Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in IFNAR-/- mice

English version

Autoři: Stephen R. Welch ^aff001; Jana M. Ritter ^aff002; Anita K. McElroy ^aff001; Jessica R. Harmon ^aff001; JoAnn D. Coleman-McCray ^aff001; Florine E. M. Scholte ^aff001; Gary P. Kobinger ^aff004; Éric Bergeron ^aff001; Sherif R. Zaki ^aff002; Stuart T. Nichol ^aff001; Jessica R. Spengler ^aff001; Christina F. Spiropoulou ^aff001
Působiště autorů: Viral Special Pathogens Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America ^aff001; Infectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America ^aff002; Division of Pediatric Infectious Disease, University of Pittsburgh School of Medicine, UPMC Children’s Hospital of Pittsburgh, Center for Vaccine Research Pittsburgh, Pennsylvania, United States of America ^aff003; Department of Microbiology, Immunology and Infectious Diseases, Université Laval, Quebec City, Quebec, Canada ^aff004
Vyšlo v časopise: Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in IFNAR-/- mice. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008183
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008183

Souhrn

Crimean-Congo hemorrhagic fever virus (CCHFV, order Bunyavirales, family Nairoviridae, genus Orthonairovirus) is the tick-borne etiological agent of Crimean-Congo hemorrhagic fever (CCHF) in humans. Animals are generally susceptible to CCHFV infection but refractory to disease. Small animal models are limited to interferon-deficient mice, that develop acute fatal disease following infection. Here, using a ZsGreen1- (ZsG) expressing reporter virus (CCHFV/ZsG), we examine tissue tropism and dissemination of virus in interferon-α/β receptor knock-out (Ifnar^-/-) mice. We demonstrate that CCHFV/ZsG retains in vivo pathogenicity comparable to wild-type virus. Interestingly, despite high levels of viral RNA in all organs assessed, 2 distribution patterns of infection were observed by both fluorescence and immunohistochemistry (IHC), corresponding to the permissiveness of organ tissues. To further investigate viral dissemination and to temporally define cellular targets of CCHFV in vivo, mice were serially euthanized at different stages of disease. Flow cytometry was used to characterize CCHFV-associated alterations in hematopoietic cell populations and to classify infected cells in the blood, lymph node, spleen, and liver. ZsG signal indicated that mononuclear phagocytic cells in the lymphatic tissues were early targets of infection; in late-stage infection, overall, the highest levels of signal were detected in the liver, and ZsG was found in both antigen-presenting and lymphocyte cell populations.

Klíčová slova:

Cytokines – Flow cytometry – Immunostaining – Liver – Lymph nodes – Macrophages – Mouse models – Spleen

Zdroje

1. Bente DA, Forrester NL, Watts DM, McAuley AJ, Whitehouse CA, Bray M. Crimean-Congo hemorrhagic fever: history, epidemiology, pathogenesis, clinical syndrome and genetic diversity. Antiviral Res. 2013;100: 159–89. doi: 10.1016/j.antiviral.2013.07.006 23906741

2. Shepherd AJ, Leman PA, Swanepoel R. Viremia and antibody response of small African and laboratory animals to Crimean-Congo hemorrhagic fever virus infection. Am J Trop Med Hyg. 1989;40: 541–547. Available: http://www.ncbi.nlm.nih.gov/pubmed/2499205 doi: 10.4269/ajtmh.1989.40.541

3. Shepherd AJJ, Swanepoel R, Shepherd SPP, Leman PAA, Mathee O. Viraemic transmission of Crimean-Congo haemorrhagic fever virus to ticks. Epidemiol Infect. 1991;106: 373–82. doi: 10.1017/s0950268800048524 1902186

4. World Health Organization. Crimean-Congo haemorrhagic fever (CCHF) [Internet]. https://www.who.int/emergencies/diseases/crimean-congo-haemorrhagic-fever/en/

5. Bente DA, Alimonti JB, Shieh WW-J, Camus G, Stroher U, Zaki S, et al. Pathogenesis and Immune Response of Crimean-Congo Hemorrhagic Fever Virus in a STAT-1 Knockout Mouse Model. J Virol. 2010;84: 11089–11100. doi: 10.1128/JVI.01383-10 20739514

6. Bereczky S, Lindegren G, Karlberg H, Åkerström S, Klingström J, Mirazimi A, et al. Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. J Gen Virol. 2010;91: 1473–1477. doi: 10.1099/vir.0.019034-0 20164263

7. Zivcec M, Safronetz D, Scott D, Robertson S, Ebihara H, Feldmann H. Lethal Crimean-Congo hemorrhagic fever virus infection in interferon α/β receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy. J Infect Dis. 2013;207: 1909–21. doi: 10.1093/infdis/jit061 23417661

8. Spengler JR, Kelly Keating M, McElroy AK, Zivcec M, Coleman-McCray JD, Harmon JR, et al. Crimean-Congo Hemorrhagic Fever in Humanized Mice Reveals Glial Cells as Primary Targets of Neurological Infection. J Infect Dis. 2017;216: 1386–1397. doi: 10.1093/infdis/jix215 28482001

9. Haddock E, Feldmann F, Hawman DW, Zivcec M, Hanley PW, Saturday G, et al. A cynomolgus macaque model for Crimean-Congo haemorrhagic fever. Nat Microbiol. Springer US; 2018;3: 556–562. doi: 10.1038/s41564-018-0141-7 29632370

10. Lindquist ME, Zeng X, Altamura LA, Daye SP, Delp KL, Blancett C, et al. Exploring Crimean-Congo hemorrhagic fever virus-induced hepatic injury using antibody-mediated type I interferon blockade in mice. J Virol. 2018; JVI.01083-18. doi: 10.1128/JVI.01083-18 30111561

11. Welch SR, Scholte FEMM, Flint M, Chatterjee P, Nichol ST, Bergeron É, et al. Identification of 2’-deoxy-2’-fluorocytidine as a potent inhibitor of Crimean-Congo hemorrhagic fever virus replication using a recombinant fluorescent reporter virus. Antiviral Res. Elsevier; 2017;147: 91–99. doi: 10.1016/j.antiviral.2017.10.008

12. De Swart RL, Ludlow M, De Witte L, Yanagi Y, Van Amerongen G, McQuaid S, et al. Predominant infection of CD150+ lymphocytes and dendritic cells during measles virus infection of macaques. PLoS Pathog. 2007;3: 1771–1781. doi: 10.1371/journal.ppat.0030178 18020706

13. Marsh GA, Virtue ER, Smith I, Todd S, Arkinstall R, Frazer L, et al. Recombinant Hendra viruses expressing a reporter gene retain pathogenicity in ferrets. Virol J. 2013;10: 1–7.

14. Czakó R, Vogel L, Lamirande EW, Bock KW, Moore IN, Ellebedy AH, et al. In Vivo Imaging of Influenza Virus Infection in Immunized Mice. MBio. 2017;8: 1–13. doi: 10.1128/mBio.00714-17 28559489

15. Joubert JR, King JB, Rossouw DJ, Copper R. A nosocomial outbreak of Crimean-Congo haemorrhagic fever at Tygerberg Hospital. Part III. Clinical pathology and pathogenesis. S Afr Med J. 1985;68: 722–728. 3933128

16. Swanepoel R, Gill DEE, Shepherd AJJ, Leman PAA, Mynhardt JHH, Harvey S. The Clinical Pathology of Crimean-Congo Hemorrhagic Fever. Rev Infect Dis. 1989;11: 794–800. doi: 10.1093/clinids/11.Supplement_4.S794 2749111

17. Bastug A, Kayaaslan B, Kazancioglu S, Aslaner H, But A, Akinci E, et al. Crimean-congo hemorrhagic fever: Prognostic factors and the association of leukocyte counts with mortality. Jpn J Infect Dis. 2016;69: 51–55. doi: 10.7883/yoken.JJID.2014.566 26073733

18. Akinci E, Yilmaz M, Bodur H, Öngürü P, Bayazit FN, Erbay A, et al. Analysis of lymphocyte subgroups in Crimean-Congo hemorrhagic fever. Int J Infect Dis. 2009;13: 560–563. doi: 10.1016/j.ijid.2008.08.027 19112036

19. Yilmaz M, Aydin K, Akdogan E, Sucu N, Sonmez M, Omay SB, et al. Peripheral blood natural killer cells in Crimean-Congo hemorrhagic fever. J Clin Virol. 2008;42: 415–417. doi: 10.1016/j.jcv.2008.03.003 18434247

20. Geisbert TW, Jahrling PB. Exotic emerging viral diseases: progress and challenges. Nat Med. 2004;10: S110–21. doi: 10.1038/nm1142 15577929

21. Papa A, Bino S, Velo E, Harxhi A, Kota M, Antoniadis A. Cytokine levels in Crimean-Congo hemorrhagic fever. J Clin Virol. 2006;36: 272–276. doi: 10.1016/j.jcv.2006.04.007 16765637

22. Saksida A, Duh D, Wraber B, Dedushaj I, Ahmeti S, Avsic-Zupanc T, et al. Interacting roles of immune mechanisms and viral load in the pathogenesis of crimean-congo hemorrhagic fever. Clin Vaccine Immunol. 2010;17: 1086–1093. doi: 10.1128/CVI.00530-09 20484568

23. Connolly-Andersen A-M, Moll G, Andersson C, Akerström S, Karlberg H, Douagi I, et al. Crimean-Congo hemorrhagic fever virus activates endothelial cells. J Virol. 2011;85: 7766–74. doi: 10.1128/JVI.02469-10 21632768

24. Burt FJ, Swanepoel R, Shieh WJ, Smith JF, Leman P a, Greer PW, et al. Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in human tissues and implications for CCHF pathogenesis. Arch Pathol {&} Lab Med. 1997;121: 839–846. Available: http://www.ncbi.nlm.nih.gov/pubmed/9278612

25. Bergeron É, Zivcec M, Chakrabarti AK, Nichol ST, Albariño CG, Spiropoulou CF, et al. Recovery of Recombinant Crimean Congo Hemorrhagic Fever Virus Reveals a Function for Non-structural Glycoproteins Cleavage by Furin. PLoS Pathog. 2015;11: e1004879. doi: 10.1371/journal.ppat.1004879 25933376

26. Scholte FEMM, Zivcec M, Dzimianski J V., Deaton MK, Spengler JR, Welch SR, et al. Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease. Cell Rep. United States; 2017;20: 2396–2407. doi: 10.1016/j.celrep.2017.08.040 28877473

27. Scholte FEM, Hua BL, Spengler JR, Dzimianski JV., Coleman-McCray JD, Welch SR, et al. Stable Occupancy of the Crimean-Congo Hemorrhagic Fever Virus-Encoded Deubiquitinase Blocks Viral Infection. Ortiz CR, editor. MBio. 2019;10. doi: 10.1128/mBio.01065-19 31337717

28. Spengler JR, Welch SR, Scholte FEM, Coleman-McCray JD, Harmon JR, Nichol ST, et al. Heterologous protection against Crimean-Congo hemorrhagic fever in mice after a single dose of replicon particle vaccine. Antiviral Res. 2019;170: 104573. doi: 10.1016/j.antiviral.2019.104573 31377243

29. Scholte FEM, Spengler JR, Welch SR, Harmon JR, Coleman-McCray JD, Freitas BT, et al. Single-dose replicon particle vaccine provides complete protection against Crimean-Congo hemorrhagic fever virus in mice. Emerg Microbes Infect. 2019;8: 575–578. doi: 10.1080/22221751.2019.1601030 30947619

30. Mate SE, Kugelman JR, Nyenswah TG, Ladner JT, Wiley MR, Cordier-Lassalle T, et al. Molecular Evidence of Sexual Transmission of Ebola Virus. N Engl J Med. 2015;373: 2448–2454. doi: 10.1056/NEJMoa1509773 26465384

31. Diallo B, Sissoko D, Loman NJ, Bah HA, Bah H, Worrell MC, et al. Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days. Clin Infect Dis. 2016;63: 1353–1356. doi: 10.1093/cid/ciw601 27585800

32. Sow MS, Etard J-F, Baize S, Magassouba N, Faye O, Msellati P, et al. New Evidence of Long-lasting Persistence of Ebola Virus Genetic Material in Semen of Survivors. J Infect Dis. 2016;214: 1475–1476. doi: 10.1093/infdis/jiw078 27142204

33. Perry DL, Huzella LM, Bernbaum JG, Holbrook MR, Jahrling PB, Hagen KR, et al. Ebola Virus Localization in the Macaque Reproductive Tract during Acute Ebola Virus Disease. Am J Pathol. Elsevier; 2018;188: 550–558. doi: 10.1016/j.ajpath.2017.11.004 29429544

34. Pshenichnaya NY, Leblebicioglu H, Bozkurt I, Sannikova IV, Abuova GN, Zhuravlev AS, et al. Crimean-Congo hemorrhagic fever in pregnancy: A systematic review and case series from Russia, Kazakhstan and Turkey. Int J Infect Dis. International Society for Infectious Diseases; 2017;58: 58–64. doi: 10.1016/j.ijid.2017.02.019 28249811

35. Gozel MG, Elaldi N, Engin A, Akkar OB, Bolat F, Celik C. Favorable outcomes for both mother and baby are possible in pregnant women with Crimean-Congo hemorrhagic fever disease: a case series and literature review. Gynecol Obstet Invest. 2014;77: 266–271. doi: 10.1159/000360699 24732981

36. Ünlüsoy-Aksu A, Havali C, Tapisiz A, Aktaş F, Ezgu F. Crimean-congo haemorrhagic fever in pregnancy and in newborn: a case with a unique clinical course. J Obstet Gynaecol. 2014;34: 360. doi: 10.3109/01443615.2013.874984 24484082

37. Ergonul O, Celikbas A, Yildirim U, Zenciroglu A, Erdogan D, Ziraman I, et al. Pregnancy and Crimean-Congo haemorrhagic fever. Clin Microbiol Infect. European Society of Clinical Infectious Diseases; 2010;16: 647–650. doi: 10.1111/j.1469-0691.2009.02905.x 19778302

38. Dizbay M, Aktas F, Gaygisiz U, Ozger HS, Ozdemir K. Crimean-Congo hemorrhagic fever treated with ribavirin in a pregnant woman. J Infect. Elsevier Ltd; 2009;59: 281–283. doi: 10.1016/j.jinf.2009.08.004 19698746

39. Aydemir O, Erdeve O, Oguz SS, Dilmen U. A healthy newborn born to a mother with Crimean-Congo hemorrhagic fever: is there protection from transplacental transmission? Int J Infect Dis. 2010;14: e450. doi: 10.1016/j.ijid.2009.07.001 19695920

40. Pshenichnaya NY, Sydenko IS, Klinovaya EP, Romanova EB, Zhuravlev AS. Possible sexual transmission of Crimean-Congo hemorrhagic fever. Int J Infect Dis. International Society for Infectious Diseases; 2016;45: 109–111. doi: 10.1016/j.ijid.2016.02.1008 26972040

41. Bray M, Geisbert TW. Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. Int J Biochem {&} Cell Biol. 2005;37: 1560–1566. doi: 10.1016/j.biocel.2005.02.018 15896665

42. Baize S, Kaplon J, Faure C, Pannetier D, Georges-Courbot M-C, Deubel V. Lassa Virus Infection of Human Dendritic Cells and Macrophages Is Productive but Fails to Activate Cells. J Immunol. 2004;172: 2861–2869. doi: 10.4049/jimmunol.172.5.2861 14978087

43. Olejnik J, Ryabchikova E, Corley RB, Mühlberger E. Intracellular events and cell fate in filovirus infection. Viruses. 2011;3: 1501–31. doi: 10.3390/v3081501 21927676

44. Yun NE, Walker DH. Pathogenesis of lassa fever. Viruses. 2012;4: 2031–2048. doi: 10.3390/v4102031 23202452

45. 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. J Virol. 2013;87: 3801–3814. doi: 10.1128/JVI.02695-12 23345511

46. Rodriguez SE, McAuley AJ, Gargili A, Bente DA. Interactions of human dermal dendritic cells and langerhans cells treated with hyalomma tick saliva with crimean-congo hemorrhagic fever virus. Viruses. 2018;10: 1–12. doi: 10.3390/v10070381 30036960

47. Peyrefitte CN, Perret M, Garcia S, Rodrigues R, Bagnaud A, Lacote S, et al. Differential activation profiles of Crimean-Congo hemorrhagic fever virus- and Dugbe virus-infected antigen-presenting cells. J Gen Virol. 2010;91: 189–198. doi: 10.1099/vir.0.015701-0

48. Dikopoulos N, Bertoletti A, Kröger A, Hauser H, Schirmbeck R, Reimann J. Type I IFN negatively regulates CD8+ T cell responses through IL-10-producing CD4+ T regulatory 1 cells. J Immunol. 2005;174: 99–109. doi: 10.4049/jimmunol.174.1.99 15611232

49. Mestas J, Hughes CCW. Of Mice and Not Men: Differences between Mouse and Human Immunology. J Immunol. 2004;172: 2731–2738. doi: 10.4049/jimmunol.172.5.2731 14978070

50. Papa A, Tsergouli K, Çağlayık DY, Bino S, Como N, Uyar Y, et al. Cytokines as Biomarkers of Crimean-Congo Hemorrhagic Fever. J Med Virol. 2016;88: 21–27. doi: 10.1002/jmv.24312 26118413

51. Papa A, Yagci Caglayık D, Christova I, Tsergouli K, Korukluoglu G, Uyar Y. Crimean-Congo Hemorrhagic Fever: CXCL10 Correlates With the Viral Load. J Med Virol. 2015;87: 899–903. doi: 10.1002/jmv.24141 25648521

52. Ergönül Ö, Şeref C, Eren Ş, Çelikbaş A, Baykam N, Dokuzoğuz B, et al. Cytokine response in crimean-congo hemorrhagic fever virus infection. J Med Virol. 2017;89: 1707–1713. doi: 10.1002/jmv.24864 28547808

53. Cevik M a, Erbay A, Bodur H, Gülderen E, Baştuğ A, Kubar A, et al. Clinical and laboratory features of Crimean-Congo hemorrhagic fever: predictors of fatality. Int J Infect Dis. 2008;12: 374–379. doi: 10.1016/j.ijid.2007.09.010 18063402

54. Eren SH, Zengin S, Büyüktuna SA, Gözel MG. Clinical severity in forecasting platelet to lymphocyte ratio in Crimean-Congo hemorrhagic fever patients. J Med Microbiol. 2016;65: 1100–1104. doi: 10.1099/jmm.0.000330 27501696

55. Hoogstraal H. The epidemiology of tick-borne Crimean-Congo hemorrhagic fever in Asia, Europe, and Africa. J Med Entomol. 1979;15: 307–417. Available: http://www.ncbi.nlm.nih.gov/pubmed/113533 doi: 10.1093/jmedent/15.4.307

56. Ergönül Ö. Crimean-Congo haemorrhagic fever. Lancet Infect Dis. 2006;6: 203–214. doi: 10.1016/S1473-3099(06)70435-2 16554245

57. Hawman DW, Haddock E, Meade-White K, Williamson B, Hanley PW, Rosenke K, et al. Favipiravir (T-705) but not ribavirin is effective against two distinct strains of Crimean-Congo hemorrhagic fever virus in mice. Antiviral Res. 2018;157: 18–26. doi: 10.1016/j.antiviral.2018.06.013 29936152

58. Hawman DW, Meade-White K, Haddock E, Habib R, Scott D, Thomas T, et al. A Crimean-Congo Hemorrhagic Fever Mouse Model Recapitulating Human Convalescence. J Virol. 2019; doi: 10.1128/JVI.00554-19 31292241

59. Ergonul O, Tuncbilek S, Baykam N, Celikbas A, Dokuzoguz B. Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever. J Infect Dis. 2006;193: 941–944. doi: 10.1086/500836 16518755

60. Papa A, Drosten C, Bino S, Papadimitriou Ε, Panning M, Velo E, et al. Viral Load and Crimean-Congo Hemorrhagic Fever. Emerg Infect Dis. 2007;13: 805–806. doi: 10.3201/eid1305.061588 18044055

61. Ergonul O, Celikbas a, Baykam N, Eren S, Dokuzoguz B. Analysis of risk-factors among patients with Crimean-Congo haemorrhagic fever virus infection: severity criteria revisited. Clin Microbiol Infect. 2006;12: 551–554. doi: 10.1111/j.1469-0691.2006.01445.x 16700704

62. National Research Council of the National Academies. Guide for the Care and Use of Laboratory Animals: Eight Edition. 8th ed. Washington, D.C.: The National Academy Press; 2011.

63. Reed LJ, Muench H. A simple method for estimating fifty percent endpoints. Am J Epidemiol. 1938;27: 493–497. Available: https://doi.org/10.1093/oxfordjournals.aje.a118408