Innate immunity in coronavirus infection

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Coronaviruses (CoVs) comprise a polymorphic group of respiratory viruses causing acute inflammatory diseases in domestic and agricultural animals (chicken, pig, buffalo, cat, dog). Until recently, this infection in humans was mainly observed during the autumn-winter period and characterized by a mild, often asymptomatic, course. The situation changed dramatically in 2003, when SARS outbreak caused by pathogenic CoV (SARS-CoV) was recorded in China. A decade later, a new CoV outbreak occurred in the form of the Middle East respiratory syndrome (MERS-CoV), whereas in December 2019, SARS-CoV-2 (COVID-19) cases were recorded, which transformed within the first months of 2020 into the pandemic. In all three cases, CoV disease led to severe bronchopulmonary lesions, varying from dry, debilitating cough to acute respiratory distress syndrome (ARDS). At the same time, multiple changes in innate immunity were noted most often manifested as a pronounced inflammatory reaction in the lower respiratory tract, featured by damaged type II pneumocytes, apoptosis, hyalinization of alveolar membranes, focal or generalized pulmonary edema. Destructive processes in the respiratory tract were accompanied by migration of monocytes/macrophages and granulocyte neutrophils to the inflammatory focus. Such events were accompanied by production of pro-inflammatory cytokines, which magnitude could ascend up to a cytokine storm. SARS-CoV is characterized by symptoms of secondary immunosuppression, manifested by the late onset of interferon production and activation of NLRP3 inflammasomes – the key inflammatory factor. The reason for such reaction may be accounted for by CoV arsenal containing extensive set of structural and non-structural proteins exerting pro-inflammatory and immunosuppressive properties. Delayed IFN production allowed CoV to replicate actively and freely, and when type I IFN synthesis was eventually triggered, its activity was detrimental and accompanied by an aggravated infection course. Thus, SARS can surely be referred to immune-dependent infections with a marked immunopathological component. The purpose of this review was to describe some mechanisms underlying formation of innate immune response to infection caused by pathogenic coronaviruses SARS-CoV, MERS-CoV and SARS-CoV-2 (COVID-19).

About the authors

V. S. Smirnov

St. Petersburg Pasteur Institute; JSC MBNPK “Cytomed”

Author for correspondence.
ORCID iD: 0000-0002-2723-1496

Vyacheslav S. Smirnov – PhD, MD (Medicine), Professor, Leading Researcher, Laboratory Molecular Immunology, St. Petersburg Pasteur Institute; Head Researcher, JSC MВSPC “Cytomed”

197101, St. Petersburg, Mira str., 14
Phone: +7 911 948-59-22 (mobile) 

Russian Federation

Areg A. Totolyan

St. Petersburg Pasteur Institute

ORCID iD: 0000-0003-4571-8799

RAS Full Member, PhD, MD (Medicine), Professor, Head of the Department of Immunology, Pavlov First St. Petersburg State Medical University; Director, St. Petersburg Pasteur Institute

St. Petersburg

Russian Federation


  1. Никифоров В.В., Суранова Т.Г., Миронов А.Ю., Забозлаев Ф.Г. Новая коронавирусная инфекция (COVID-19): этиология, эпидемиология, клиника, диагностика, лечение и профилактика. Москва, 2020. 48 с.
  2. Смирнов В.С., Зарубаев В.В., Петленко С.В. Биология возбудителей и контроль гриппа и ОРВИ. СПб.: Гиппократ, 2020. 336 c.
  3. Amer H.M. Bovine-like Coronaviruses in domestic and wild ruminants Anim. Health Res. Rev., 2018, vol. 19, no. 2, pp. 113–124. doi: 10.1017/S1466252318000117
  4. Ang A., Pullar J.M., Currie M.J., Vissers M.C.M. Vitamin C and immune cell function in inflammation and cancer. Biochem. Soc. Trans., 2018, vol. 46, no. 5, pp. 1147–1159. doi: 10.1042/BST20180169
  5. Bowie A.G., O’Neill L.A.J. Vitamin C inhibits NF-κB activation by TNF via the activation of p38 mitogen-activated protein kinase. J. Immunol., 2000, vol. 165, pp. 7180–7188. doi: 10.4049/jimmunol.165.12.7180
  6. Broz P., Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signal-ling. Nat. Rev. Immunol., 2016, vol. 16, pp. 407–420. doi: 10.1038/nri.2016.58
  7. Cameron M.J., Bermejo-Martin J.F., Danesh A., Muller M.P., Kelvin D.J. Human Immunopatho-genesis of Severe Acute Respiratory Syndrome (SARS). Virus Res., 2008, vol. 133, no. 1, pp. 13–19. doi: 10.1016/j.virusres.2007.02.014
  8. Carr A.C., Maggini S. Vitamin C and immune function. Nutrients, 2017, vol. 9, no. 11, p. 1211. doi: 10.3390/nu9111211
  9. Channappanavar R., Fehr A.R., Vijay R., Mack M., Zhao J., Meyerholz D.K., S. Perlman. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell. Host. Microbe, 2016, vol. 19, no. 2, pp. 181–193. doi: 10.1016/j.chom.2016.01.007
  10. Channappanavar R., Fehr A. R., Zheng J., Wohlford-Lenane C., Abrahante J.E., Mack M., Sompallae R., McCray P.B. Jr, Meyerholz D.K., Perlman S. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J. Clin. Invest., 2019, vol. 129, no. 9, pp. 625–3639. doi: 10.1172/JCI126363
  11. Channappanavar R. Perlman S. Pathogenic human coronavirus infections: causes and con-sequences of cytokine storm and immunopathology. Semin. Immunopathol., 2017, vol. 39, pp. 529–539. doi: 10.1007/s00281-017-0629
  12. Chen I-Y., Moriyama M., Chang M.-F., Ichinohe T. Severe acute respiratory syndrome coronavirus viroporin 3a activates the NLRP3 inflammasome. Front. Microbiol., 2019, vol. 10, p. 50. doi: 10.3389/fmicb.2019.00050
  13. Chien J.-Y., Hsueh P.-R., Cheng W.-C., Yu C.-J., Yang P.-C. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome. Respirology, 2006, vol. 11, no. 6, pp. 715–722. doi: 10.1111/j.14401843.2006.00942.x
  14. Cong Y., Hart B. J., Gross R., Zhou H., Frieman M., Bollinger L., Wada J. Hensley L.E., Jahrling P.B., Dyall J., Holbrook M.R. MERS-CoV pathogenesis and antiviral efficacy of licensed drugs in human monocyte-derived antigen-presenting cells. PLoS One, 2018, vol. 13, no. 3, pp. e0194868. doi: 10.1371/journal.pone.0194868
  15. Cui J., Li F., Shi Z.-L. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol., 2019 vol. 17, pp. 181–192. doi: 10.1038/s41579-018-0118-9
  16. DeDiego M.L., Nieto-Torres J.L. Jimenez-Guarde ño J.M, Regla-Nava J.A., Castaño-Rodriguez C., Fernandez-Delgado R., Usera F., Enjuanes L. Coronavirus virulence genes with main focus on SARS-CoV envelope gene. Virus Res., 2014, vol. 19, no. 194, pp. 124–137. doi: 10.1016/j.virusres.2014.07.024.
  17. Drosten C., G ünther S., Preiser W., van der Werf S., Brodt H.-R., Becker S., Rabenau H., Pan-ning M., Kolesnikova L., Fouchier R.A.M., Berger A., Burgui ère A.-M, Cinatl J., Eickmann M., Escriou N., Grywna K., Kramme S., Manuguerra J.-C., M üller S., Rickerts V., Stürmer M., Vieth S., Klenk H.-D., Osterhaus A.D.M.E., Schmitz H., Doerr H.W. Identification of a novel corona-virus in patients with severe acute respiratory syndrome. N. Engl. J. Med., 2003, vol. 348, no. 20, pp. 1967–1976. doi: 10.1056/NEJMoa030747
  18. Feng B, Zhang Q, Wang J, Dong H., Mu X., Hu G., Zhang T. IFIT1 expression patterns induced by H9N2 virus and inactivated viral particle in human umbilical vein endothelial cells and bronchus epithelial cells. Mol. Cells, 2018, vol. 41, no. 4, pp. 271–281. doi: 10.14348/molcells.2018.2091.
  19. Gao J., Tian Z., Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci. Trends., 2020, vol. 14, no. 1, pp. 72–73. doi: 10.5582/bst.2020.01047
  20. Grainger J., Boachie-Ansah G. Anandamide-induced relaxation of sheep coronary arter-ies: the role of the vascular endothelium, arachidonic acid metabolites and potassium channels. Br. J. Pharmacol., 2001, vol. 134, no. 5, pp. 1003–1012. doi: 10.1038/sj.bjp.0704340
  21. Gralinski L.E., Bankhead III A., Jeng S., Menachery V.D., Proll S., Belisle S.E., Matzke M., Webb-Robertson B.-J.M., Luna M.L., Shukla A.K., Ferris M.T., Bolles M., Chang J., Aicher L., Waters K.M., Smith R.D., Metz T.O., Law G.L., Katze M.G., McWeeney S., Baric R.S. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio., 2013, vol. 4, no 4: e00271-13. doi: 10.1128/mBio.00271-13
  22. Gralinski L.E., Baric R.S. Molecular pathology of emerging coronavirus infections. J. Pathol., 2015, vol. 235, no. 2, pp. 185–195. doi: 10.1002/path.4454.
  23. Guo H., Callaway J.B., Ting J.P.-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med., 2015, vol. 21, no. 7, pp. 677–687. doi: 10.1038/nm.3893
  24. Guo Y.-R., Cao Q.-D., Hong Z.-S., Tan Y.-Y., Chen S.-D., Jin H.-J., K.-S. Tan, Wang D.-Y., Yan Y. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil. Med. Res., 2020, vol. 7, no. 1, p 11. doi: 10.1186/s40779-020-00240-0
  25. He Y., Hara H., N úñ ez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci., 2016, vol. 4, no. 12, pp. 1012–1021 doi: 10.1016/j.tibs.2016.09.002
  26. Hemil ä H. Vitamin C and Infections. Nutrients, 2017, vol. 9, no. 4, p. 339. doi: 10.3390/nu9040339.
  27. Hemil ä H., Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database Syst. Rev., 2013, no. 1: CD000980. doi: 10.1002/14651858.CD000980.pub4
  28. Hendrickson C.M., Matthay M.A. Viral pathogens and acute lung injury: investigations inspired by the SARS epidemic and the 2009 H1N1 influenza pandemic. Semin. Respir. Crit. Care Med., 2013, vol. 34, no. 4, pp. 475–486. doi: 10.1055/s-0033-1351122.
  29. Hornung V., Latz E. Critical functions of priming and lysosomal damage for NLRP3 activation. Eur. J. Immunol., 2010, vol. 40, pp. 20–623. doi: 10.1002/eji.200940185.
  30. Humphries E.S.A., Dart C. Neuronal and cardiovascular potassium channels as therapeutic drug targets. J. Biomol. Screen., 2015, vol. 20, no. 9, pp. 1055–1073. doi: 10.1177/1087057115601677
  31. Ishiguro T., Kobayashi Y., Uozumi R., Takata N., Takaku Y., Kagiyama N., Kanauchi T., Shimizu Y., Takayanagi N. Viral pneumonia requiring differentiation from acute and progressive diffuse interstitial lung diseases. Intern. Med., 2019, vol. 58, no. 24, pp. 3509–3519. doi: 10.2169/internalmedicine.2696-19
  32. Jacobs S.R., Damania B. NLRs, inflammasomes, and viral infection. J. Leukoc. Biol., 2012, vol. 92, no. 3, pp. 469–477. doi: 10.1189/jlb.0312132
  33. Khomich O.A., Kochetkov S.N., Bartosch B. Ivano A.V. Redox biology of respiratory viral infections. Viruses, 2018, vol. 10, no. 8, pp. 392. doi: 10.3390/v10080392.
  34. Kim E.S., Choe P.G., Park W.B., Oh H.S., Kim E.J., Nam E.Y., Na S.H., Kim M. Song K.H., Bang J.H., Park S.W., Kim H.B., Kim N.J., Oh M.D. Clinical progression and cytokine profiles of middle east respiratory syndrome coronavirus infection. J. Korean Med. Sci., 2016, vol. 31, no. 11, pp. 1717–1725. doi: 10.3346/jkms.2016.31.11.1717
  35. Kopecky-Bromberg S.A., Martinez-Sobrido L., Frieman M., Baric R.A., Palese P. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J. Virol., 2007, vol. 81, no. 2, pp. 548–557. doi: 10.1128/JVI.01782-06.
  36. Kuhn J.H., Li W., Choe H., Farzan M. Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus. Cell Mol. Life Sci., 2004, vol. 61, no. 21, pp. 2738–43. doi: 10.1007/s00018-004-4242-5
  37. Latz E., Xiao T.S., Stutz A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol., 2013, vol. 13, pp. 397–411. doi: 10.1038/nri3452
  38. Li G. Fan Y. Lai Y. Han T., Li Z., Zhou P., Pan P., Wang W., Hu D., Liu X., Zhang Q., Wu J. Coronavirus infections and immune responses. J. Med. Virol., 2020, vol. 92, pp. 424–432. doi: 10.1002/jmv.25685
  39. Li S., Yuan L., Dai G., Chen R.A., Liu D.X., Fung T.S. Regulation of the ER stress response by the ion channel activity of the infectious bronchitis coronavirus envelope protein modulates virion release, apoptosis, viral fitness, and pathogenesis. Front. Microbiol., 2020, vol. 10, p. 322. doi: 10.3389/fmicb.2019.03022
  40. Lui P.-Y., Wong L.-Y. R., Fung C.-L., Siu K.-L., Yeung M.-L., Yuen K.-S., Chan C.-P., Woo P.C.-Y., Yuen K.-Y., Jin D.-Y. Middle East respiratory syndrome corona-virus M protein suppresses type I interferon expression through the inhibition of TBK1dependent phosphorylation of IRF3. Emerg. Microbes Infect., 2016, vol. 5, no. 4: e39. doi: 10.1038/emi.2016.33
  41. Mackay I.M., Arden K.E. MERS coronavirus: diagnostics, epidemiology and transmission. Virol. J., 2015, vol. 12, p. 222. doi: 10.1186/s12985-015-0439-5
  42. Marku š i ć M., Š antak M., Ko š uti ć -Gulija T., Jergovi ć M., Jug R., For č i ć D. Induction of IFN-α subtypes and their antiviral activity in mumps virus infection. Viral Immunol., 2014, vol. 27, no. 10, pp. 497–505. doi: 10.1089/vim.2014.0028
  43. Marmolejo-Murillo L.G., Ar é chiga-Figueroa I.A., Cui M., Moreno-Galindo E.G., Navarro-Polanco R.A., S á nchez-Chapula J.A., Ferrer T., Rodr íguez-Menchaca A.A. Inhibition of Kir4.1 potassium channels by quinacrine. Brain Res., 2017, vol. 1663, pp. 87–94. doi: 10.1016/j.brainres.2017.03.009
  44. Mart ín-Vicente M., Medrano L.M., Resino S., García-Sastre A., Martínez I. TRIM25 in the regulation of the antiviral innate immunity. Front. Immunol., 2017, vol. 8, p. 1187. doi: 10.3389/fimmu.2017.01187
  45. Menachery V.D., Mitchell H.D., Cockrell A.S., Gralinski L.E., Yount B.L. Jr, Graham R.L., McAnarney E.T., Douglas M.G., Scobey T., Beall A., Dinnon 3 rd K., Kocher J.F., Hale A.E., Stratton K.G., Waters K.M., Baric R.S. MERS-CoV accessory ORFs play key role for infection and pathogenesis. mBio, 2017, vol. 8, no. 4. doi: 10.1128/mBio.00665-17
  46. Mubarak A., Alturaikiand W., Hemida M.G. Middle East respiratory syndrome coronavirus (MERS-CoV): infection, immunological response, and vaccine development. J. Immunol. Res., 2019, p. 6491738. doi: 10.1155/2019/6491738.
  47. Mu ñ oz-Planillo R., Kuffa P., Mart í nez-Col ó n G., Smith B.L., Rajendiran T.M., N úñ ez G. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate. Matter. Immunity, 2013, vol. 38, no. 6, pp. 1142–1153. doi: 10.1016/j.immuni.2013.05.016
  48. Murakami T., Ockinger J., Yu J., Byles V., McColl A., Hofer A.M., Horng T. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl. Acad. Sci. USA, 2012, vol. 109, pp. 11282–11287. doi: 10.1073/pnas.1117765109
  49. Narayanan K., Huang C., Makino S. SARS coronavirus accessory proteins. Virus Res., 2008, vol. 133, no. 1, pp. 113–121. doi: 10.1016/j.virusres.2007.10.009
  50. Nelemans T., Kikkert M. Viral Innate immune evasion and the pathogenesis of emerging RNA virus infections. Viruses, 2019, vol. 11, no. 10, p. 961. doi: 10.3390/v11100961
  51. Nieto-Torres J. L., Verdiá-Báguena C., Jimenez-Guardeño J.M., Regla-Nava J.A., Castaño-Rodriguez C., Fernandez-Delgado R., Torres J., Aguilella V.M., Enjuanes L. Severe acute respiratory syndrome coronavirus e protein transports calcium ions and activates the NLRP3 inflammasome. Virology, 2015, vol. 485, pp. 330–339. doi: 10.1016/j.virol.2015.08.010
  52. Prompetchara E., Ketloy C., Palaga T. Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic. Asian Pac. J. Allergy Immunol., 2020, vol. 38, no. 1, pp. 1–9. doi: 10.12932/AP-200220-0772
  53. Rathinam V.A.K., Chan F.K.-M. Inflammasome, inflammation and tissue homeostasis. Trends. Mol. Med., 2018, vol. 24, no. 3, pp. 304–318. doi: 10.1016/j.molmed.2018.01.004
  54. Shi C.-S., Qi H.-Y., Boularan C., Huang N.-N., Abu-Asab M., Shelhamer J.H., Kehrl J.H. SARS-CoV ORF9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J. Immunol., 2014, vol. 193, no. 6, pp. 30803089. doi: 10.4049/jimmunol.1303196
  55. Shokri S., Mahmoudvand S., Taherkhani R., Farshadpour F. Modulation of the immune response by middle east respiratory syndrome coronavirus. J. Cell. Physiol., 2019, vol. 234, no. 3, pp. 2143–2151. doi: 10.1002/jcp.27155
  56. Silva da Costa L., Outlioua A., Anginot A., Akarid K., Arnoult D. RNA viruses promote activation of the NLRP3 inflammasome through cytopathogenic effect-induced potassium efflux. Cell Death Dis., 2019, vol. 10, no. 5, p. 346. doi: 10.1038/s41419-019-1579-0
  57. Simmons G., Zmora P., Gierer S., Heurich A., P öhlmann S,. Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research. Antiviral Res., 2013, vol. 100, no. 3, pp. 605–614. doi: 10.1016/j.antiviral.2013.09.028
  58. Singhal T.A Review of coronavirus disease-2019 (COVID-19). Indian J. Pediatr., 2020, vol. 87, no. 4, pp. 281–286. doi: 10.1007/s12098-020-03263-6
  59. Song Z., Xu Y., Bao L., Zhang L., Yu P., Qu Y., Zhu H., Zhao W., Han Y., Qin C. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses., 2019, vol. 11, no. 1: 59. doi: 10.3390/v11010059
  60. Su S., Wong G., Shi W., Liu J., Lai A.C.K., Zhou J., Liu W., Bi Y., Gao G.F. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol., 2016, vol. 24, no. 6, pp. 490–502. doi: 10.1016/j.tim.2016.03.003
  61. Thiel V., Weber F. Interferon and cytokine responses to SARS-coronavirus infection. Cytokine Growth Factor Rev., 2008, vol. 19, no. 2, pp. 121–132 doi.10.1016/j.cytogfr.2008.01.001
  62. Tykocki N.R., Boerman E.M., Jackson W.F. Smooth muscle ion channels and regulation of vascular tone in resistance arteries and arterioles. Compr. Physiol., 2017, vol. 7, no. 2, pp. 485–581. doi: 10.1002/cphy.c160011
  63. Tynell J., Westenius V., R ö nkk ö E. , Munster V.J., Mel é n K., Ö sterlund P., Julkunen I. Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J. Gen. Virol., 2016, vol. 97, no. 2, pp. 344–355. doi: 10.1099/jgv.0.000351
  64. Van der Meer Y., van Tol H., Locker J.K., Snijder E.J. ORF1a-encoded replicase subunits are involved in the membrane association of the arterivirus replication complex. J. Virol., 1998, vol. 72, no. 8, pp. 6689–6698. PMID: 9658116
  65. Wang K., Chen W., Zhou Y.-S., Lian J.-Q., Zhang Z., Du P., Gong L., Zhang Y., Cui H.-Y., Geng J.-J., Wang B., Sun X.-X., Wang C.-F., Yang X., Lin P., Deng Y.-Q., Wei D., Yang X.-M., Zhu Y.-M., Zhang K., Zheng Z.-H., Miao J.-L., Guo T., Shi Y., Zhang J., Fu L., Wang Q.-Y., Bian H., Zhu P., Chen Z.-N. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. Preprint, 2020. doi: 10.1101/2020.03.14.988345
  66. Wang Y., Shi P., Chen Q., Huang Z., Zou D., Zhang J., Gao X., Lin Z. Mitochondrial ROS promote macrophage pyroptosis by inducing GSDMD oxidation. J. Mol. Cell Biol., 2019, vol. 11, no. 12, pp. 1069–1082. doi: 10.1093/jmcb/mjz020
  67. Xu X., Chen P., Wang J., Feng J., Zhou H., Li X., Zhong W., Hao P. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci. China Life Sci., 2020, vol. 63, no. 3, pp. 457–460. doi: 10.1007/s11427-020-1637-5
  68. Yue Y., Nabar N. R., Shi C.-S., Kamenyeva O., Xiao X., Hwang I.-Y., Wang M., Kehrl J.H. SARS-coronavirus open reading frame-3a drives multimodal necrotic cell death. Cell Death Dis., 2018, vol. 9, no. 9, p. 904. doi: 10.1038/s41419-018-0917-y
  69. Zhao C., Zhao W. NLRP3 Inflammasome — a key player in antiviral responses. Front. Immunol., 2020, vol. 11, p. 211. doi: 10.3389/fimmu.2020.00211
  70. Zumla A., Chan J.F.W., Azhar E.I. Coronaviruses — drug discovery and therapeutic options. Nat. Rev. Drug Discov., 2016, vol. 15, no. 5, pp. 327–347. doi: 10.1038/nrd.2015.37

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