Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing

Nature Immunology, Journal Year: 2016, Volume and Issue: 17(10), P. 1142 - 1149

Published: Sept. 20, 2016

Language: Английский

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STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors

Immunity, Journal Year: 2014, Volume and Issue: 41(5), P. 843 - 852

Published: Nov. 1, 2014

Language: Английский

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STING: infection, inflammation and cancer

Nature reviews. Immunology, Journal Year: 2015, Volume and Issue: 15(12), P. 760 - 770

Published: Nov. 25, 2015

Language: Английский

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Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids

Annual Review of Immunology, Journal Year: 2014, Volume and Issue: 32(1), P. 461 - 488

Published: March 21, 2014

The innate immune system utilizes pattern-recognition receptors (PRRs) to detect the invasion of pathogens and initiate host antimicrobial responses such as production type I interferons proinflammatory cytokines. Nucleic acids, which are essential genetic information carriers for all living organisms including viral, bacterial, eukaryotic pathogens, major structures detected by system. However, inappropriate detection self nucleic acids can result in autoimmune diseases. PRRs that recognize cells include several endosomal members Toll-like receptor family cytosolic sensors DNA RNA. Here, we review recent advances understanding mechanism acid sensing signaling cytosol mammalian well emerging role autoimmunity.

Language: Английский

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ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death

Science, Journal Year: 2016, Volume and Issue: 352(6283), P. 359 - 362

Published: March 25, 2016

Repairing tears in the nuclear envelope The segregates genomic DNA from cytoplasm and regulates protein trafficking between cytosol nucleus. Maintaining integrity during interphase is considered crucial. However, Raab et al. Denais show that migrating immune cancer cells experience frequent transitory ruptures when they move through tight spaces (see Perspective by Burke). reseals rapidly interphase, assisted components of ESCRT III membrane-remodeling machinery. Science , this issue pp. 359 353 ; see also p. 295

Language: Английский

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The cGAS-cGAMP-STING Pathway of Cytosolic DNA Sensing and Signaling

Molecular Cell, Journal Year: 2014, Volume and Issue: 54(2), P. 289 - 296

Published: April 1, 2014

Language: Английский

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Aicardi–Goutières syndrome and the type I interferonopathies

Nature reviews. Immunology, Journal Year: 2015, Volume and Issue: 15(7), P. 429 - 440

Published: June 5, 2015

Language: Английский

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Immune Responses to Viral Gene Therapy Vectors

Molecular Therapy, Journal Year: 2020, Volume and Issue: 28(3), P. 709 - 722

Published: Jan. 10, 2020

Several viral vector-based gene therapy drugs have now received marketing approval. A much larger number of additional vectors are in various stages clinical trials for the treatment genetic and acquired diseases, with many more pre-clinical testing. Efficiency transfer ability to provide long-term make these vector systems very attractive. In fact, has been able treat or even cure diseases which there had no only suboptimal treatments. However, innate adaptive immune responses their transgene products constitute substantial hurdles development wider use patients. This review provides an overview type that documented animal models humans who one three widely tested systems, namely adenoviral, lentiviral, adeno-associated vectors. Particular emphasis is given mechanisms leading responses, efforts reduce immunogenicity, potential solutions problems. At same time, we point out gaps our knowledge should be filled problems need addressed going forward. Gene can a variety both inherited emerged as preferred platform delivery. Once genome replaced therapeutic cassette, stripping virus replicative pathogenic traits, such well suited vehicles. An ideal reliably efficiently carry deliver target cells direct expression. Viruses naturally satisfy criteria, except they prone host mammalian system evolved recognize infectious agents. Past ongoing utilized several different vectors, including adenovirus (Ad), (AAV), lentivirus (LV), murine γ-retrovirus, herpes simplex (HSV). Marketing approval granted two AAV-based therapies form congenital blindness (Luxturna) spinal muscular atrophy (Zolgensma), γ-retrovirus-based primary deficiency adenosine deaminase severe combined immunodeficiency (ADA-SCID) (Strimvelis), LV-based CD19-directed genetically modified chimeric antigen receptor (CAR)-T cell immunotherapies acute lymphoblastic leukemia non-Hodgkin lymphoma (Kymriah Yescarta), HSV-based oncolytic virotherapy melanoma (Imlygic).1High K.A. Roncarolo M.-G. therapy.N. Engl. J. Med. 2019; 381: 455-464Crossref PubMed Scopus (27) Google Scholar The suitability application depends on multiple factors, tissues, tropism, ex vivo versus transfer, packaging capacity, integration (and insertional mutagenesis), also propensity immunotoxicities. While LV correction (in particular hematopoietic stem [HSCs]), AAV due its favorable safety profile compared other transduce availability large capsids tropism. Although derived from viruses takes advantage refined evolutionary fitness human cells, advantages co-evolved equally sophisticated aimed at protecting tissues by eliminating foreign invaders perceived dangerous. To system, certain components indistinguishable parent (such nucleic acids carried protein coat). Such therefore subject similar wild-type viruses. Innate receptors, pattern recognition receptors (PRRs), detect recognizing conserved molecular motifs unique acid conformations trigger antiviral immunity (Figure 1). virally capsid envelope proteins become 2). Furthermore, trasn product constitutes neo-antigen may similarly targeted humoral cellular Immune-mediated rejection represents most significant therapy. comprehensive understanding processes underlying deleterious directed against critical developing modalities mitigate immune-mediated rejection. body research interrogated mechanisms, reviewed herein. We will focus studied systems: Ad, AAV, 2; Table 1).Figure 2Examples Molecular Structures Antigens Viral Vectors Are Recognized Immune Sensors Targeted Antigen-Specific Adaptive (B T Cell) ResponsesShow full caption(A) Adenoviral (B) (C) Lentiviral Abbreviations follows: dsDNA, double-stranded DNA; TLR, Toll-like receptor; cGAS, cyclic guanosine monophosphate-AMP synthase; IFN, interferon; APC, antigen-presenting cell; CTL, cytotoxic lymphocyte; dsRNA, RNA; MDA5, differentiation-associated 5; pDC, plasmacytoid dendritic ssRNA, single-stranded RNA.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Overview Their ResponsesViral VectorAdAAVLVVirion genomecapsid; 36-kb dsDNA genomecapsid, ≤5-kb ssDNA (or ∼2.5-kb scDNA genome)enveloped containing ∼10-kb ssRNA genomeInnate immunitypotent response, activation vascular endothelial platelets, inflammatory cytokine production, macrophage deathcomparatively weak transient response; TLR9 signaling promotes CD8+ responses; complement immunotoxicities seen some patients receiving high-dose systemic transferstrong IFN-α/β response limits transduction drives responsesImmunity populationpre-existing serotypespre-existing varies between serotypes geographic locationlow pre-existing immunityIn cellsefficientinefficientefficientUse vaccine carriervaccine cancer applicationslimitedtargeting developmentAdaptive vectorNAB formation; (except high-capacity vectors)NAB capsidNAB possibly proteinAdaptive productefficient inducer antibody formation possibleleast efficient Ad LV; risk highly variable depending design dose, route administration, factorsefficient B unless expression tightly controlled miRNA promoter professional APCs eliminateddsDNA, ssDNA, scDNA, self-complementary TLR9, 9; NAB, neutralizing antibody; miRNA, microRNA; cell. Open table new tab (A) RNA. comprised complex interwoven network types collaborate protect further infection mobilize cadre effectors tailored specifically eliminate invading pathogen. generally broken up into arms. occur early, not specific, do result immunological memory. conditioned environment created sensing, rely clonal expansion antigen-specific (effector) differentiation, generate share commonalities natural but distinctly non-replicative, delivered single high-titer bolus, introduced unnatural site. So, although canonical concepts applied, unwanted inherently aspects. Vector particles identical antigens exposed neutralized antibodies upon injection because immunity. Recognition structures (e.g., acids) sensors cause tissue infiltration production interferon (IFN)-α/β (type 1 hereafter abbreviated T1 IFN), thereby inducing state reducing transduction, signal responses. Activation of, subsequent presentation by, (DCs) step linking immunity, activation/differentiation cells. major histocompatibility (MHC) class I (MHC I)-restricted (cytotoxic lymphocytes [CTLs]) capable lysing infected MHC II II)-restricted CD4+ help optimal activation, formation. helper (Th) generation memory first investigated was early failures highlight how pivotal durability overall this intervention.2Crystal R.G. Adenovirus: effective delivery vector.Hum. Ther. 2014; 25: 3-11Crossref (99) Early enthusiasm largely based high efficiency capacity. robust met resulted immunotoxicity, resulting death patient. Because effectively activate shifted toward carriers contain ∼36-kb DNA packaged capsid. Various genes removed render replication defective. It possible remove coding sequences produce "gutted" "helper-dependent" adenoviral Some AdHu5 (with particularly tropism hepatocytes), while infecting described. Upon remains episomal. spectrum pathways tools study Hepatic achieved intravenous vector. within minutes hours, blood pressure changes, thrombocytopenia, inflammation, fever.3Seiler M.P. Cerullo V. Lee B. dependent mediated liver therapy: challenges prospects.Curr. 2007; 7: 297-305Crossref (57) Dysregulation coagulation spread organs lead DIC (disseminated intravascular coagulation). results release ultra-large-molecular-weight multimers von Willebrand factor (vWF), platelet adhesion. platelets induce exposure adhesion molecule P-selectin platelet-leukocyte aggregates, ultimately causing thrombocytopenia thus bleeding.4Othman M. Labelle A. Mazzetti I. Elbatarny H.S. Lillicrap D. Adenovirus-induced thrombocytopenia: role mediating accelerated clearance.Blood. 109: 2832-2839Crossref (88) Important interactions occurring after involve hepatic Kupffer hepatocytes, splenic macrophages (MFs) DCs.5Atasheva S. Yao Shayakhmetov D.M. adenovirus: lessons mice.FEBS Lett. 593: 3461-3483Crossref (1) blood-borne, hexon component binds X (FX), shown colleagues.6Atasheva Adenovirus sensing system.Curr. Opin. Virol. 2016; 21: 109-113Crossref (12) Scholar,7Doronin K. Flatt J.W. Di Paolo N.C. Khare R. Kalyuzhniy O. Acchione Sumida J.P. Ohto U. Shimizu T. Akashi-Takamura et al.Coagulation activates species C adenovirus.Science. 2012; 338: 795-798Crossref decorated FX (TLR)4 surface MFs nuclear κB (NF-κB)-dependent interleukin (IL)-1β, attracting polymorphonuclear leukocytes marginal zone spleen. These reflecting co-evolution defend pathogens, contribute rapid clearance vessel, molecules survey circulation critically influence Besides binding γ-carboxyglutamic (GLA) domains, bind C3 immunoglobulin (Ig)M antibodies, instance neutrophil activation.8Tam J.C.H. Bidgood S.R. McEwan W.A. James L.C. Intracellular autonomous immunity.Science. 345: 1256070Crossref (65) Scholar, 9Parker A.L. Waddington S.N. Nicol C.G. Buckley S.M. Denby L. Kemball-Cook G. Ni Lieber McVey J.H. al.Multiple vitamin K-dependent zymogens promote adenovirus-mediated hepatocytes.Blood. 2006; 108: 2554-2561Crossref (210) 10Shayakhmetov Gaggar Li Z.-Y. factors hepatotoxicity.J. 2005; 79: 7478-7491Crossref (313) 11Allen R.J. Byrnes A.P. Interaction complement, factors.FEBS 3449-3460Crossref 12Cotter M.J. Zaiss A.K. Muruve D.A. Neutrophils interact via Fc 1.J. 14622-14631Crossref (48) Antibody-virus complexes chemokine through intracellular TRIM21.13McEwan Tam Watkinson R.E. Mallery D.L. antibody-bound pathogens stimulate TRIM21.Nat. Immunol. 2013; 14: 327-336Crossref (174) 14Fletcher A.J. Coordinated neutralization cytosolic TRIM21.J. 90: 4856-4859Crossref 15Khare Hillestad M.L. Xu Z. Barry M.A. Circulating modulators pharmacology.J. 87: 3678-3686Crossref (34) 16Bottermann Foss van Tienen L.M. Vaysburd Cruickshank O'Connell Clark Mayes Higginson Hirst J.C. al.TRIM21 mediates inhibition adenovirus-based vaccination.Proc. Natl. Acad. Sci. USA. 2018; 115: 10440-10445Crossref (9) Interestingly, appears compete shielding it subsequently promoting TLR4 spleen.17Xu Qiu Q. Tian Smith J.S. Conenello G.M. Morita Coagulation shields 5 attack complement.Nat. 19: 452-457Crossref (94) shed effect requires extensive studies.18Houri N. Huang K.-C. Nalbantoglu coxsackievirus (CAR) undergoes ectodomain shedding regulated intramembrane proteolysis (RIP).PLoS ONE. 8: e73296Crossref (10) Scholar,19Wang H. Ducournau C. Saydaminova Richter Yumul Ho Carter Zubieta Fender P. desmoglein 2 triggered adenoviruses Ad3, Ad14, Ad14P1.J. 2015; 89: 10841-10859Crossref (15) inflammation site doses death. Much learned studies macrophages. typically fiber knob capsid, RGD loops penton secondary integrins. For example, collagenous structure (MARCO) subset trap Ad.20Di Baldwin L.K. Irons E.E. Papayannopoulou Tomlinson IL-1α cooperate triggering local neutrophilic virus-containing cells.PLoS Pathog. 10: e1004035Crossref (28) Binding integrin β3 IL-1α, turn causes IL-1 receptor, chemokines, recruitment order kill macrophages.21Di Miao E.A. Iwakura Y. Murali-Krishna Aderem Flavell R.A. Virus plasma membrane triggers interleukin-1α-mediated proinflammatory vivo.Immunity. 2009; 31: 110-121Abstract Full Text PDF (0) Resident (Kupffer cells) undergo necrotic mechanism fully understood IFN regulatory 3 (IRF3).22Manickan E. Eggerman T.L. Lozier J.N. Muller Rapid vectors.Mol. 13: 108-117Abstract (102) NALP3 inflammasome, process (independent likely representing sensing), IL-1β expression, leads death.23Muruve Pétrilli White L.R. S.A. Ross P.J. Parks Tschopp inflammasome recognizes microbial response.Nature. 2008; 452: 103-107Crossref (664) Cytosolic synthase (cGAS; see "Immune Responses Vectors" below detail pathway) silencing transfer.24Suzuki Bertin T.K. Rogers G.L. Cela Zolotukhin Palmer D.J. Ng Herzog R.W. Differential interferon-dependent helper-dependent vs. vivo.Mol. 796-805Abstract (30) Scholar,25Anghelina Lam Falck-Pedersen Diminished cGAS/STING-deficient mice minimally impacts immunity.J. 5915-5927Crossref (21) Nonetheless, sensed endosomal resulting, IL-6 during DCs (pDCs). Roles TLRs demonstrated. Finally, increase decrease immunity.26Wang Wen Cao X. Nuclear hnRNPA2B1 initiates amplifies viruses.Science. 365: eaav0758Crossref (13) Scholar,27Avgousti D.C. Herrmann Kulej Pancholi N.J. Sekulic Petrescu Molden R.C. Blumenthal Paris Reyes E.D. al.A core nucleosomes sequester danger signals.Nature. 535: 173-177Crossref Pre-existing Ad-derived led alternative serotype chimpanzee Ads.28Ertl H.C. carriers.Curr. 1-8Crossref (19) As expected elicit (NAB) prevent re-administration. Moreover, conventional pDCs vivo. considered contributor products.29Jooss Yang Fisher K.J. Wilson J.M. Transduction directs muscle fibers.J. 1998; 72: 4212-4223Crossref Scholar,30Yang Su Role destructive vector-transduced mouse lungs.J. 1996; 70: 7209-7212Crossref potent facilitated induction Th1 immunity.31Fields P.A. Kowalczyk D.W. Arruda V.R. Armstrong McCleland Hagstrom Pasi Ertl High subsets secreted IX.Mol. 2000; 1: 225-235Abstract Elimination all tissue-specific promoters (APCs) strategies employed Blockage co-stimulatory required successful studies.32Yang CD40 ligand-dependent activation: requirement B7-CD28 CD40.Science. 273: 1862-1864Crossref Scholar,33Yang Grewal I.S. Schilz Transient subversion ligand function diminishes lung tissues.J. 6370-6377Crossref substantially complicates translation approaches, disease abandoned. small non-enveloped parvovirus about kb non-pathogenic sequences, when viruses, V genomes persist mostly episomal form. features profile, still following doses.34Penaud-Budloo François Clément Ayuso Pharmacology recombinant production.Mol. Methods Clin. Dev. 166-180Abstract (18) Scholar,35Colella Ronzitti Mingozzi F. Emerging issues AAV-mediated therapy.Mol. 2017; 87-104Abstract (120) being types, CNS, liver, skeletal cardiac muscle, eye, lung. addition US Food Drug Administration (FDA)-approved Leber's amaurosis (LCA) (SMA), reached phase III liver-directed hemophilia B.1High Scholar,36Butterfield J.S.S. Hege K.M. Kaczmarek revolution hemophilia.Mol. (Published online November 13, 2019)https://doi.org/10.1016/j.ymthe.2019.11.006Abstract Initial ocular limited using subretinal injection. Likely privilege administration eye could later followed contralateral second repeat possible.37Bennett Ashtari Wellman Marshall Cyckowski L.L. Chung McCague Pierce Chen Bennicelli J.L. al.AAV2 readministration adults blindness.Sci. Transl. 4: 120ra15Crossref (259) Scholar,38Weed Ammar Zhou Wei Serrano L.W. Sun Maguire A.M. Bennett Aleman T.S. Safety same-eye sequential AAV2-hRPE65v2 non-human primates.Mol. 15: 133-148Abstract Other routes associated NABs re-administration develop childhood.35Colella Seroprevalence geographically, serotypes, cross-reactivity. highest prevalences AAV2, AAVs present population, diverse AAV5 lowest prevalences. Overall, seroprevalences appear vary 5%

Language: Английский

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Intracellular sensing of viral genomes and viral evasion

Experimental & Molecular Medicine, Journal Year: 2019, Volume and Issue: 51(12), P. 1 - 13

Published: Dec. 1, 2019

Abstract During viral infection, virus-derived cytosolic nucleic acids are recognized by host intracellular specific sensors. The efficacy of this recognition system is crucial for triggering innate defenses, which then stimulate more adaptive immune responses against the virus. Recent studies show that signal transduction pathways activated sensing proteins positively or negatively regulated many modulators to maintain homeostasis. However, viruses have evolved several strategies counteract/evade reactions. These systems involve interact with sensor and prevent them from detecting genome initiating signaling. In review, we discuss key regulators based on experimental evidence.

Language: Английский

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Discriminating self from non-self in nucleic acid sensing

Nature reviews. Immunology, Journal Year: 2016, Volume and Issue: 16(9), P. 566 - 580

Published: July 25, 2016

Language: Английский

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