Research in the DeFilippis laboratory focuses on mammalian innate immunity. The innate immune system represents a rapid response to microbial pathogens or diseased tissue that drives elimination of proliferative threats. This includes infection with multiple viruses and bacteria but also invasive cancers. Innate immune processes are fundamentally triggered by engagement of germline-encoded pattern recognition receptors (PRRs) that detect molecular patterns indicative or simulative of undesirable tissue states. These, in turn, activate signaling cascades that culminate in the transcription or catalytic processing of intracellular proteins as well as immunologically active cyto/chemokines. These factors then drive processes important for many aspects related to maintaining homeostasis either directly as effector molecules but also through generation of proinflammatory conditions that potentiate adaptive immune responses. This includes directing and enhancing both antibody and T cell-mediated activity targeting specific antigens associated with infection or disease. In this way, innate immune activity is required for the establishment of protective and therapeutic immune responses that guard against pathogens and cancers.
One critical innate immune process is represented by reactivity to cytoplasmic DNA, which does not occur under normal physiological conditions. However, situations such as infection with DNA-based microbes, phagocytosis of diseased/dying cells, and DNA replication errors can expose DNA to the cytoplasm and thus constitute signals of potentially dangerous irregularity. In response to this, a network of sentinel proteins termed cytoplasmic DNA receptors (CDR) has evolved to activate innate immune signaling. Most prominent among these is the protein cGAS, which catalyzes the synthesis of a cyclic dinucleotide secondary messenger that then activates the protein STING. This leads to a strong induction of myriad and multifunctional cytokines, especially type I interferons. This activation is important for numerous fundamental processes including molecular blocking of microbial growth, enhancement of adaptive responses to infection, and immune-mediated clearing of tumor cells.
Our work focuses on understanding the biochemical and molecular mechanisms that underpin cGAS- and STING-mediated innate immune processes. This includes exploration of the cellular factors involved in regulation of the pathway, phenotypic impact of pathway-mediated transcriptional profiles, and the importance of cGAS/STING for immune responses to both virus replication and tumor growth. Importantly, we are also exploring pharmacologic induction of cGAS/STING for therapeutic and preventative outcomes. This involves discovery and characterization of small molecules that activate STING-dependent phenotypes and can be harnessed for use as broad-spectrum antiviral compounds, vaccine adjuvants, and anti-cancer drugs. Experimental systems that we use to investigate these phenomena include mouse and nonhuman primate models of emerging RNA viruses such as Chikungunya and Zika. We also employ mouse models of numerous cancers. Moreover, we heavily rely on molecular and in vitro methods including CRSIPR/Cas9 genome editing, high-throughput screening, and RNAseq-based transcriptomics.
Victor DeFilippis is an assistant scientist 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.
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]