structural Model for PB1 Domain Interaction in Plant Auxin Responses. J Biol Chem 2015 Apr 3. (In Press) PMCID: PMC4432302
27. Leung DW, Borek D, Luthra P, Binning JM, Anantpadma M, Liu G, Harvey IB, Su Z, Endlich-Frazier A, Pan J, Shabman RS, Chiu W, Davey RA, Otwinowski Z, Basler CF, Amarasinghe GK. An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions. Cell Rep 2015 Apr 21;11(3):376-389. PMCID: PMC4599368
28. Pinto AK, Williams GD, Szretter KJ, White JP, Proenca-Modena JL, Liu G, Olejnik J, Brien JD, Ebihara H, Muhlberger E, Amarasinghe GK, Diamond MS, Boon AC. Human and Murine IFIT1 Proteins Do Not Restrict Invection of Negative-Sense RNA Viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families. J Virol 2015 Sep 15;89(18):9465-9476. PMCID: PMC4542382.
29. Edwards MR, Liu G, Mire CE, Sureshchandra S, Luthra P, Yen B, Shabman RS, Leung DW, Messaoudi I, Geisbert TW, Amarasinghe GK*, Basler CF* (*co-corresponding) Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins. Cell Rep. 2016 Feb 23;14(7):1632-40. doi: 10.1016/j.celrep.2016.01.049. Epub 2016 Feb 11.
Last Updated: 6/6/2016 9:08:55 AM