Interferon-γ Inhibits Ebola Virus Infection

English version České info

Filovirus outbreaks occur sporadically, but with increasing frequency. With no current approved filovirus therapeutics, the 2014 Makona Ebola virus epidemic in Guinea, Sierra Leone and Liberia emphasizes the need for effective treatments against this highly pathogenic family of viruses. The use of this FDA-approved drug to inhibit Ebola virus infection would allow rapid implementation of a novel antiviral therapy for future crises. Interferon gamma elicits an antiviral state in antigen-presenting cells and stimulates cellular immune responses. We demonstrate that interferon gamma profoundly inhibits Ebola virus infection of macrophages, which are early cellular targets of Ebola virus. We also identify novel interferon gamma-stimulated genes in human macrophage populations that have not been previously appreciated to inhibit filoviruses or other negative strand RNA viruses. Finally and most importantly, we show that interferon gamma given 24 hours prior to or after virus infection protects mice from lethal Ebola virus challenge, suggesting that this drug may serve as an effective prophylactic and/or therapeutic strategy against this deadly virus.

Vyšlo v časopise: Interferon-γ Inhibits Ebola Virus Infection. PLoS Pathog 11(11): e32767. doi:10.1371/journal.ppat.1005263
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005263

Souhrn

Zdroje

1. Leroy EM, Gonzalez JP, Baize S. Ebola and Marburg haemorrhagic fever viruses: major scientific advances, but a relatively minor public health threat for Africa. Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2011;17(7):964–76. 21722250.

2. Gire SK, Goba A, Andersen KG, Sealfon RS, Park DJ, Kanneh L, et al. Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak. Science (New York, NY). 2014;345(6202):1369–72. doi: 10.1126/science.1259657 25214632.

3. Geisbert TW, Young HA, Jahrling PB, Davis KJ, Larsen T, Kagan E, et al. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. The American journal of pathology. 2003;163(6):2371–82. Epub 2003/11/25. 14633609; PubMed Central PMCID: PMCPMC1892396.

4. Bray M, Geisbert TW. Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. The international journal of biochemistry & cell biology. 2005;37(8):1560–6. Epub 2005/05/18. doi: 10.1016/j.biocel.2005.02.018 15896665.

5. Gupta M, Mahanty S, Ahmed R, Rollin PE. Monocyte-derived human macrophages and peripheral blood mononuclear cells infected with ebola virus secrete MIP-1alpha and TNF-alpha and inhibit poly-IC-induced IFN-alpha in vitro. Virology. 2001;284(1):20–5. 11352664.

6. Hensley LE, Young HA, Jahrling PB, Geisbert TW. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunology letters. 2002;80(3):169–79. 11803049.

7. Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. The Journal of infectious diseases. 2003;188(11):1618–29. doi: 10.1086/379724 14639531.

8. Bray M, Mahanty S. Ebola hemorrhagic fever and septic shock. The Journal of infectious diseases. 2003;188(11):1613–7. Epub 2003/11/26. doi: 10.1086/379727 14639530.

9. Stroher U, West E, Bugany H, Klenk HD, Schnittler HJ, Feldmann H. Infection and activation of monocytes by Marburg and Ebola viruses. Journal of virology. 2001;75(22):11025–33. Epub 2001/10/17. 11602743; PubMed Central PMCID: PMCPMC114683.

10. Sanchez A, Lukwiya M, Bausch D, Mahanty S, Sanchez AJ, Wagoner KD, et al. Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. Journal of virology. 2004;78(19):10370–7. 15367603; PubMed Central PMCID: PMC516433.

11. Jahrling PB, Geisbert TW, Geisbert JB, Swearengen JR, Bray M, Jaax NK, et al. Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections. The Journal of infectious diseases. 1999;179 Suppl 1:S224–34. Epub 1999/02/13. 9988188.

12. Smith LM, Hensley LE, Geisbert TW, Johnson J, Stossel A, Honko A, et al. Interferon-beta therapy prolongs survival in rhesus macaque models of Ebola and Marburg hemorrhagic fever. The Journal of infectious diseases. 2013;208(2):310–8. doi: 10.1093/infdis/jis921 23255566; PubMed Central PMCID: PMC3685222.

13. Qiu X, Wong G, Fernando L, Audet J, Bello A, Strong J, et al. mAbs and Ad-vectored IFN-alpha therapy rescue Ebola-infected nonhuman primates when administered after the detection of viremia and symptoms. Science translational medicine. 2013;5(207):207ra143. Epub 2013/10/18. doi: 10.1126/scitranslmed.3006605 24132638.

14. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14–20. doi: 10.1016/j.immuni.2014.06.008 25035950; PubMed Central PMCID: PMC4123412.

15. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000prime reports. 2014;6:13. doi: 10.12703/P6-13 24669294; PubMed Central PMCID: PMC3944738.

16. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. The Journal of clinical investigation. 2012;122(3):787–95. doi: 10.1172/JCI59643 22378047; PubMed Central PMCID: PMC3287223.

17. Liu SY, Sanchez DJ, Aliyari R, Lu S, Cheng G. Systematic identification of type I and type II interferon-induced antiviral factors. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(11):4239–44. doi: 10.1073/pnas.1114981109 22371602; PubMed Central PMCID: PMC3306696.

18. Morrow AN, Schmeisser H, Tsuno T, Zoon KC. A novel role for IFN-stimulated gene factor 3II in IFN-gamma signaling and induction of antiviral activity in human cells. Journal of immunology (Baltimore, Md: 1950). 2011;186(3):1685–93. doi: 10.4049/jimmunol.1001359 21178011; PubMed Central PMCID: PMC3417313.

19. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. Journal of leukocyte biology. 2004;75(2):163–89. 14525967.

20. Towner JS, Paragas J, Dover JE, Gupta M, Goldsmith CS, Huggins JW, et al. Generation of eGFP expressing recombinant Zaire ebolavirus for analysis of early pathogenesis events and high-throughput antiviral drug screening. Virology. 2005;332(1):20–7. Epub 2005/01/22. doi: 10.1016/j.virol.2004.10.048 15661137.

21. Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011;477(7364):340–3. Epub 2011/08/26. doi: 10.1038/nature10348 21866103; PubMed Central PMCID: PMCPMC3175325.

22. Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, et al. Ebola virus entry requires the host-programmed recognition of an intracellular receptor. The EMBO journal. 2012;31(8):1947–60. Epub 2012/03/08. doi: 10.1038/emboj.2012.53 22395071; PubMed Central PMCID: PMCPmc3343336.

23. Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, et al. T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(20):8426–31. doi: 10.1073/pnas.1019030108 21536871; PubMed Central PMCID: PMC3100998.

24. Irie T, Carnero E, Garcia-Sastre A, Harty RN. In Vivo Replication and Pathogenesis of Vesicular Stomatitis Virus Recombinant M40 Containing Ebola Virus L-Domain Sequences. Infectious diseases. 2012;5:59–64. Epub 2013/06/25. doi: 10.4137/idrt.s10652 23794798; PubMed Central PMCID: PMCPmc3686127.

25. Moller-Tank S, Kondratowicz AS, Davey RA, Rennert PD, Maury W. Role of the phosphatidylserine receptor TIM-1 in enveloped-virus entry. Journal of virology. 2013;87(15):8327–41. doi: 10.1128/JVI.01025-13 23698310; PubMed Central PMCID: PMC3719829.

26. Monick MM, Carter AB, Gudmundsson G, Geist LJ, Hunninghake GW. Changes in PKC isoforms in human alveolar macrophages compared with blood monocytes. The American journal of physiology. 1998;275(2 Pt 1):L389–97. Epub 1998/08/12. 9700101.

27. Monick MM, Carter AB, Hunninghake GW. Human alveolar macrophages are markedly deficient in REF-1 and AP-1 DNA binding activity. The Journal of biological chemistry. 1999;274(25):18075–80. Epub 1999/06/11. 10364260.

28. Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nature reviews Immunology. 2005;5(5):375–86. 15864272.

29. Taniguchi T, Takaoka A. A weak signal for strong responses: interferon-alpha/beta revisited. Nature reviews Molecular cell biology. 2001;2(5):378–86. 11331912.

30. Ling PD, Warren MK, Vogel SN. Antagonistic effect of interferon-beta on the interferon-gamma-induced expression of Ia antigen in murine macrophages. Journal of immunology (Baltimore, Md: 1950). 1985;135(3):1857–63. 3926890.

31. Yoshida R, Murray HW, Nathan CF. Agonist and antagonist effects of interferon alpha and beta on activation of human macrophages. Two classes of interferon gamma receptors and blockade of the high-affinity sites by interferon alpha or beta. The Journal of experimental medicine. 1988;167(3):1171–85. 2965208; PubMed Central PMCID: PMC2188875.

32. Martinez O, Johnson JC, Honko A, Yen B, Shabman RS, Hensley LE, et al. Ebola virus exploits a monocyte differentiation program to promote its entry. Journal of virology. 2013;87(7):3801–14. Epub 2013/01/25. doi: 10.1128/jvi.02695-12 23345511; PubMed Central PMCID: PMC3624207.

33. Knipe DM, Howley PM. Fields virology. 6th ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins Health; 2013. 2 volumes p.

34. Marcus PI, Engelhardt DL, Hunt JM, Sekellick MJ. Interferon action: inhibition of vesicular stomatitis virus RNA synthesis induced by virion-bound polymerase. Science (New York, NY). 1971;174(4009):593–8. 4329841.

35. Schoggins JW. Interferon-stimulated genes: roles in viral pathogenesis. Current opinion in virology. 2014;6:40–6. doi: 10.1016/j.coviro.2014.03.006 24713352; PubMed Central PMCID: PMC4077717.

36. Gough DJ, Messina NL, Hii L, Gould JA, Sabapathy K, Robertson AP, et al. Functional crosstalk between type I and II interferon through the regulated expression of STAT1. PLoS biology. 2010;8(4):e1000361. Epub 2010/05/04. doi: 10.1371/journal.pbio.1000361 20436908; PubMed Central PMCID: PMCPmc2860501.

37. Galindo-Moreno J, Iurlaro R, El Mjiyad N, Diez-Perez J, Gabaldon T, Munoz-Pinedo C. Apolipoprotein L2 contains a BH3-like domain but it does not behave as a BH3-only protein. Cell death & disease. 2014;5:e1275. doi: 10.1038/cddis.2014.237 24901046.

38. Luo C, Chen M, Madden A, Xu H. Expression of complement components and regulators by different subtypes of bone marrow-derived macrophages. Inflammation. 2012;35(4):1448–61. doi: 10.1007/s10753-012-9458-1 22450524.

39. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Current opinion in virology. 2011;1(6):519–25. Epub 2012/02/14. doi: 10.1016/j.coviro.2011.10.008 22328912; PubMed Central PMCID: PMC3274382.

40. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472(7344):481–5. Epub 2011/04/12. doi: 10.1038/nature09907 21478870; PubMed Central PMCID: PMC3409588.

41. Audette M, Larouche L, Lussier I, Fugere N. Stimulation of the ICAM-1 gene transcription by the peroxovanadium compound [bpV(Pic)] involves STAT-1 but not NF-kappa B activation in 293 cells. European journal of biochemistry / FEBS. 2001;268(6):1828–36. Epub 2001/03/15. 11248703.

42. Yokosawa N, Yokota S, Kubota T, Fujii N. C-terminal region of STAT-1alpha is not necessary for its ubiquitination and degradation caused by mumps virus V protein. Journal of virology. 2002;76(24):12683–90. Epub 2002/11/20. 12438594; PubMed Central PMCID: PMCPmc136684.

43. Wen Z, Zhong Z, Darnell JE Jr., Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82(2):241–50. Epub 1995/07/28. 7543024.

44. Yee JK, Friedmann T, Burns JC. Generation of high-titer pseudotyped retroviral vectors with very broad host range. Methods in cell biology. 1994;43 Pt A:99–112. Epub 1994/01/01. 7823872.

45. Hastie E, Cataldi M, Marriott I, Grdzelishvili VZ. Understanding and altering cell tropism of vesicular stomatitis virus. Virus research. 2013;176(1–2):16–32. Epub 2013/06/26. doi: 10.1016/j.virusres.2013.06.003 23796410; PubMed Central PMCID: PMCPmc3865924.

46. Younes HM, Amsden BG. Interferon-γ therapy: Evaluation of routes of administration and delivery systems. Journal of pharmaceutical sciences. 2002;91(1):2–17. 11782893

47. Janardhana V, Tachedjian M, Crameri G, Cowled C, Wang LF, Baker ML. Cloning, expression and antiviral activity of IFNgamma from the Australian fruit bat, Pteropus alecto. Developmental and comparative immunology. 2012;36(3):610–8. Epub 2011/11/19. doi: 10.1016/j.dci.2011.11.001 22093696.

48. Consales CA, Mendonca RZ, Gallina NM, Pereira CA. Cytopathic effect induced by rabies virus in McCoy cells. Journal of virological methods. 1990;27(3):277–85. Epub 1990/03/01. 1691201.

49. Barkhouse DA, Garcia SA, Bongiorno EK, Lebrun A, Faber M, Hooper DC. Expression of interferon gamma by a recombinant rabies virus strongly attenuates the pathogenicity of the virus via induction of type I interferon. Journal of virology. 2015;89(1):312–22. Epub 2014/10/17. doi: 10.1128/jvi.01572-14 25320312; PubMed Central PMCID: PMCPmc4301114.

50. Cheon H, Holvey-Bates EG, Schoggins JW, Forster S, Hertzog P, Imanaka N, et al. IFNbeta-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. The EMBO journal. 2013;32(20):2751–63. Epub 2013/09/26. doi: 10.1038/emboj.2013.203 24065129; PubMed Central PMCID: PMCPmc3801437.

51. 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. 2014;505(7485):691–5. doi: 10.1038/nature12862 24284630; PubMed Central PMCID: PMC4077721.

52. Maloney NS, Thackray LB, Goel G, Hwang S, Duan E, Vachharajani P, et al. Essential cell-autonomous role for interferon (IFN) regulatory factor 1 in IFN-gamma-mediated inhibition of norovirus replication in macrophages. Journal of virology. 2012;86(23):12655–64. Epub 2012/09/14. doi: 10.1128/jvi.01564-12 22973039; PubMed Central PMCID: PMCPmc3497668.

53. Man SM, Karki R, Malireddi RK, Neale G, Vogel P, Yamamoto M, et al. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nature immunology. 2015;16(5):467–75. Epub 2015/03/17. doi: 10.1038/ni.3118 25774715; PubMed Central PMCID: PMCPmc4406811.

54. Jouvenet N, Neil SJ, Zhadina M, Zang T, Kratovac Z, Lee Y, et al. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. Journal of virology. 2009;83(4):1837–44. Epub 2008/11/28. doi: 10.1128/jvi.02211-08 19036818; PubMed Central PMCID: PMCPmc2643743.

55. Okumura A, Pitha PM, Harty RN. ISG15 inhibits Ebola VP40 VLP budding in an L-domain-dependent manner by blocking Nedd4 ligase activity. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(10):3974–9. Epub 2008/02/29. doi: 10.1073/pnas.0710629105 18305167; PubMed Central PMCID: PMCPmc2268823.

56. Malakhova OA, Zhang DE. ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. The Journal of biological chemistry. 2008;283(14):8783–7. Epub 2008/02/22. doi: 10.1074/jbc.C800030200 18287095; PubMed Central PMCID: PMCPmc2276364.

57. Spiropoulou CF, Ranjan P, Pearce MB, Sealy TK, Albarino CG, Gangappa S, et al. RIG-I activation inhibits ebolavirus replication. Virology. 2009;392(1):11–5. Epub 2009/07/25. doi: 10.1016/j.virol.2009.06.032 19628240.

58. Reid SP, Leung LW, Hartman AL, Martinez O, Shaw ML, Carbonnelle C, et al. Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. Journal of virology. 2006;80(11):5156–67. Epub 2006/05/16. 16698996; PubMed Central PMCID: PMCPmc1472181.

59. Toth K, Lee SR, Ying B, Spencer JF, Tollefson AE, Sagartz JE, et al. STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control. PLoS pathogens. 2015;11(8):e1005084. Epub 2015/08/21. doi: 10.1371/journal.ppat.1005084 26291525; PubMed Central PMCID: PMCPmc4546297.

60. Huang IC, Bailey CC, Weyer JL, Radoshitzky SR, Becker MM, Chiang JJ, et al. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS pathogens. 2011;7(1):e1001258. doi: 10.1371/journal.ppat.1001258 21253575; PubMed Central PMCID: PMC3017121.

61. Williams BR, Kerr IM. Inhibition of protein synthesis by 2'-5' linked adenine oligonucleotides in intact cells. Nature. 1978;276(5683):88–90. 740027.

62. Taylor MW, Feng GS. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1991;5(11):2516–22. 1907934.

63. Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annual review of immunology. 1997;15:563–91. 9143700.

64. Young HA. Regulation of interferon-gamma gene expression. Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research. 1996;16(8):563–8. 8877725.

65. Bosio CM, Aman MJ, Grogan C, Hogan R, Ruthel G, Negley D, et al. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. The Journal of infectious diseases. 2003;188(11):1630–8. Epub 2003/11/26. doi: 10.1086/379199 14639532.

66. Mahanty S, Hutchinson K, Agarwal S, McRae M, Rollin PE, Pulendran B. Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses. Journal of immunology (Baltimore, Md: 1950). 2003;170(6):2797–801. Epub 2003/03/11. 12626527.

67. Audet J, Kobinger GP. Immune evasion in ebolavirus infections. Viral immunology. 2015;28(1):10–8. Epub 2014/11/15. doi: 10.1089/vim.2014.0066 25396298.

68. Baize S, Leroy EM, Georges-Courbot MC, Capron M, Lansoud-Soukate J, Debre P, et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nature medicine. 1999;5(4):423–6. 10202932.

69. Baize S, Leroy EM, Georges AJ, Georges-Courbot MC, Capron M, Bedjabaga I, et al. Inflammatory responses in Ebola virus-infected patients. Clinical and experimental immunology. 2002;128(1):163–8. 11982604; PubMed Central PMCID: PMC1906357.

70. Bente D, Gren J, Strong JE, Feldmann H. Disease modeling for Ebola and Marburg viruses. Disease models & mechanisms. 2009;2(1–2):12–7. doi: 10.1242/dmm.000471 19132113; PubMed Central PMCID: PMC2615158.

71. Bradfute SB, Warfield KL, Bray M. Mouse models for filovirus infections. Viruses. 2012;4(9):1477–508. Epub 2012/11/22. doi: 10.3390/v4091477 23170168; PubMed Central PMCID: PMCPMC3499815.

72. Nakayama E, Saijo M. Animal models for Ebola and Marburg virus infections. Frontiers in microbiology. 2013;4:267. doi: 10.3389/fmicb.2013.00267 24046765; PubMed Central PMCID: PMC3763195.

73. Cooksley WG. Treatment of hepatitis B with interferon and combination therapy. Clinics in liver disease. 2004;8(2):353–70. 15481344.

74. Shepherd J, Waugh N, Hewitson P. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review. Health technology assessment. 2000;4(33):1–67. 11134916.

75. Todd PA, Goa KL. Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease. Drugs. 1992;43(1):111–22. 1372855.

76. Key LL Jr., Ries WL, Rodriguiz RM, Hatcher HC. Recombinant human interferon gamma therapy for osteopetrosis. The Journal of pediatrics. 1992;121(1):119–24. 1320672.

77. Nunoi H, Ishibashi F, Mizukami T, Hidaka F. Clinical evaluation of interferon-gamma treatment to chronic granulomatous disease patients with splice site mutations. Japanese journal of infectious diseases. 2004;57(5):S25–6. 15507763.

78. Marciano BE, Wesley R, De Carlo ES, Anderson VL, Barnhart LA, Darnell D, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2004;39(5):692–9. 15356785.

79. Ebihara H, Theriault S, Neumann G, Alimonti JB, Geisbert JB, Hensley LE, et al. In vitro and in vivo characterization of recombinant Ebola viruses expressing enhanced green fluorescent protein. The Journal of infectious diseases. 2007;196 Suppl 2:S313–22. doi: 10.1086/520590 17940966.

80. Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. The Journal of infectious diseases. 1998;178(3):651–61. 9728532.

81. Gao Y, Whitaker-Dowling P, Watkins SC, Griffin JA, Bergman I. Rapid adaptation of a recombinant vesicular stomatitis virus to a targeted cell line. Journal of virology. 2006;80(17):8603–12. doi: 10.1128/JVI.00142-06 16912309; PubMed Central PMCID: PMC1563842.

82. Yang ZY, Duckers HJ, Sullivan NJ, Sanchez A, Nabel EG, Nabel GJ. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nature medicine. 2000;6(8):886–9. 10932225.

83. Jeffers SA, Sanders DA, Sanchez A. Covalent modifications of the ebola virus glycoprotein. Journal of virology. 2002;76(24):12463–72. 12438572; PubMed Central PMCID: PMC136726.

84. Sinn PL, Hickey MA, Staber PD, Dylla DE, Jeffers SA, Davidson BL, et al. Lentivirus vectors pseudotyped with filoviral envelope glycoproteins transduce airway epithelia from the apical surface independently of folate receptor alpha. Journal of virology. 2003;77(10):5902–10. 12719583; PubMed Central PMCID: PMC154009.

85. Whelan SP, Barr JN, Wertz GW. Identification of a minimal size requirement for termination of vesicular stomatitis virus mRNA: implications for the mechanism of transcription. Journal of virology. 2000;74(18):8268–76. Epub 2000/08/23. 10954524; PubMed Central PMCID: PMCPmc116335.

86. Cherry S, Doukas T, Armknecht S, Whelan S, Wang H, Sarnow P, et al. Genome-wide RNAi screen reveals a specific sensitivity of IRES-containing RNA viruses to host translation inhibition. Genes & development. 2005;19(4):445–52. Epub 2005/02/17. doi: 10.1101/gad.1267905 15713840; PubMed Central PMCID: PMCPmc548945.

87. Lennemann NJ, Rhein BA, Ndungo E, Chandran K, Qiu X, Maury W. Comprehensive functional analysis of N-linked glycans on Ebola virus GP1. mBio. 2014;5(1):e00862–13. Epub 2014/01/30. doi: 10.1128/mBio.00862-13 24473128; PubMed Central PMCID: PMCPMC3950510.

88. Maury W. Monocyte maturation controls expression of equine infectious anemia virus. Journal of virology. 1994;68(10):6270–9. 8083967; PubMed Central PMCID: PMC237047.

89. Gross TJ, Powers LS, Boudreau RL, Brink B, Reisetter A, Goel K, et al. A microRNA processing defect in smokers' macrophages is linked to SUMOylation of the endonuclease DICER. The Journal of biological chemistry. 2014;289(18):12823–34. doi: 10.1074/jbc.M114.565473 24668803; PubMed Central PMCID: PMC4007470.

90. Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. American Journal of Epidemiology. 1938;27(3):493–7.

91. Whelan SP, Wertz GW. Transcription and replication initiate at separate sites on the vesicular stomatitis virus genome. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(14):9178–83. doi: 10.1073/pnas.152155599 12089339; PubMed Central PMCID: PMC123114.

92. Shabman RS, Hoenen T, Groseth A, Jabado O, Binning JM, Amarasinghe GK, et al. An upstream open reading frame modulates ebola virus polymerase translation and virus replication. PLoS pathogens. 2013;9(1):e1003147. doi: 10.1371/journal.ppat.1003147 23382680; PubMed Central PMCID: PMC3561295.

93. Gerke AK, Pezzulo AA, Tang F, Cavanaugh JE, Bair TB, Phillips E, et al. Effects of vitamin D supplementation on alveolar macrophage gene expression: preliminary results of a randomized, controlled trial. Multidisciplinary respiratory medicine. 2014;9(1):18. doi: 10.1186/2049-6958-9-18 24669961; PubMed Central PMCID: PMC3986866.

94. Smyth G. Limma: linear models for microarray data. In: 'Bioinformatics and Computational Biology Solutions using R and Bioconductor'. R. Gentleman VC, Dudoit S., Irizarry R., Huber W. editor. New York: Springer; 2005. 397–420 p.

95. Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. The Journal of experimental medicine. 1996;183(3):1161–72. Epub 1996/03/01. 8642258; PubMed Central PMCID: PMCPmc2192324.

96. Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Current protocols in cell biology / editorial board, Juan S Bonifacino [et al]. 2006;Chapter 3:Unit 3 22. doi: 10.1002/0471143030.cb0322s30 18228490.

97. Kim DH, Behlke MA, Rose SD, Chang MS, Choi S, Rossi JJ. Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nature biotechnology. 2005;23(2):222–6. Epub 2004/12/28. doi: 10.1038/nbt1051 15619617.

98. El-Andaloussi S, Lee Y, Lakhal-Littleton S, Li J, Seow Y, Gardiner C, et al. Exosome-mediated delivery of siRNA in vitro and in vivo. Nature protocols. 2012;7(12):2112–26. Epub 2012/11/17. 23154783.

99. Bray M, Davis K, Geisbert T, Schmaljohn C, Huggins J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. The Journal of infectious diseases. 1999;179 Suppl 1:S248–58. 9988191.