Nucleic Acid Sensors as Therapeutic Targets for Human Disease
2020; Cell Press; Volume: 53; Issue: 1 Linguagem: Inglês
10.1016/j.immuni.2020.04.004
ISSN1097-4180
AutoresSarah M. McWhirter, Caroline A. Jefferies,
Tópico(s)Immune Response and Inflammation
ResumoInnate immune sensors that detect nucleic acids are attractive targets for therapeutic intervention because of their diverse roles in many disease processes. In detecting RNA and DNA from either self or non-self, nucleic acid sensors mediate the pathogenesis of many autoimmune and inflammatory conditions. Despite promising pre-clinical data and investigational use in the clinic, relatively few drugs targeting nucleic acid sensors are approved for therapeutic use. Nevertheless, there is growing appreciation for the untapped potential of nucleic acid sensors as therapeutic targets, driven by the need for better therapies for cancer, infectious diseases, and autoimmune disorders. This review highlights the diverse mechanisms by which nucleic acid sensors are activated and exert their biological effects in the context of various disease settings. We discuss current therapeutic strategies utilizing agonists and antagonists targeting nucleic acid sensors to treat infectious disease, cancer, and autoimmune and inflammatory disorders. Innate immune sensors that detect nucleic acids are attractive targets for therapeutic intervention because of their diverse roles in many disease processes. In detecting RNA and DNA from either self or non-self, nucleic acid sensors mediate the pathogenesis of many autoimmune and inflammatory conditions. Despite promising pre-clinical data and investigational use in the clinic, relatively few drugs targeting nucleic acid sensors are approved for therapeutic use. Nevertheless, there is growing appreciation for the untapped potential of nucleic acid sensors as therapeutic targets, driven by the need for better therapies for cancer, infectious diseases, and autoimmune disorders. This review highlights the diverse mechanisms by which nucleic acid sensors are activated and exert their biological effects in the context of various disease settings. We discuss current therapeutic strategies utilizing agonists and antagonists targeting nucleic acid sensors to treat infectious disease, cancer, and autoimmune and inflammatory disorders. Pattern recognition receptors (PRRs) comprise a diverse set of proteins that detect pathogen-associated molecules (“patterns”) to trigger innate and adaptive immune defense (Janeway, 1989Janeway C.A.J. Approaching the asymptote? Evolution and revolution in immunology.Cold Spring Harbor Symp. Quant. Biol. 1989; 54: 1-13Crossref PubMed Google Scholar). PRRs include nucleic acid sensors that evolved to initiate host defense in response to exogenous nucleic acids from microbial RNA and DNA. Dysregulation of innate responses to nucleic acids is a feature of both cancer and autoimmune disease. Released nucleic acids stimulate immunosurveillance of stressed, dying, damaged, or transformed cells and are important for shaping the innate and adaptive immune responses through type I interferon (IFN) induction. However, inappropriate pathway activation, or a breakdown in systems designed to limit endogenous nucleic acid exposure (e.g., RNases and DNases), is also a hallmark of a numerous autoimmune conditions. Extensive literature exists that links RNA- and DNA-sensing pathways with elevated type I IFNs (IFN-α and IFN-β) and autoimmune disease and inflammatory conditions, including cardiovascular and Alzheimer’s disease. Thus nucleic acid sensors are compelling targets for agonist or antagonist development for the treatment of infection, cancer, and autoimmunity. This review describes insights and emerging principles that link nucleic acid-sensing pathways to various diseases states and the novel drugs and therapeutic strategies based on these pathways under investigation. Sensors that evolved to detect foreign nucleic acids also detect endogenous nucleic acids to respond to cellular damage, stress, and disruption of homeostasis and are grouped into two major classes on the basis of cellular location. Endosomal sensors of the Toll-like receptor (TLR) family respond to RNA or DNA internalized by receptor-mediated endocytosis. Sensors that detect cytosolic RNA or DNA include the RNA-sensing RIG-I-like receptors (RLRs) and the principal DNA sensor cGAS (cyclic GMP-AMP synthase) that generates the second messenger 2′-3′-cyclic GMP-AMP (cGAMP) that signals through STING. Several additional nucleic acid sensors are being investigated, including cytosolic DNA sensors such as AIM2 and DNA-PK (Lugrin and Martinon, 2018Lugrin J. Martinon F. The AIM2 inflammasome: sensor of pathogens and cellular perturbations.Immunol. Rev. 2018; 281: 99-114Crossref PubMed Scopus (71) Google Scholar, Burleigh et al., 2020Burleigh K. Maltbaek J.H. Cambier S. Green R. Gale Jr., M. James R.C. Stetson D.B. Human DNA-PK activates a STING-independent DNA sensing pathway.Sci. Immunol. 2020; 5: eaba4219Crossref PubMed Scopus (4) Google Scholar), as well as receptors reported to localize to the nucleus, such as IFI16 and IFIX (Diner et al., 2015Diner B.A. Lum K.K. Cristea I.M. The emerging role of nuclear viral DNA sensors.J. Biol. Chem. 2015; 290: 26412-26421Crossref PubMed Scopus (40) Google Scholar), including cGAS itself (Gentili et al., 2019Gentili M. Lahaye X. Nadalin F. Nader G.P.F. Puig Lombardi E. Herve S. De Silva N.S. Rookhuizen D.C. Zueva E. Goudot C. et al.The N-terminal domain of cGAS determines preferential association with centromeric DNA and innate immune activation in the nucleus.Cell Rep. 2019; 26: 2377-2393.e13Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, Volkman et al., 2019Volkman H.E. Cambier S. Gray E.E. Stetson D.B. Tight nuclear tethering of cGAS is essential for preventing autoreactivity.eLife. 2019; 8: e47491Crossref PubMed Scopus (5) Google Scholar). No nucleic acid sensors have been detected within the mitochondria. This review focuses on endosomal TLR3, TLR7, TLR8, and TLR9, as well as cytosolic sensors RIG-I, MDA5, and cGAS-STING, currently being targeted by therapeutics (Figure 1). Natural ligands for most nucleic acid sensors are derived from motifs preferentially found in pathogen-associated nucleic acids. For example, TLR3 recognizes double-stranded RNA (dsRNA), a molecular signature of many viruses by virtue of their genome or replication intermediates (Alexopoulou et al., 2001Alexopoulou L. Holt A.C. Medzhitov R. Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.Nature. 2001; 413: 732-738Crossref PubMed Scopus (4318) Google Scholar). 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Immune complexes bound to mitochondrial DNA, endogenous retroviral elements, genomic DNA, oxidized DNA damage products, or RNA transcripts have been proposed to trigger autoimmune diseases. These nucleic acids may arise from defective DNA repair, enhanced NETosis (extracellular extrusion of DNA and histones from the nucleus of neutrophils), defective RNA or DNA clearance, or enhanced stress driving reactive oxygen species (ROS)-dependent oxidation and release of mitochondrial DNA (Figure 1). Immunoreactive RNA and DNA are internalized via anti-RNA or anti-dsDNA autoantibodies or by binding to LL-37 or via the HMGB1-RAGE pathway (Mustelin et al., 2019Mustelin T. Lood C. Giltiay N.V. Sources of pathogenic nucleic acids in systemic lupus erythematosus.Front. Immunol. 2019; 10: 1028Crossref PubMed Scopus (6) Google Scholar). Regardless of route, engulfed RNA and DNA localizes to endosomes, facilitating TLR activation. 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Cell. 2019; 75: 372-381.e5Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). SLC19A1 is highly expressed on myeloid cells, possibly explaining the ability of these cells to respond to exogenous cGAMP in the absence of transfection. The role of endosomal TLRs, RLRs, and cGAS-STING in mediating antiviral immunity is well established (Barrat et al., 2016Barrat F.J. Elkon K.B. Fitzgerald K.A. Importance of nucleic acid recognition in inflammation and autoimmunity.Annu. Rev. Med. 2016; 67: 323-336Crossref PubMed Google Scholar) with multiple nucleic acid-sensing pathways responding to a viral infection. For instance, both TLR9 and cGAS-STING pathways mediated resistance to ectromelia virus infection but were required in different cells types (Xu et al., 2015Xu R.H. Wong E.B. Rubio D. Roscoe F. Ma X. Nair S. Remakus S. Schwendener R. John S. Shlomchik M. Sigal L.J. 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More recently, therapies for chronic hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are being developed using nucleic acid sensor agonists in combination with approved antivirals (Table 1). For example, orally administered TLR7 (RO7020531 and TQ-A334) and TLR8 (GS-9688, selgantolimod) agonists are being tested as HBV therapies both alone and in combination with approved antiviral therapies (Table 1). The TLR agonist AIC649, a Parapoxvirus ovis particle preparation reported to activate pDCs through TLR9, has also been in clinical development (Paulsen et al., 2015Paulsen D. Weber O. Ruebsamen-Schaeff H. Tennant B.C. Menne S. AIC649 induces a Bi-phasic treatment response in the woodchuck model of chronic hepatitis B.PLoS ONE. 2015; 10 (e0144383)Crossref Scopus (8) Google Scholar). The dinucleotide SB-9200 (inarigivir soproxil), an orally administered RIG-I and NOD2 agonist, had been in phase II trials (Korolowicz et al., 2016Korolowicz K.E. Iyer R.P. Czerwinski S. 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For example, the TLR7 agonist GS-9620 (vesatolimod) was shown to reduce viral reservoir in simian immunodeficiency virus (SIV)-infected monkeys (Lim et al., 2018Lim S.Y. Osuna C.E. Hraber P.T. Hesselgesser J. Gerold J.M. Barnes T.L. Sanisetty S. Seaman M.S. Lewis M.G. Geleziunas R. et al.TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy.Sci. Transl. Med. 2018; 10: eaao4521Crossref PubMed Scopus (40) Google Scholar) and is being investigated clinically together with antiretroviral therapy. MGN1703 (lefitolimod), a nuclease-resistant TLR9 agonist, induces HIV-specific immune responses and reverses latency in HIV patients (Vibholm et al., 2019Vibholm L.K. Konrad C.V. Schleimann M.H. Frattari G. Winckelmann A. Klastrup V. Jensen N.M. Jensen S.S. Schmidt M. Wittig B. et al.Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals.AIDS. 2019; 33: 1315-1325Crossref PubMed Scopus (5) Google Scholar), providing a rationale for combination with virus-neutralizing antibodies (Table 1).Table 1Ongoing Clinical Trials Targeting Nucleic Sensor Agonists for Infectious DiseaseTargetDrug NameDeveloperDiseasePhaseCombination AgentTrial IDTLR7imiquimod (Aldara)3M PharmaceuticalsHBVII/IIIHBV vaccineNCT04083157influenzaIIIinfluenza vaccineNCT04143451TLR7RO7020531 (RG7854)Hoffmann-La RocheHBVInoneNCT02956850TLR7TQ-A3334 (AL-034)JanssenHBVIIRT inhibitorNCT04180150TLR7GS-9620 (vesatolimod)GileadHIVIARTNCT03060447TLR7/83M-052-AF3M, IDRIHIVIHIV-1 vaccineNCT04177355TLR8GS-9688 (selgantolimod)GileadHBVIIoral antiviral agentsNCT03491553HBVIIRT inhibitorNCT03615066TLR9MGN1703 (lefitolimod)Mologen AGHIVIIbNabNCT03837756TLR9CpG 1018Dynavax TechnologiesHIVIHIV-1 vaccineNCT04177355RIG-ISB-9200 (inarigivir soproxil)Spring Bank PharmaceuticalsHBVIIRT inhibitorNCT04023721HBVIInoneNCT03932513HBVIIRT inhibitorNCT04059198HBVIIRT inhibitorNCT03434353Source: ClinicalTrials.gov.ART, antiretroviral therapy; bNab, broadly neutralizing antibody; HBV, hepatitis B virus; HIV, human immunodeficiency virus; RT, reverse transcriptase. Open table in a new tab Source: ClinicalTrials.gov. ART, antiretroviral therapy; bNab, broadly neutralizing antibody; HBV, hepatitis B virus; HIV, human immunodeficiency virus; RT, reverse transcriptase. Nucleic acid sensors have long been recognized as potential targets for vaccine adjuvants on the basis of their ability to elicit humoral and cellular immunity (Coffman et al., 2010Coffman R.L. Sher A. Seder R.A. Vaccine adjuvants: putting innate immunity to work.Immunity. 2010; 33: 492-503Abstract Full Text Full Text PDF PubMed Scopus (896) Google Scholar). One of the few approved therapies targeting a nucleic acid sensor uses the TLR9 agonist CpG 1018 as a vaccine adjuvant in HEPLISAV-B, a preventive HBV vaccine. Other TLR agonists have also been extensively explored as vaccine adjuvants. Agonists of TLR3 and MDA5 have histories of clinical use and consist of synthetic dsRNA including poly-IC, the RNase-resistant derivative poly-ICLC (Hiltonol), and poly-IC12U (Ampligen), a TLR3-specific agonist (Martins et al., 2015Martins K.A.O. Bavari S. Salazar A.M. Vaccine adjuvant uses of poly-IC and derivatives.Expert Rev. Vaccines. 2015; 14: 447-459Crossref PubMed Scopus (63) Google Scholar). Poly-IC was shown to mediate robust adjuvant effects via induction of type I IFNs (Longhi et al., 2009Longhi M.P. Trumpfheller C. Idoyaga J. Caskey M. Matos I. Kluger C. Salazar A.M. Colonna M. Steinman R.M. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant.J. Exp. Med. 2009; 206: 1589-1602Crossref PubMed Scopus (395) Google Scholar). Poly-ICLC induced an innate immune response in HIV patients undergoing stan
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