Research in Dr. DeFilippis’ laboratory focuses on the molecular biology of innate immune signaling and its multiple links with adaptive immune responses such as the generation of antibody and T cell responses. This includes investigating mechanistic questions that yield insight into the basic biology of related phenomena as well as translational projects that apply these principles to problems such as identifying novel antiviral therapies, enhancing vaccine potency, and potentiating cancer immunotherapies. The primary area of research involves the cGAS-STING innate signaling pathway. This is an evolutionarily conserved intracellular apparatus that reacts to the atypical presence of cytosolic DNA. The detection of DNA in the cytosol leads to an array of inducible responses that include secretion of cytokines (especially type I interferons), apoptosis, and autophagy. Ultimately these processes lead to establishment of inflammatory tissue states that both block microbial growth and drive adaptive immune responses. As such, its dysfunction can lead to serious disease but it can also be harnessed pharmacologically to devise novel tools and clinical interventions for a wide array of conditions.
The laboratory employs many techniques of cellular and molecular biology including forward and reverse genetics approaches (ectopic expression methods, CRISPR/Cas genome editing) as well as larger scale methods such as functional genomics, transcriptomics, and high throughput chemical screens. Many transgenic mouse and nonhuman primate models are also employed in the context of vaccine function and cancer.
Specific foci of inquiry include the following:
1) Discovery and characterization of novel compounds that stimulate cGAS-STING induction
The host innate immune response can be highly effective in both preventing replication of phylogenetically diverse viral pathogens but also in enhancing the initiation and establishment of adaptive immune responses. This is particularly true of the response induced by cGAS-STING activation. In light of this we employ high throughput screening strategies to identify new small molecules capable of triggering cGAS-STING associated phenotypes. We then dissect their mechanisms of action using molecular biological methods and characterize their in vivo utility as vaccine adjuvants and ability to enhance cancer therapies.
2) Development of novel vaccines against emerging viruses
Mosquito transmitted viruses such as Chikungunya and Zika represent globally impactful infections that can arise with remarkable swiftness. As such, adaptable vaccine platforms are needed to address the inevitability and unknown nature of their emergence. To address this the laboratory utilizes in vitro synthesized virus like particles as a replication incompetent viral mimic and pairs this with novel adjuvant combinations to identify safe and efficacious ways to elicit protective immunity. These platforms also represent powerful tools to investigate the mechanistic bases of vaccine function.
Victor DeFilippis is an associate professor at the Vaccine and Gene Therapy Institute. After receiving his bachelor's degree from the University of Montana he received a Master's degree in Biology from Wayne State University. He completed his Ph.D. examining virus evolution at the University of California, Irvine. He conducted his postdoctoral work at the Vaccine and Gene Therapy Institute of OHSU.
Abraham J, Botto S, Mizuno N, Pryke K, Gall B, Boehm D, Sali TM, Jin H, Nilsen A, Gough M, Baird J, Shaktoura M, Subra C, Trautmann L, Haddad EK, and DeFilippis VR. 2020. Characterization of a Novel Compound that Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner. Frontiers in Immunology.
Botto S, Abraham J, Mizuno N, Pryke K, Gall B, Landais I, Streblow DN, Früh KJ, DeFilippis VR. 2019. Human Cytomegalovirus Immediate Early 86-kDa Protein Blocks Transcription and Induces Degradation of the Immature Interleukin-1β Protein during Virion-Mediated Activation of the AIM2 Inflammasome. mBio 10:257.
Gall B, Pryke K, Abraham J, Mizuno N, Botto S, Sali TM, Broeckel R, Haese N, Nilsen A, Placzek A, Morrison T, Heise M, Streblow D, DeFilippis VR. 2018. Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway. Journal of Virology 92:8
Pryke KM, Abraham J, Sali TM, Gall BJ, Archer I, Liu A, Bambina S, Baird J, Gough M, Chakhtoura M, Haddad EK, Kirby IT, Nilsen A, Streblow DN, Hirsch AJ, Smith JL, DeFilippis VR. 2017. A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses. mBio 8:e00452–17.
Sali TM, Pryke KM, Abraham J, Liu A, Archer I, Broeckel R, Staverosky JA, Smith JL, Al-Shammari A, Amsler L, Sheridan K, Nilsen A, Streblow DN, DeFilippis VR. 2015. Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoS Pathog 11:e1005324.
Gall BJ, DeFilippis VR. High-Throughput Screening for Identification of Novel Innate Immune Activators. Methods Mol Biol.2017;1656:183-193. doi: 10.1007/978-1-4939-7237-1_12. [PMID: 28808971]
Pryke KM, Abraham J, Sali TM, Gall BJ, Archer I, Liu A, Bambina S, Baird J, Gough M, Chakhtoura M, Haddad EK, Kirby IT, Nilsen A, Streblow DN, Hirsch AJ, Smith JL, DeFilippis VR. A Novel Agonist of the TRIFPathway Induces a Cellular State Refractory to Replication of Zika,Chikungunya, and Dengue Viruses. MBio. 2017 May 2;8(3). pii: e00452-17. doi:10.1128/mBio.00452-17. [PMID: 28465426]
Hirsch AJ, Smith JL, Haese NN, Broeckel RM, Parkins CJ,Kreklywich C, DeFilippis VR, Denton M, Smith PP, Messer WB, Colgin LM, Ducore RM, Grigsby PL, Hennebold JD, Swanson T, Legasse AW, Axthelm MK, MacAllister R, Wiley CA, Nelson JA, Streblow DN. Zika Virus infection of rhesus macaques leads to viral persistence in multiple tissues. PLoS Pathog. 2017 Mar9;13(3):e1006219. doi: 10.1371/journal.ppat.1006219. [PMID: 28278237]
Greene TT, Tokuyama M, Knudsen GM, Kunz M, Lin J, GreningerAL, DeFilippis VR, DeRisi JL, Raulet DH, Coscoy L. A Herpesviral induction ofRAE-1 NKG2D ligand expression occurs through release of HDAC mediatedrepression. Elife. 2016 Nov 22;5. pii: e14749. doi: 10.7554/eLife.14749. [PMID:27874833]
Uhrlaub JL, Pulko V, DeFilippis VR, Broeckel R, Streblow DN, Coleman GD, Park BS, Lindo JF, Vickers I, Anzinger JJ, Nikolich-Žugich J. Dysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus. PLoSPathog. 2016 Oct 13;12(10):e1005891. doi: 10.1371/journal.ppat.1005891.eCollection 2016 Oct. [PMID: 27736984]
Sali TM, Pryke KM, Abraham J, Liu A, Archer I, Broeckel R,Staverosky JA, Smith JL, Al-Shammari A, Amsler L, Sheridan K, Nilsen A,Streblow DN, DeFilippis VR. Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. PLoSPathog. 2015 Dec 8;11(12):e1005324. doi: 10.1371/journal.ppat.1005324.eCollection 2015 Dec. [PMID: 26646986]
Whitmer T, Malouli D, Uebelhoer LS, DeFilippis VR, Früh K,Verweij MC. The ORF61 Protein Encoded by Simian Varicella Virus andVaricella-Zoster Virus Inhibits NF-κB Signaling by Interfering with IκBαDegradation. J Virol. 2015 Sep;89(17):8687-700. doi: 10.1128/JVI.01149-15. Epub2015 Jun 17. [PMID: 26085158]
Chiang C, Beljanski V, Yin K, Olagnier D, Ben Yebdri F,Steel C, Goulet ML, DeFilippis VR, Streblow DN, Haddad EK, Trautmann L, Ross T,Lin R, Hiscott J. Sequence-Specific Modifications Enhance the Broad-SpectrumAntiviral Response Activated by RIG-I Agonists. J Virol. 2015 Aug;89(15):8011-25.doi: 10.1128/JVI.00845-15. Epub 2015 May 27. [PMID: 26018150]
Verweij MC, Wellish M, Whitmer T, Malouli D, Lapel M, JonjićS, Haas JG, DeFilippis VR, Mahalingam R, Früh K. Varicella Viruses InhibitInterferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms. PLoSPathog. 2015 May 14;11(5):e1004901. doi: 10.1371/journal.ppat.1004901.eCollection 2015 May. [PMID: 25973608]
- Malouli D, Hansen SG, Nakayasu ES, Marshall EE, Hughes CM, Ventura AB, Gilbride RM, Lewis MS, Xu G, Kreklywich C, Whizin N, Fischer M, Legasse AW, Viswanathan K, Siess D, Camp DG 2nd, Axthelm MK, Kahl C, DeFilippis VR, Smith RD, Streblow DN, Picker LJ, Früh K. Cytomegalovirus pp65 limits dissemination but is dispensable for persistence. J Clin Invest. 2014 May 1;124(5):1928-44. [PMID: 24691437, PMCID: PMC4002596] Epub 2014 Apr 1.
- Amsler L, Verweij MC, DeFilippis VR. The tiers and dimensions of evasion of the type I interferon response by human cytomegalovirus. J Mol Biol. 2013 Dec 13;425(24):4857-71. (doi: 10.1016/j.jmb.2013.08.023.) [PMID: 24013068, PMCID: PMC3864659] Epub 2013 Sep 5.
- Messaoudi I, Vomaske J, Totonchy T, Kreklywich CN, Haberthur K, Springgay L, Brien JD, Diamond MS, Defilippis VR, Streblow DN. Chikungunya virus infection results in higher and persistent viral replication in aged rhesus macaques due to defects in anti-viral immunity. PLoS Negl Trop Dis. 2013 Jul 25;7(7):e2343. doi: 10.1371/journal.pntd.0002343. [PMID: 23936572, PMCID: PMC3723534]Print 2013.
- Amsler L, Malouli D, DeFilippis V. The inflammasome as a target of modulation by DNA viruses. Future Virol. 2013 Apr 1;8(4):357-370. [PMID: 24955107, PMCID: PMC4061697]
- Pissani F, Malherbe DC, Robins H, DeFilippis VR, Park B, Sellhorn G, Stamatatos L, Overbaugh J, Haigwood NL. Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially. Vaccine. 2012 Aug 10;30(37):5519-26. doi: 10.1016/j.vaccine.2012.06.042. [PMID: 22749601, PMCID: PMC3447634] Epub 2012 Jun 27.
- Robinson BA, O'Connor MA, Li H, Engelmann F, Poland B, Grant R, DeFilippis V, Estep RD, Axthelm MK, Messaoudi I, Wong SW. Viral interferon regulatory factors are critical for delay of the host immune response against rhesus macaque rhadinovirus infection. J Virol. 2012 Mar;86(5):2769-79. (doi: 10.1128/JVI.05657-11.) [PMID: 22171275, PMCID: PMC3302252] Epub 2011 Dec 14.
- Botto S, Streblow DN, DeFilippis V, White L, Kreklywich CN, Smith PP, Caposio P. IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. Blood. 2011 Jan 6;117(1):352-61. doi: 10.1182/blood-2010-06-291245.
- White LK, Sali T, Alvarado D, Gatti E, Pierre P, Streblow D, Defilippis VR. Chikungunya virus induces IPS-1-dependent innate immune activation and protein kinase R-independent translational shutoff. J Virol. 2011 Jan;85(1):606-20. (doi: 10.1128/JVI.00767-10.) [PMID: 20962078, PMCID: PMC3014158] Epub 2010 Oct 20.
- DeFilippis VR, Sali T, Alvarado D, White L, Bresnahan W, Früh KJ. Activation of the interferon response by human cytomegalovirus occurs via cytoplasmic double-stranded DNA but not glycoprotein B. J Virol. 2010 Sep;84(17):8913-25. (doi: 10.1128/JVI.00169-10.) [PMID: 20573816, PMCID: PMC2919031] Epub 2010 Jun 23.
- Viswanathan K, Früh K, DeFilippis V. Viral hijacking of the host ubiquitin system to evade interferon responses. Curr Opin Microbiol. 2010 Aug;13(4):517-23. (doi: 10.1016/j.mib.2010.05.012.) [PMID: 20699190, PMCID: PMC2939720] Epub 2010 Jun 17.
- DeFilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J Virol. 2010 Jan;84(1):585-98. (doi: 10.1128/JVI.01748-09.) [PMID: 19846511, PMCID: PMC2798427]
- Vomaske J, Melnychuk RM, Smith PP, Powell J, Hall L, DeFilippis V, Früh K, Smit M, Schlaepfer DD, Nelson JA, Streblow DN. Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility. PLoS Pathog. 2009 Feb;5(2):e1000304. (doi: 10.1371/journal.ppat.1000304.) [PMID: 19229316, PMCID: PMC2637432] Epub 2009 Feb 20.
- Medigeshi GR, Lancaster AM, Hirsch AJ, Briese T, Lipkin WI, Defilippis V, Früh K, Mason PW, Nikolich-Zugich J, Nelson JA. West Nile virus infection activates the unfolded protein response, leading to CHOP induction and apoptosis. J Virol. 2007 Oct;81(20):10849-60. [PMID: 17686866, PMCID: PMC2045561] Epub 2007 Aug 8.
- Streblow DN, van Cleef KW, Kreklywich CN, Meyer C, Smith P, Defilippis V, Grey F, Früh K, Searles R, Bruggeman C, Vink C, Nelson JA, Orloff SL. Rat cytomegalovirus gene expression in cardiac allograft recipients is tissue specific and does not parallel the profiles detected in vitro. J Virol. 2007 Apr;81(8):3816-26. [PMID: 17251289, PMCID: PMC1866122] Epub 2007 Jan 24.
- DeFilippis VR. Induction and evasion of the type I interferon response by cytomegaloviruses. Adv Exp Med Biol. 2007;598:309-24.[ PMID: 17892221]
- DeFilippis VR, Robinson B, Keck TM, Hansen SG, Nelson JA, Früh KJ. Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection. J Virol. 2006 Jan;80(2):1032-7. [PMID: 16379004, PMCID: PMC1346858]
- Hirsch AJ, Medigeshi GR, Meyers HL, DeFilippis V, Früh K, Briese T, Lipkin WI, Nelson JA. The Src family kinase c-Yes is required for maturation of West Nile virus particles. J Virol. 2005 Sep;79(18):11943-51. [PMID: 16140770, PMCID: PMC1212629]
- DeFilippis V, Früh K. Rhesus cytomegalovirus particles prevent activation of interferon regulatory factor 3. J Virol. 2005 May;79(10):6419-31. [PMID: 15858025, PMCID: PMC1091669]
- Rue CA, Jarvis MA, Knoche AJ, Meyers HL, DeFilippis VR, Hansen SG, Wagner M, Früh K, Anders DG, Wong SW, Barry PA, Nelson JA. A cyclooxygenase-2 homologue encoded by rhesus cytomegalovirus is a determinant for endothelial cell tropism. J Virol. 2004 Nov;78(22):12529-36. [PMID: 15507640, PMCID: PMC525102]
- McAllister SC, Hansen SG, Ruhl RA, Raggo CM, DeFilippis VR, Greenspan D, Früh K, Moses AV. Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood. 2004 May 1;103(9):3465-73. [PMID: 14726403]
- DeFilippis V, Raggo C, Moses A, Früh K. Functional genomics in virology and antiviral drug discovery. Trends Biotechnol. 2003 Oct;21(10):452-7. [PMID: 14512232]
- DeFilippis VR, Ayala FJ, Villarreal LP. Evidence of diversifying selection in human papillomavirus type 16 E6 but not E7 oncogenes. J Mol Evol. 2002 Oct;55(4):491-9. [PMID: 12355268]