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Principal Investigator: VICTOR Robert DEFILIPPIS
Organization: OREGON HEALTH & SCIENCE UNIVERSITY
Fiscal Year: 2023
Award: $773,026
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The goals of this R01 proposal include the molecular and immunological characterization of vaccine adjuvant
activity associated with processes mediated by the protein Stimulator of Interferon Genes (STING). Two vital
insufficiencies are currently evident regarding adjuvanted human vaccines. First, very few adjuvants are
approved for clinical use in the U.S. Second, the precise mechanistic bases of adjuvant-associated immune
augmentation are poorly understood. Effective adjuvants trigger rapid, localized innate immune responses
following their administration. Fundamentally, the innate signaling is initiated through engagement of pattern
recognition receptors (PRRs) by ligands indicative or imitative of microbial infection. This, in turn, leads to
expression of immunomodulatory and proinflammatory factors that ultimately direct adaptive immune responses
capable of eliminating infected tissues. STING represents the PRR that senses cyclic dinucleotides (CDN), a
product of the cellular enzyme cyclic GMP-AMP synthase (cGAS) following its detection of cytoplasmic dsDNA
derived from microbes, mitochondria, or the nucleus. STING-mediated phenotypes are ultimately conferred by
genes that are transcriptionally induced by the activated protein. This crucially involves the transcription factors
IFN regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB), which synthesize mRNAs of distinct ontologies yet
whose functional roles are mostly unexplored. Moreover, STING appears to control physiological processes that
differ dramatically between cell types of the immune system including stromal, myeloid, and T cells. Intriguingly,
pharmacologic induction of STING-dependent activity in murine models greatly enhances vaccine efficacy as
indicated by protective immunity elicited against diverse pathogens. Unfortunately, the precise molecular and
innate correlates of adaptive immune potentiation associated with STING activity remain largely unexamined.
Furthermore, whether STING adjuvants elicit similarly effective immunogenic outcomes in primates has not been
examined. We plan to couple these with our powerful CRISPR and transcriptomic technologies to obtain
penetrative insight into the fundamental bases of STING-mediated immune outcomes. We hypothesize that the
enhancement of antigen-directed adaptive immunity associated with STING-based adjuvants is functionally
linked to molecular and cellular processes that are discernable using these models. We have also identified a
first-in-class small molecule that activates cGAS-STING across species and enhances immunogenicity to Zika
virus antigen. Including this alongside CDN in in vitro, murine, and nonhuman primate (NHP) models will allow
us to: 1) Validate and characterize cGAS as a new immunotherapeutic target; 2) Demonstrate STING adjuvant
efficacy in a highly clinically relevant model species; and 3) Identify species-specific similarities and differences
with respect to STING-mediated immune responses.
Terms: <Adjuvant><Agonist><Animal Model><Animal Models and Related Studies><Antigen-Presenting Cells><Antigens><Basal Transcription Factor><Basal transcription factor genes><Biological><Biology><Blood monocyte><Body Tissues><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Categories><Cell Body><Cell Communication and Signaling><Cell Function><Cell Line><Cell Nucleus><Cell Process><Cell Signaling><Cell physiology><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemicals><Chemosensitization><Chemosensitization/Potentiation><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Cyclic GMP><Cyclicity><Cytoplasm><Detection><Dinucleoside Phosphates><Dissection><Double-Stranded DNA><Enzyme Gene><Enzymes><Evaluation><Exhibits><Experimental Models><Formulation><Gene Activation><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Goals><Guanosine Cyclic Monophosphate><Human><IFN-regulatory factor 3><IRF-3 protein><IRF3><IRF3 gene><Immune><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Stimulation><Immunological><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunomodulation><Immunostimulation><Immunotherapeutic agent><In Vitro><Infection><Inflammatory><Innate Immune Response><Interferon Regulatory Factor 3><Intracellular Communication and Signaling><Ligands><Link><Lymphoid Cell><M mulatta><M. mulatta><Macaca mulatta><Marrow monocyte><Mediating><Messenger RNA><Mice><Mice Mammals><Microbe><Mitochondria><Modeling><Modern Man><Molecular><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Nuclear><Nucleus><Ontology><Organism-Level Process><Organismal Process><Outcome><Pathway interactions><Pattern><Pattern recognition receptor><Periodicity><Phenotype><Physiologic Processes><Physiological Processes><Potentiation><Primates><Primates Mammals><Process><Proteins><RNA Expression><Research><Rhesus Macaque><Rhesus Monkey><Rhythmicity><Role><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Solubility><Stimulator of Interferon Genes><Strains Cell Lines><Subcellular Process><System><T-Cells><T-Lymphocyte><Technology><Testing><Tissues><Transcript><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Vaccination><Vaccine Adjuvant><Vaccines><Viral Antigens><ZIKV><Zika Virus><accessory cell><adaptive immune response><adaptive immunity><analog><base><bases><biologic><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cGMP><cell type><clinical relevance><clinically relevant><cultured cell line><cyclic GMP-AMP synthase/STING><dinucleotide><ds-DNA><dsDNA><gene function><host response><human model><immune drugs><immune modulation><immune regulation><immune system response><immune-based therapeutics><immunogen><immunogenic><immunogenicity><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><in vivo><innate immune function><insight><mRNA><microbe pathogen><microbial><microbial pathogen><mitochondrial><model of animal><model of human><monocyte><mouse model><murine model><non-human primate><nonhuman primate><novel><outcome following vaccination><outcome following vaccine><pathogen><pathogenic microbe><pathway><pharmacologic><recruit><response><result following vaccination><result following vaccine><small molecule><social role><thymus derived lymphocyte><tool><transcription factor><transcriptomics><vaccination outcome><vaccination result><vaccine efficacy><vaccine outcome><vaccine result><virus antigen><zikav>