Archives of Virology

, Volume 164, Issue 2, pp 439–446 | Cite as

Both type I and type III interferons are required to restrict measles virus growth in lung epithelial cells

  • Midori Taniguchi
  • Yusuke YanagiEmail author
  • Shinji OhnoEmail author
Original Article


Measles virus (MeV) first infects immune cells in the respiratory tract of a human host, spreads to lymphoid organs throughout the body, and finally enters and grows in respiratory epithelial cells before being released and transmitted to the next host. Thus, efficient growth in respiratory epithelial cells is important for the person-to-person transmission of MeV. Upon viral entry, host cells detect viral nucleic acids and produce interferons (IFNs) to control viral growth. Type I (IFN-α/β) and type III (IFN-λ) IFNs have largely common induction and signaling mechanisms and stimulate expression of similar target genes but utilize distinct receptors. To determine the relative contributions of type I and type III IFNs to the control of MeV growth in epithelial cells, we examined the growth of MeV and that of its mutants lacking either type I or type III IFN receptor in the human lung epithelial cell line H358. Our results revealed that both type I and type III IFNs are required to restrict MeV growth in H358 cells and that the induction of type III as well as type I IFNs was increased in the absence of the MeV nonstructural V protein.



This study was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI grant number 24115005 and the Uehara Memorial Foundation.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Research involving human participants and/or animals

Not applicable.

Informed consent

Not applicable.


  1. 1.
    Andreakos E, Salagianni M, Galani IE, Koltsida O (2017) Interferon-lambdas: front-line guardians of immunity and homeostasis in the respiratory tract. Front Immunol 8:1232CrossRefGoogle Scholar
  2. 2.
    Berghall H, Siren J, Sarkar D, Julkunen I, Fisher PB, Vainionpaa R, Matikainen S (2006) The interferon-inducible RNA helicase, mda-5, is involved in measles virus-induced expression of antiviral cytokines. Microbes Infect 8:2138–2144CrossRefGoogle Scholar
  3. 3.
    Brower M, Carney DN, Oie HK, Gazdar AF, Minna JD (1986) Growth of cell lines and clinical specimens of human non-small cell lung cancer in a serum-free defined medium. Cancer Res 46:798–806Google Scholar
  4. 4.
    Childs K, Stock N, Ross C, Andrejeva J, Hilton L, Skinner M, Randall R, Goodbourn S (2007) mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology 359:190–200CrossRefGoogle Scholar
  5. 5.
    Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–823CrossRefGoogle Scholar
  6. 6.
    Coughlin MM, Beck AS, Bankamp B, Rota PA (2017) Perspective on global measles epidemiology and control and the role of novel vaccination strategies. Viruses 9:11CrossRefGoogle Scholar
  7. 7.
    Cuevas RA, Ghosh A, Wallerath C, Hornung V, Coyne CB, Sarkar SN (2016) MOV10 provides antiviral activity against RNA viruses by enhancing RIG-I-MAVS-independent IFN induction. J Immunol 196:3877–3886CrossRefGoogle Scholar
  8. 8.
    Davis ME, Wang MK, Rennick LJ, Full F, Gableske S, Mesman AW, Gringhuis SI, Geijtenbeek TB, Duprex WP, Gack MU (2014) Antagonism of the phosphatase PP1 by the measles virus V protein is required for innate immune escape of MDA5. Cell Host Microbe 16:19–30CrossRefGoogle Scholar
  9. 9.
    Frenzke M, Sawatsky B, Wong XX, Delpeut S, Mateo M, Cattaneo R, von Messling V (2013) Nectin-4-dependent measles virus spread to the cynomolgus monkey tracheal epithelium: role of infected immune cells infiltrating the lamina propria. J Virol 87:2526–2534CrossRefGoogle Scholar
  10. 10.
    Galani IE, Triantafyllia V, Eleminiadou EE, Koltsida O, Stavropoulos A, Manioudaki M, Thanos D, Doyle SE, Kotenko SV, Thanopoulou K, Andreakos E (2017) Interferon-lambda mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity 46(875–890):e876Google Scholar
  11. 11.
    Griffin DE (2013) Measles virus. In: Knipe DM, Howley PM (eds) Fields virology, 6th edn. Wolters Kluwer Health/Lippincott Williams & Wilkins Co, Philadelphia, pp 1042–1069Google Scholar
  12. 12.
    Hamming OJ, Terczynska-Dyla E, Vieyres G, Dijkman R, Jorgensen SE, Akhtar H, Siupka P, Pietschmann T, Thiel V, Hartmann R (2013) Interferon lambda 4 signals via the IFNlambda receptor to regulate antiviral activity against HCV and coronaviruses. EMBO J 32:3055–3065CrossRefGoogle Scholar
  13. 13.
    Hashimoto K, Ono N, Tatsuo H, Minagawa H, Takeda M, Takeuchi K, Yanagi Y (2002) SLAM (CD150)-independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein. J Virol 76:6743–6749CrossRefGoogle Scholar
  14. 14.
    Ikegame S, Takeda M, Ohno S, Nakatsu Y, Nakanishi Y, Yanagi Y (2010) Both RIG-I and MDA5 RNA helicases contribute to the induction of alpha/beta interferon in measles virus-infected human cells. J Virol 84:372–379CrossRefGoogle Scholar
  15. 15.
    Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S S (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105CrossRefGoogle Scholar
  16. 16.
    Kawai T, Akira S (2008) Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 1143:1–20CrossRefGoogle Scholar
  17. 17.
    Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP (2003) IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol 4:69–77CrossRefGoogle Scholar
  18. 18.
    Lazear HM, Nice TJ, Diamond MS (2015) Interferon-lambda: immune functions at barrier surfaces and beyond. Immunity 43:15–28CrossRefGoogle Scholar
  19. 19.
    Lemon K, de Vries RD, Mesman AW, McQuaid S, van Amerongen G, Yuksel S, Ludlow M, Rennick LJ, Kuiken T, Rima BK, Geijtenbeek TB, Osterhaus AD, Duprex WP, de Swart RL (2011) Early target cells of measles virus after aerosol infection of non-human primates. PLoS Pathog 7:e1001263CrossRefGoogle Scholar
  20. 20.
    Leonard VH, Sinn PL, Hodge G, Miest T, Devaux P, Oezguen N, Braun W, McCray PB Jr, McChesney MB, Cattaneo R (2008) Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed. J Clin Investig 118:2448–2458Google Scholar
  21. 21.
    Ludlow M, Lemon K, de Vries RD, McQuaid S, Millar EL, van Amerongen G, Yuksel S, Verburgh RJ, Osterhaus AD, de Swart RL, Duprex WP (2013) Measles virus infection of epithelial cells in the macaque upper respiratory tract is mediated by subepithelial immune cells. J Virol 87:4033–4042CrossRefGoogle Scholar
  22. 22.
    Mahlakoiv T, Hernandez P, Gronke K, Diefenbach A, Staeheli P (2015) Leukocyte-derived IFN-alpha/beta and epithelial IFN-lambda constitute a compartmentalized mucosal defense system that restricts enteric virus infections. PLoS Pathog 11:e1004782CrossRefGoogle Scholar
  23. 23.
    Muhlebach MD, Mateo M, Sinn PL, Prufer S, Uhlig KM, Leonard VH, Navaratnarajah CK, Frenzke M, Wong XX, Sawatsky B, Ramachandran S, McCray PB Jr, Cichutek K, von Messling V, Lopez M, Cattaneo R (2011) Adherens junction protein nectin-4 is the epithelial receptor for measles virus. Nature 480:530–533CrossRefGoogle Scholar
  24. 24.
    Nice TJ, Baldridge MT, McCune BT, Norman JM, Lazear HM, Artyomov M, Diamond MS, Virgin HW (2015) Interferon-lambda cures persistent murine norovirus infection in the absence of adaptive immunity. Science 347:269–273CrossRefGoogle Scholar
  25. 25.
    Noyce RS, Bondre DG, Ha MN, Lin LT, Sisson G, Tsao MS, Richardson CD (2011) Tumor cell marker PVRL4 (nectin 4) is an epithelial cell receptor for measles virus. PLoS Pathog 7:e1002240CrossRefGoogle Scholar
  26. 26.
    Okabayashi T, Kojima T, Masaki T, Yokota S, Imaizumi T, Tsutsumi H, Himi T, Fujii N, Sawada N (2011) Type-III interferon, not type-I, is the predominant interferon induced by respiratory viruses in nasal epithelial cells. Virus Res 160:360–366CrossRefGoogle Scholar
  27. 27.
    Ono N, Tatsuo H, Hidaka Y, Aoki T, Minagawa H, Yanagi Y (2001) Measles viruses on throat swabs from measles patients use signaling lymphocytic activation molecule (CDw150) but not CD46 as a cellular receptor. J Virol 75:4399–4401CrossRefGoogle Scholar
  28. 28.
    Onoguchi K, Yoneyama M, Takemura A, Akira S, Taniguchi T, Namiki H, Fujita T (2007) Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem 282:7576–7581CrossRefGoogle Scholar
  29. 29.
    Pfaller CK, Mastorakos GM, Matchett WE, Ma X, Samuel CE, Cattaneo R (2015) Measles virus defective interfering RNAs are generated frequently and early in the absence of C protein and can be destabilized by adenosine deaminase acting on RNA-1-like hypermutations. J Virol 89:7735–7747CrossRefGoogle Scholar
  30. 30.
    Plumet S, Herschke F, Bourhis JM, Valentin H, Longhi S, Gerlier D (2007) Cytosolic 5′-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response. PLoS One 2:e279CrossRefGoogle Scholar
  31. 31.
    Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway M, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O’Brien TR (2013) A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet 45:164–171CrossRefGoogle Scholar
  32. 32.
    Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F (2013) Genome engineering using the CRISPR-Cas9 system. Nat Protoc 8:2281–2308CrossRefGoogle Scholar
  33. 33.
    Sanchez-Aparicio MT, Feinman LJ, Garcia-Sastre A, Shaw ML (2018) Paramyxovirus V proteins interact with the RIG-I/TRIM25 regulatory complex and inhibit RIG-I signaling. J Virol 92:e01960-17CrossRefGoogle Scholar
  34. 34.
    Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM (2003) IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol 4:63–68CrossRefGoogle Scholar
  35. 35.
    Shingai M, Ebihara T, Begum NA, Kato A, Honma T, Matsumoto K, Saito H, Ogura H, Matsumoto M, Seya T (2007) Differential type I IFN-inducing abilities of wild-type versus vaccine strains of measles virus. J Immunol 179:6123–6133CrossRefGoogle Scholar
  36. 36.
    Shivakoti R, Hauer D, Adams RJ, Lin WH, Duprex WP, de Swart RL, Griffin DE (2015) Limited in vivo production of type I or type III interferon after infection of macaques with vaccine or wild-type strains of measles virus. J Interferon Cytokine Res 35:292–301CrossRefGoogle Scholar
  37. 37.
    Takeda M, Takeuchi K, Miyajima N, Kobune F, Ami Y, Nagata N, Suzaki Y, Nagai Y, Tashiro M (2000) Recovery of pathogenic measles virus from cloned cDNA. J Virol 74:6643–6647CrossRefGoogle Scholar
  38. 38.
    Takeda M, Ohno S, Seki F, Nakatsu Y, Tahara M, Yanagi Y (2005) Long untranslated regions of the measles virus M and F genes control virus replication and cytopathogenicity. J Virol 79:14346–14354CrossRefGoogle Scholar
  39. 39.
    Takeda M, Tahara M, Nagata N, Seki F (2011) Wild-type measles virus is intrinsically dual-tropic. Front Microbiol 2:279Google Scholar
  40. 40.
    Takeuchi K, Kadota SI, Takeda M, Miyajima N, Nagata K (2003) Measles virus V protein blocks interferon (IFN)-alpha/beta but not IFN-gamma signaling by inhibiting STAT1 and STAT2 phosphorylation. FEBS Lett 545:177–182CrossRefGoogle Scholar
  41. 41.
    Tatsuo H, Ono N, Tanaka K, Yanagi Y (2000) SLAM (CDw150) is a cellular receptor for measles virus. Nature 406:893–897CrossRefGoogle Scholar
  42. 42.
    Van Nguyen N, Kato SI, Nagata K, Takeuchi K (2016) Differential induction of type I interferons in macaques by wild-type measles virus alone or with the hemagglutinin protein of the Edmonston vaccine strain. Microbiol Immunol 60:501–505CrossRefGoogle Scholar
  43. 43.
    Wang Z, Ji J, Peng D, Ma F, Cheng G, Qin FX (2016) Complex regulation pattern of IRF3 activation revealed by a novel dimerization reporter system. J Immunol 196:4322–4330CrossRefGoogle Scholar
  44. 44.
    Zilliox MJ, Moss WJ, Griffin DE (2007) Gene expression changes in peripheral blood mononuclear cells during measles virus infection. Clin Vaccine Immunol 14:918–923CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Virology, Faculty of MedicineKyushu UniversityFukuokaJapan
  2. 2.Department of Virology, Graduate School of MedicineUniversity of the RyukyusNakagamiJapan

Personalised recommendations