AHR is a Zika virus host factor and a candidate target for antiviral therapy.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
31
10
2019
accepted:
03
06
2020
pubmed:
22
7
2020
medline:
6
11
2020
entrez:
22
7
2020
Statut:
ppublish
Résumé
Zika virus (ZIKV) is a flavivirus linked to multiple birth defects including microcephaly, known as congenital ZIKV syndrome. The identification of host factors involved in ZIKV replication may guide efficacious therapeutic interventions. In genome-wide transcriptional studies, we found that ZIKV infection triggers aryl hydrocarbon receptor (AHR) activation. Specifically, ZIKV infection induces kynurenine (Kyn) production, which activates AHR, limiting the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, ZIKV-triggered AHR activation suppresses intrinsic immunity driven by the promyelocytic leukemia (PML) protein, which limits ZIKV replication. AHR inhibition suppressed the replication of multiple ZIKV strains in vitro and also suppressed replication of the related flavivirus dengue. Finally, AHR inhibition with a nanoparticle-delivered AHR antagonist or an inhibitor developed for human use limited ZIKV replication and ameliorated newborn microcephaly in a murine model. In summary, we identified AHR as a host factor for ZIKV replication and PML protein as a driver of anti-ZIKV intrinsic immunity.
Identifiants
pubmed: 32690969
doi: 10.1038/s41593-020-0664-0
pii: 10.1038/s41593-020-0664-0
pmc: PMC7897397
mid: NIHMS1668695
doi:
Substances chimiques
Receptors, Aryl Hydrocarbon
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
939-951Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102807
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI126880
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI093903
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI131135
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS087867
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI093903
Pays : United States
Organisme : NIAID NIH HHS
ID : R33 AI100190
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI100190
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA207021
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Baud, D., Gubler, D. J., Schaub, B., Lanteri, M. C. & Musso, D. An update on Zika virus infection. Lancet 390, 2099–2109 (2017).
pubmed: 28647173
doi: 10.1016/S0140-6736(17)31450-2
Musso, D. & Gubler, D. J. Zika virus. Clin. Microbiol. Rev. 29, 487–524 (2016).
pubmed: 27029595
pmcid: 4861986
doi: 10.1128/CMR.00072-15
Faria, N. R. et al. Establishment and cryptic transmission of Zika virus in Brazil and the Americas. Nature 546, 406–410 (2017).
pubmed: 28538727
pmcid: 5722632
doi: 10.1038/nature22401
França, G. V. A. et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 388, 891–897 (2016).
pubmed: 27372398
doi: 10.1016/S0140-6736(16)30902-3
Cao-Lormeau, V. M. et al. Guillain–Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case–control study. Lancet 387, 1531–1539 (2016).
pubmed: 26948433
pmcid: 5444521
doi: 10.1016/S0140-6736(16)00562-6
Boldescu, V., Behnam, M. A. M., Vasilakis, N. & Klein, C. D. Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond. Nat. Rev. Drug Discov. 16, 565–586 (2017).
pubmed: 28473729
pmcid: 5925760
doi: 10.1038/nrd.2017.33
Yan, N. & Chen, Z. J. Intrinsic antiviral immunity. Nat. Immunol. 13, 214–222 (2012).
pubmed: 22344284
pmcid: 3549670
doi: 10.1038/ni.2229
Perelygin, A. A. et al. Positional cloning of the murine flavivirus resistance gene. Proc. Natl Acad. Sci. USA 99, 9322–9327 (2002).
pubmed: 12080145
pmcid: 123139
doi: 10.1073/pnas.142287799
Giovannoni, F. et al. Dengue non-structural protein 5 polymerase complexes with promyelocytic leukemia protein (PML) isoforms III and IV to disrupt PML-nuclear bodies in infected cells. Front. Cell. Infect. Microbiol. 9, 284 (2019).
Macnamara, F. N. Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria. Trans. R. Soc. Trop. Med. Hyg. 48, 139–145 (1954).
pubmed: 13157159
doi: 10.1016/0035-9203(54)90006-1
Liang, Q. et al. Zika virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy. Cell Stem Cell 19, 663–671 (2016).
pubmed: 27524440
pmcid: 5144538
doi: 10.1016/j.stem.2016.07.019
Tang, H. et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590 (2016).
pubmed: 26952870
pmcid: 5299540
doi: 10.1016/j.stem.2016.02.016
Liu, L. et al. Protection of ZIKV infection-induced neuropathy by abrogation of acute antiviral response in human neural progenitors. Cell Death Differ. 26, 2607–2621 (2019).
pubmed: 30952992
pmcid: 7224299
doi: 10.1038/s41418-019-0324-7
Lum, F. M. et al. Immunological observations and transcriptomic analysis of trimester-specific full-term placentas from three Zika virus-infected women. Clin. Transl. Immunol. 8, e01082 (2019).
doi: 10.1002/cti2.1082
Gutierrez-Vazquez, C. & Quintana, F. J. Regulation of the immune response by the aryl hydrocarbon receptor. Immunity 48, 19–33 (2018).
pubmed: 29343438
pmcid: 5777317
doi: 10.1016/j.immuni.2017.12.012
Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).
doi: 10.1038/nature10491
pubmed: 21976023
Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).
pubmed: 27279226
pmcid: 4902174
doi: 10.1038/nature18296
Rothhammer, V. & Quintana, F. J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 19, 184–197 (2019).
pubmed: 30718831
doi: 10.1038/s41577-019-0125-8
Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).
pubmed: 29769726
pmcid: 6422159
doi: 10.1038/s41586-018-0119-x
Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med 22, 586–597 (2016).
pubmed: 27158906
pmcid: 4899206
doi: 10.1038/nm.4106
Yamaguchi, M. & Hankinson, O. 2,3,7,8-Tetrachlorodibenzopdioxin suppresses the growth of human liver cancer HepG2 cells in vitro: involvement of cell signaling factors. Int J. Oncol. 53, 1657–1666 (2018).
pubmed: 30066859
pmcid: 6086623
Choi, E. Y., Lee, H., Dingle, R. W., Kim, K. B. & Swanson, H. I. Development of novel CH223191-based antagonists of the aryl hydrocarbon receptor. Mol. Pharm. 81, 3–11 (2012).
doi: 10.1124/mol.111.073643
Richardson, R. B. et al. A CRISPR screen identifies IFI6 as an ER-resident interferon effector that blocks flavivirus replication. Nat. Microbiol. 3, 1214–1223 (2018).
pubmed: 30224801
pmcid: 6202210
doi: 10.1038/s41564-018-0244-1
Elong Ngono, A. & Shresta, S. Immune response to dengue and zika. Annu. Rev. Immunol. 36, 279–308 (2018).
doi: 10.1146/annurev-immunol-042617-053142
Pfeffer, L. M. et al. Role of nuclear factor-κB in the antiviral action of interferon and interferon-regulated gene expression. J. Biol. Chem. 279, 31304–31311 (2004).
pubmed: 15131130
doi: 10.1074/jbc.M308975200
Luecke, S., Wincent, E., Backlund, M., Rannug, U. & Rannug, A. Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappaB. Chem. Biol. Interact. 184, 466–473 (2010).
pubmed: 20132803
doi: 10.1016/j.cbi.2010.01.038
Yamada, T. et al. Constitutive aryl hydrocarbon receptor signaling constrains type I interferon–mediated antiviral innate defense. Nat. Immunol. 17, 687–694 (2016).
pubmed: 27089381
doi: 10.1038/ni.3422
Dixit, E. et al. Peroxisomes are signaling platforms for antiviral innate immunity. Cell 141, 668–681 (2010).
pubmed: 20451243
pmcid: 3670185
doi: 10.1016/j.cell.2010.04.018
Franz, K. M., Neidermyer, W. J., Tan, Y.-J., Whelan, S. P. J. & Kagan, J. C. STING-dependent translation inhibition restricts RNA virus replication. Proc. Natl Acad. Sci. USA 115, E2058–E2067 (2018).
pubmed: 29440426
pmcid: 5834695
doi: 10.1073/pnas.1716937115
Hubackova, S., Krejcikova, K., Bartek, J. & Hodny, Z. Interleukin 6 signaling regulates promyelocytic leukemia protein gene expression in human normal and cancer cells. J. Biol. Chem. 287, 26702–26714 (2012).
pubmed: 22711534
pmcid: 3411009
doi: 10.1074/jbc.M111.316869
Stanford, E. A. et al. The role of the aryl hydrocarbon receptor in the development of cells with the molecular and functional characteristics of cancer stem-like cells. BMC Biol. 14, 20 (2016).
pubmed: 26984638
pmcid: 4794823
doi: 10.1186/s12915-016-0240-y
Taguwa, S. et al. Defining Hsp70 subnetworks in dengue virus replication reveals key vulnerability in flavivirus infection. Cell 163, 1108–1123 (2015).
pubmed: 26582131
pmcid: 4869517
doi: 10.1016/j.cell.2015.10.046
Brass, A. L. et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, west nile virus, and dengue virus. Cell 139, 1243–1254 (2009).
pubmed: 20064371
pmcid: 2824905
doi: 10.1016/j.cell.2009.12.017
Zhang, R. et al. A CRISPR screen defines a signal peptide processing pathway required by flaviviruses. Nature 535, 164–168 (2016).
pubmed: 27383988
pmcid: 4945490
doi: 10.1038/nature18625
Marceau, C. D. et al. Genetic dissection of Flaviviridae host factors through genome-scale CRISPR screens. Nature 535, 159–163 (2016).
pubmed: 27383987
pmcid: 4964798
doi: 10.1038/nature18631
Zhou, Q., Lavorgna, A., Bowman, M., Hiscott, J. & Harhaj, E. W. Aryl hydrocarbon receptor interacting protein targets IRF7 to suppress antiviral signaling and the induction of type I interferon. J. Biol. Chem. 290, 14729–14739 (2015).
pubmed: 25911105
pmcid: 4505538
doi: 10.1074/jbc.M114.633065
Nganou-Makamdop, K. et al. Type I IFN signaling blockade by a PASylated antagonist during chronic SIV infection suppresses specific inflammatory pathways but does not alter T cell activation or virus replication. PLoS Pathog. 14, e1007246 (2018).
pubmed: 30142226
pmcid: 6126880
doi: 10.1371/journal.ppat.1007246
Gagliani, N. et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).
pubmed: 25924064
pmcid: 4498984
doi: 10.1038/nature14452
Takenaka, M. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 22, 729–740 (2019).
pubmed: 30962630
pmcid: 8052632
doi: 10.1038/s41593-019-0370-y
Schiering, C. et al. Feedback control of AHR signalling regulates intestinal immunity. Nature 542, 242–245 (2017).
pubmed: 28146477
pmcid: 5302159
doi: 10.1038/nature21080
Yockey, L. J. et al. Type I interferons instigate fetal demise after Zika virus infection. Sci. Immunol. 3, eaao1680 (2018).
Hernandez-Ochoa, I., Karman, B. N. & Flaws, J. A. The role of the aryl hydrocarbon receptor in the female reproductive system. Biochem. Pharmacol. 77, 547–559 (2009).
pubmed: 18977336
doi: 10.1016/j.bcp.2008.09.037
Lawrence, B. P. & Vorderstrasse, B. A. New insights into the aryl hydrocarbon receptor as a modulator of host responses to infection. Semin. Immunopathol. 35, 615–626 (2013).
pubmed: 23963494
doi: 10.1007/s00281-013-0395-3
Wheeler, J. L. H., Martin, K. C. & Lawrence, B. P. Novel cellular targets of AHR underlie alterations in neutrophilic inflammation and inducible nitric oxide synthase expression during influenza virus infection. J. Immunol. 190, 659–668 (2012).
pubmed: 23233726
doi: 10.4049/jimmunol.1201341
Winans, B. et al. Linking the aryl hydrocarbon receptor with altered DNA methylation patterns and developmentally induced aberrant antiviral CD8
pubmed: 25810390
doi: 10.4049/jimmunol.1402044
Safe, S., Cheng, Y. & Jin, U. H. The aryl hydrocarbon receptor (AhR) as a drug target for cancer chemotherapy. Curr. Opin. Toxicol. 2, 24–29 (2017).
pubmed: 28459113
pmcid: 5407490
doi: 10.1016/j.cotox.2017.01.012
Geoffroy, M.-C. & Chelbi-Alix, M. K. Role of promyelocytic leukemia protein in host antiviral defense. J. Interferon Cytokine Res. 31, 145–158 (2011).
pubmed: 21198351
doi: 10.1089/jir.2010.0111
Franchini, A. M. & Lawrence, B. P. Environmental exposures are hidden modifiers of anti-viral immunity. Curr. Opin. Toxicol. 10, 54–59 (2018).
pubmed: 30035244
pmcid: 6051538
doi: 10.1016/j.cotox.2018.01.004
Thackray, L. B. et al. Oral antibiotic treatment of mice exacerbates the disease severity of multiple flavivirus infections. Cell Rep. 22, 3440–3453.e3446 (2018).
pubmed: 29590614
pmcid: 5908250
doi: 10.1016/j.celrep.2018.03.001
Manfredo Vieira, S. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 359, 1156–1161 (2018).
pubmed: 29590047
doi: 10.1126/science.aar7201
Judd, N. P. et al. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness. Cancer Res. 72, 365–374 (2012).
pubmed: 22086849
doi: 10.1158/0008-5472.CAN-11-1831
Bosch, I. et al. Rapid antigen tests for dengue virus serotypes and Zika virus in patient serum. Sci. Transl. Med. 9, ii: eaan1589 (2017).
Chan, J. F. et al. Improved detection of Zika virus RNA in human and animal specimens by a novel, highly sensitive and specific real-time RT-PCR assay targeting the 5′-untranslated region of Zika virus. Trop. Med. Int. Health 22, 594–603 (2017).
pubmed: 28214373
doi: 10.1111/tmi.12857
Lanciotti, R. S. et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg. Infect. Dis. 14, 1232–1239 (2008).
pubmed: 18680646
pmcid: 2600394
doi: 10.3201/eid1408.080287
Soumillon, M., Cacchiarelli, D., Semrau, S., van Oudenaarden, A. & Mikkelsen, T. S. Characterization of Directed Differentiation by High-throughput Single-cell RNA-Seq (Cold Spring Harbor Laboratory, 2014).