Resistance to ectromelia virus infection requires cGAS in bone marrow-derived cells which can be bypassed with cGAMP therapy

Autoři: Eric B. Wong aff001;  Brian Montoya aff001;  Maria Ferez aff001;  Colby Stotesbury aff001;  Luis J. Sigal aff001
Působiště autorů: Thomas Jefferson University, Department of Microbiology and Immunology, Philadelphia, Pennsylvania, United States of America aff001
Vyšlo v časopise: Resistance to ectromelia virus infection requires cGAS in bone marrow-derived cells which can be bypassed with cGAMP therapy. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008239
Kategorie: Research Article


Cells sensing infection produce Type I interferons (IFN-I) to stimulate Interferon Stimulated Genes (ISGs) that confer resistance to viruses. During lympho-hematogenous spread of the mouse pathogen ectromelia virus (ECTV), the adaptor STING and the transcription factor IRF7 are required for IFN-I and ISG induction and resistance to ECTV. However, it is unknown which cells sense ECTV and which pathogen recognition receptor (PRR) upstream of STING is required for IFN-I and ISG induction. We found that cyclic-GMP-AMP (cGAMP) synthase (cGAS), a DNA-sensing PRR, is required in bone marrow-derived (BMD) but not in other cells for IFN-I and ISG induction and for resistance to lethal mousepox. Also, local administration of cGAMP, the product of cGAS that activates STING, rescues cGAS but not IRF7 or IFN-I receptor deficient mice from mousepox. Thus, sensing of infection by BMD cells via cGAS and IRF7 is critical for resistance to a lethal viral disease in a natural host.

Klíčová slova:

Cytokines – Chemokines – Interferons – NK cells – Skin infections – Spleen – Viral replication


1. Flint J, Racaniello VR, Rall GF, Skalka AM. Principles of Virology, Fourth Edition, Bundle. American Society of Microbiology; 2015. doi: 10.1128/9781555819521

2. Chapman JL, Nichols DK, Martinez MJ, Raymond JW. Animal models of orthopoxvirus infection. Vet Pathol. 4 ed. SAGE PublicationsSage CA: Los Angeles, CA; 2010;47: 852–870. doi: 10.1177/0300985810378649 20682806

3. Virgin HW. Immune regulation of viral infection and vice versa. Immunol Res. 2005;32: 293–315. doi: 10.1385/IR:32:1-3:293 16106080

4. Esteban DJ, Buller RML. Ectromelia virus: the causative agent of mousepox. Journal of General Virology. Microbiology Society; 2005;86: 2645–2659. doi: 10.1099/vir.0.81090-0

5. McNab F, Mayer-Barber K, Sher A, Wack A, O’Garra A. Type I interferons in infectious disease. Nature Reviews Immunology. Nature Publishing Group; 2015;15: 87–103. doi: 10.1038/nri3787 25614319

6. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annual Review of Immunology. Annual Reviews; 2014;32: 513–545. doi: 10.1146/annurev-immunol-032713-120231 24555472

7. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol. 2011;1: 519–525. doi: 10.1016/j.coviro.2011.10.008 22328912

8. Karupiah G, Fredrickson TN, Holmes KL, Khairallah LH, Buller RM. Importance of interferons in recovery from mousepox. Journal of Virology. American Society for Microbiology (ASM); 1993;67: 4214–4226.

9. Xu R-H, Cohen M, Tang Y, Lazear E, Whitbeck JC, Eisenberg RJ, et al. The orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination. The Journal of Experimental Medicine. Rockefeller University Press; 2008;205: 981–992. doi: 10.1084/jem.20071854 18391063

10. Rubio D, Xu R-H, Remakus S, Krouse TE, Truckenmiller ME, Thapa RJ, et al. Crosstalk between the Type 1 Interferon and Nuclear Factor Kappa B Pathways Confers Resistance to a Lethal Virus Infection. Cell Host & Microbe. 2013;13: 701–710. doi: 10.1016/j.chom.2013.04.015 23768494

11. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140: 805–820. doi: 10.1016/j.cell.2010.01.022 20303872

12. Wu J, Chen ZJ. Innate immune sensing and signaling of cytosolic nucleic acids. Annual Review of Immunology. 2014;32: 461–488. doi: 10.1146/annurev-immunol-032713-120156 24655297

13. Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annual Review of Immunology. Annual Reviews; 2015;33: 257–290. doi: 10.1146/annurev-immunol-032414-112240 25581309

14. Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nature Immunology. Nature Publishing Group; 2015;16: 343–353. doi: 10.1038/ni.3123 25789684

15. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. John Wiley & Sons, Ltd (10.1111); 2009;227: 75–86. doi: 10.1111/j.1600-065X.2008.00737.x 19120477

16. Xu R-H, Wong EB, Rubio D, Roscoe F, Ma X, Nair S, et al. Sequential Activation of Two Pathogen-Sensing Pathways Required for Type I Interferon Expression and Resistance to an Acute DNA Virus Infection. Immunity. 2015;43: 1148–1159. doi: 10.1016/j.immuni.2015.11.015 26682986

17. Wong E, Xu R-H, Rubio D, Lev A, Stotesbury C, Fang M, et al. Migratory Dendritic Cells, Group 1 Innate Lymphoid Cells, and Inflammatory Monocytes Collaborate to Recruit NK Cells to the Virus-Infected Lymph Node. Cell Rep. 2018;24: 142–154. doi: 10.1016/j.celrep.2018.06.004 29972776

18. Cheng W-Y, He X-B, Jia H-J, Chen G-H, Jin Q-W, Long Z-L, et al. The cGas-Sting Signaling Pathway Is Required for the Innate Immune Response Against Ectromelia Virus. Frontiers in Immunology. Frontiers; 2018;9: 1297. doi: 10.3389/fimmu.2018.01297 29963044

19. Fang M, Lanier LL, Sigal LJ. A Role for NKG2D in NK Cell–Mediated Resistance to Poxvirus Disease. PLoS Pathogens. Public Library of Science; 2008;4: e30. doi: 10.1371/journal.ppat.0040030 18266471

20. Roscoe F, Xu RH, Sigal LJ. Characterization of Ectromelia Virus Deficient in EVM036, the Homolog of Vaccinia virus F13L, and Its Application for Rapid Generation of Recombinant Viruses. Journal of Virology. American Society for Microbiology; 2012;86: 13501–13507. doi: 10.1128/JVI.01732-12 23035222

21. Xu R-H, Remakus S, Ma X, Roscoe F, Sigal LJ. Direct Presentation Is Sufficient for an Efficient Anti-Viral CD8+ T Cell Response. Früh K, editor. PLoS Pathogens. Public Library of Science; 2010;6: e1000768. doi: 10.1371/journal.ppat.1000768 20169189

22. Brownstein DG, Gras L. Chromosome mapping of Rmp-4, a gonad-dependent gene encoding host resistance to mousepox. Journal of Virology. American Society for Microbiology (ASM); 1995;69: 6958–6964.

23. Storek KM, Gertsvolf NA, Ohlson MB, Monack DM. cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection. J Immunol. American Association of Immunologists; 2015;194: 3236–3245. doi: 10.4049/jimmunol.1402764 25710914

24. Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host & Microbe. 2011;9: 363–375. doi: 10.1016/j.chom.2011.04.008 21575908

25. Almine JF, O’Hare CAJ, Dunphy G, Haga IR, Naik RJ, Atrih A, et al. IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes. Nat Commun. Nature Publishing Group; 2017;8: 14392. doi: 10.1038/ncomms14392 28194029

26. Jønsson KL, Laustsen A, Krapp C, Skipper KA, Thavachelvam K, Hotter D, et al. IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. Nat Commun. Nature Publishing Group; 2017;8: 14391. doi: 10.1038/ncomms14391 28186168

27. Marié I, Durbin JE, Levy DE. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J. 1998;17: 6660–6669. doi: 10.1093/emboj/17.22.6660 9822609

28. Li X-D, Wu J, Gao D, Wang H, Sun L, Chen ZJ. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. American Association for the Advancement of Science; 2013;341: 1390–1394. doi: 10.1126/science.1244040 23989956

29. Fang M, Orr MT, Spee P, Egebjerg T, Lanier LL, Sigal LJ. CD94 Is Essential for NK Cell-Mediated Resistance to a Lethal Viral Disease. Immunity. 2011;34: 579–589. doi: 10.1016/j.immuni.2011.02.015 21439856

30. Cai X, Chiu Y-H, Chen ZJ. The cGAS-cGAMP-STING Pathway of Cytosolic DNA Sensing and Signaling. Molecular Cell. 2014;54: 289–296. doi: 10.1016/j.molcel.2014.03.040 24766893

31. Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nature Immunology. Nature Publishing Group; 2016;17: 1142–1149. doi: 10.1038/ni.3558 27648547

32. Woo S-R, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MYK, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014;41: 830–842. doi: 10.1016/j.immuni.2014.10.017 25517615

33. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. Nature Publishing Group; 2008;455: 674–678. doi: 10.1038/nature07317 18724357

34. Barber GN. STING: infection, inflammation and cancer. Nature Reviews Immunology. Nature Publishing Group; 2015;15: 760–770. doi: 10.1038/nri3921 26603901

35. Lazear HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, et al. A Mouse Model of Zika Virus Pathogenesis. Cell Host & Microbe. 2016;19: 720–730. doi: 10.1016/j.chom.2016.03.010 27066744

36. Bourne N, Scholle F, Silva MC, Rossi SL, Dewsbury N, Judy B, et al. Early production of type I interferon during West Nile virus infection: role for lymphoid tissues in IRF3-independent interferon production. Journal of Virology. 2007;81: 9100–9108. doi: 10.1128/JVI.00316-07 17567689

37. Diamond MS. Evasion of innate and adaptive immunity by flaviviruses. Immunol Cell Biol. 2003;81: 196–206. doi: 10.1046/j.1440-1711.2003.01157.x 12752684

38. Teijaro JR. Type I interferons in viral control and immune regulation. Curr Opin Virol. 2016;16: 31–40. doi: 10.1016/j.coviro.2016.01.001 26812607

39. Paludan SR, Bowie AG. Immune Sensing of DNA. Immunity. 2013;38: 870–880. doi: 10.1016/j.immuni.2013.05.004 23706668

40. Hansen K, Prabakaran T, Laustsen A, Jørgensen SE, Rahbæk SH, Jensen SB, et al. Listeria monocytogenes induces IFNβ expression through an IFI16-, cGAS- and STING-dependent pathway. EMBO J. EMBO Press; 2014;33: 1654–1666. doi: 10.15252/embj.201488029 24970844

41. Chunfa L, Xin S, Qiang L, Sreevatsan S, Yang L, Zhao D, et al. The Central Role of IFI204 in IFN-β Release and Autophagy Activation during Mycobacterium bovis Infection. Front Cell Infect Microbiol. Frontiers; 2017;7: 169. doi: 10.3389/fcimb.2017.00169 28529930

42. Dai P, Wang W, Cao H, Avogadri F, Dai L, Drexler I, et al. Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. Barry M, editor. PLoS Pathogens. Public Library of Science; 2014;10: e1003989. doi: 10.1371/journal.ppat.1003989 24743339

43. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature. Nature Publishing Group; 2013;503: 530–534. doi: 10.1038/nature12640 24077100

44. Reinert LS, Lopušná K, Winther H, Sun C, Thomsen MK, Nandakumar R, et al. Sensing of HSV-1 by the cGAS-STING pathway in microglia orchestrates antiviral defence in the CNS. Nat Commun. Nature Publishing Group; 2016;7: 13348. doi: 10.1038/ncomms13348 27830700

45. Lam E, Stein S, Falck-Pedersen E. Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade. Journal of Virology. 2014;88: 974–981. doi: 10.1128/JVI.02702-13 24198409

46. Lio C-WJ, McDonald B, Takahashi M, Dhanwani R, Sharma N, Huang J, et al. cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection. Longnecker RM, editor. Journal of Virology. 2016;90: 7789–7797. doi: 10.1128/JVI.01040-16 27334590

47. Wu J-J, Li W, Shao Y, Avey D, Fu B, Gillen J, et al. Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein. Cell Host & Microbe. 2015;18: 333–344. doi: 10.1016/j.chom.2015.07.015 26320998

48. Gao D, Wu J, Wu Y-T, Du F, Aroh C, Yan N, et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science. American Association for the Advancement of Science; 2013;341: 903–906. doi: 10.1126/science.1240933 23929945

49. Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B, Eitson JL, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature. Nature Publishing Group; 2014;505: 691–695. doi: 10.1038/nature12862 24284630

50. Francica BJ, Ghasemzadeh A, Desbien AL, Theodros D, Sivick KE, Reiner GL, et al. TNFα and Radioresistant Stromal Cells Are Essential for Therapeutic Efficacy of Cyclic Dinucleotide STING Agonists in Nonimmunogenic Tumors. Cancer Immunol Res. 2018;6: 422–433. doi: 10.1158/2326-6066.CIR-17-0263 29472271

51. Doebel T, Voisin B, Nagao K. Langerhans Cells—The Macrophage in Dendritic Cell Clothing. Trends Immunol. 2017;38: 817–828. doi: 10.1016/ 28720426

52. Klein I, Cornejo JC, Polakos NK, John B, Wuensch SA, Topham DJ, et al. Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages. Blood. 2007;110: 4077–4085. doi: 10.1182/blood-2007-02-073841 17690256

53. Wang J, Li P, Wu MX. Natural STING Agonist as an “Ideal” Adjuvant for Cutaneous Vaccination. J Invest Dermatol. 2016;136: 2183–2191. doi: 10.1016/j.jid.2016.05.105 27287182

54. Škrnjug I, Guzmán CA, Rueckert C, Ruecker C. Cyclic GMP-AMP displays mucosal adjuvant activity in mice. Boyaka PN, editor. PLoS ONE. 2014;9: e110150. doi: 10.1371/journal.pone.0110150 25295996

55. Li T, Cheng H, Yuan H, Xu Q, Shu C, Zhang Y, et al. Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response. Sci Rep. Nature Publishing Group; 2016;6: 19049. doi: 10.1038/srep19049 26754564

56. Marcus A, Mao AJ, Lensink-Vasan M, Wang L, Vance RE, Raulet DH. Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response. Immunity. 2018;49: 754–763.e4. doi: 10.1016/j.immuni.2018.09.016 30332631

57. Alcamí A. Viral mimicry of cytokines, chemokines and their receptors. Nature Reviews Immunology. Nature Publishing Group; 2003;3: 36–50. doi: 10.1038/nri980 12511874

58. Georgana I, Sumner RP, Towers GJ, Maluquer de Motes C. Virulent Poxviruses Inhibit DNA Sensing by Preventing STING Activation. Jung JU, editor. Journal of Virology. 2018;92: 855. doi: 10.1128/JVI.02145-17 29491158

59. Ning S, Pagano JS, Barber GN. IRF7: activation, regulation, modification and function. Genes Immun. Nature Publishing Group; 2011;12: 399–414. doi: 10.1038/gene.2011.21 21490621

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 12
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se