Victor R. DeFilippis, Ph.D.
- Associate Professor, VGTI-Vaccine and Gene Therapy Institute
- Adjunct Assistant Professor of Molecular Microbiology and Immunology, School of Medicine
- Assistant Professor, Oregon National Primate Research Center
- Molecular Microbiology and Immunology Graduate Program, School of Medicine
- Program in Molecular and Cellular Biosciences, School of Medicine
Biography
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.
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.
Areas of interest
- Innate immunity, emerging viruses, vaccines
Additional information
Publications
Selected publications
- 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.
Publications
4-Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses
Journal of Medicinal ChemistryBystander monocytic cells drive infection-independent NLRP3 inflammasome response to SARS-CoV-2
mBioMayaro virus pathogenesis and immunity in rhesus macaques
PLoS neglected tropical diseasesAging alters antiviral signaling pathways resulting in functional impairment in innate immunity in response to pattern recognition receptor agonists
GeroScienceDevelopment of a next-generation chikungunya virus vaccine based on the HydroVax platform
PLoS pathogensIdentification and Characterization of Small-Molecule IRF3-Dependent Immune Activators for Pharmaceutical Development
ACS chemical biologyHuman cytomegalovirus blocks canonical TGF β signaling during lytic infection to limit induction of type I interferons
PLoS pathogensIdentification of quinolinones as antivirals against venezuelan equine Encephalitis virus
Antimicrobial agents and chemotherapyNon-replicating adenovirus based mayaro virus vaccine elicits protective immune responses and cross protects against other alphaviruses
PLoS neglected tropical diseasesTargeting Chikungunya Virus Replication by Benzoannulene Inhibitors
Journal of Medicinal ChemistryCharacterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner
Frontiers in immunologyHerpes simplex virus type 1 inflammasome activation in proinflammatory human macrophages is dependent on NLRP3, ASC, and caspase-1
PloS oneThe E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection
Frontiers in MicrobiologyDiscovery and Mechanistic Study of a Novel Human-Stimulator-of-Interferon-Genes Agonist
ACS Infectious DiseasesHuman 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
mBioSrc family kinase inhibitors block translation of alphavirus subgenomic mRNAs
Antimicrobial agents and chemotherapyStudies on Dibenzylamines as Inhibitors of Venezuelan Equine Encephalitis Virus
ACS Infectious DiseasesVaccine-induced skewing of t cell responses protects against chikungunya virus disease
Frontiers in immunologyEmerging alphaviruses are sensitive to cellular states induced by a novel small-molecule agonist of the STING pathway
Journal of virologyZika virus infection in pregnant rhesus macaques causes placental dysfunction and immunopathology
Nature communicationsA novel agonist of the trif pathway induces a cellular state refractory to replication of Zika, Chikungunya, and dengue viruses
mBioZika Virus infection of rhesus macaques leads to viral persistence in multiple tissues
PLoS pathogensA herpesviral induction of RAE-1 NKG2D ligand expression occurs through release of HDAC mediated repression
eLifeDysregulated TGF-β Production Underlies the Age-Related Vulnerability to Chikungunya Virus
PLoS pathogensCharacterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses
PLoS pathogensHuman Cytomegalovirus miR-UL112-3p Targets TLR2 and Modulates the TLR2/IRAK1/NFκB Signaling Pathway
PLoS pathogensSequence-specific modifications enhance the broad-spectrum antiviral response activated by RIG-I agonists
Journal of virology