Journal article
Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner
Frontiers in immunology, v 11, pp 1430-1430
08 Jul 2020
PMID: 32733475
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells inex vivoassays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule.
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Details
- Title
- Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner
- Creators
- Jinu Abraham - Oregon Health & Science UniversitySara Botto - Oregon Health & Science UniversityNobuyo Mizuno - Oregon Health & Science UniversityKara Pryke - Oregon Health & Science UniversityBryan Gall - Gene (China)Dylan Boehm - Oregon Health & Science UniversityTina M. Sali - Oregon Health & Science UniversityHaihong Jin - Veterans Health AdministrationAaron Nilsen - Veterans Health AdministrationMichael Gough - Integrated Therapies Laboratory, Earle A. Chiles Research Institute, Portland, OR, United States.Jason Baird - Integrated Therapies Laboratory, Earle A. Chiles Research Institute, Portland, OR, United States.Marita Chakhtoura - Drexel UniversityCaroline Subra - Henry M. Jackson FoundationLydie Trautmann - Oregon Health & Science UniversityElias K. Haddad - Drexel UniversityVictor R. DeFilippis - Oregon Health & Science University
- Publication Details
- Frontiers in immunology, v 11, pp 1430-1430
- Publisher
- Frontiers Media Sa
- Number of pages
- 19
- Grant note
- AI143660; HHSN272201400055C; AI109680 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine; Infectious Diseases (and HIV Medicine); Drexel University
- Web of Science ID
- WOS:000554030200001
- Scopus ID
- 2-s2.0-85088425600
- Other Identifier
- 991020100206004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- Web of Science research areas
- Immunology