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Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children


Primary infection with EBV, a common human herpesvirus, is typically asymptomatic in childhood but, if occurring in adolescence or later, often presents as AIM. This febrile illness is characterised by high virus loads in the blood and an exaggerated EBV-specific CD8+ T-cell response that pushes total CD8+ T-cell numbers well above normal levels. By contrast, very little is known about the events of asymptomatic primary infection. We therefore studied young Gambian children at an age at which many acquire EBV, monitoring them over six months for evidence of EBV infection by virus load in the blood, virus-specific IgM and IgG antibody status, and virus-specific CD8+ T-cell responses. Focusing on IgM-positive children with very recent EBV infection but no history of symptoms, we found that they carried a virus load equivalent to that seen in AIM patients and also mounted a classical virus-specific CD8+ T-cell response. However, that response, though it could occupy at least 15% of the circulating CD8+ T-cell pool, occurred without the huge global expansion of CD8 numbers seen in AIM. This work reinforces the idea that the host’s exaggerated CD8+ T-cell response, rather than the virus load per se, leads to the symptoms of AIM.


Vyšlo v časopise: Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004746
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004746

Souhrn

Primary infection with EBV, a common human herpesvirus, is typically asymptomatic in childhood but, if occurring in adolescence or later, often presents as AIM. This febrile illness is characterised by high virus loads in the blood and an exaggerated EBV-specific CD8+ T-cell response that pushes total CD8+ T-cell numbers well above normal levels. By contrast, very little is known about the events of asymptomatic primary infection. We therefore studied young Gambian children at an age at which many acquire EBV, monitoring them over six months for evidence of EBV infection by virus load in the blood, virus-specific IgM and IgG antibody status, and virus-specific CD8+ T-cell responses. Focusing on IgM-positive children with very recent EBV infection but no history of symptoms, we found that they carried a virus load equivalent to that seen in AIM patients and also mounted a classical virus-specific CD8+ T-cell response. However, that response, though it could occupy at least 15% of the circulating CD8+ T-cell pool, occurred without the huge global expansion of CD8 numbers seen in AIM. This work reinforces the idea that the host’s exaggerated CD8+ T-cell response, rather than the virus load per se, leads to the symptoms of AIM.


Zdroje

1. Biggar RJ, Henle G, Bocker J, Lennette ET, Fleisher G, et al. (1978) Primary Epstein-Barr virus infections in African infants. II. Clinical and serological observations during seroconversion. Int J Cancer 22: 244–250. 212370

2. Hislop AD, Taylor GS, Sauce D, Rickinson AB (2007) Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu Rev Immunol 25: 587–617. 17378764

3. Balfour HH Jr., Odumade OA, Schmeling DO, Mullan BD, Ed JA, et al. (2013) Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary epstein-barr virus infection in university students. J Infect Dis 207: 80–88. doi: 10.1093/infdis/jis646 23100562

4. Crawford DH, Macsween KF, Higgins CD, Thomas R, McAulay K, et al. (2006) A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis 43: 276–282. 16804839

5. Sumaya CV, Henle W, Henle G, Smith MH, LeBlanc D (1975) Seroepidemiologic study of Epstein-Barr virus infections in a rural community. J Infect Dis 131: 403–408. 163869

6. Callan MF, Steven N, Krausa P, Wilson JD, Moss PA, et al. (1996) Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat Med 2: 906–911. 8705861

7. Callan MF, Tan L, Annels N, Ogg GS, Wilson JD, et al. (1998) Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J Exp Med 187: 1395–1402. 9565632

8. Hislop AD, Annels NE, Gudgeon NH, Leese AM, Rickinson AB (2002) Epitope-specific evolution of human CD8(+) T cell responses from primary to persistent phases of Epstein-Barr virus infection. J Exp Med 195: 893–905. 11927633

9. Hislop AD, Gudgeon NH, Callan MF, Fazou C, Hasegawa H, et al. (2001) EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function. J Immunol 167: 2019–2029. 11489984

10. Hislop AD, Kuo M, Drake-Lee AB, Akbar AN, Bergler W, et al. (2005) Tonsillar homing of Epstein-Barr virus-specific CD8+ T cells and the virus-host balance. J Clin Invest 115: 2546–2555. 16110323

11. Woodberry T, Suscovich TJ, Henry LM, Davis JK, Frahm N, et al. (2005) Differential targeting and shifts in the immunodominance of Epstein-Barr virus—specific CD8 and CD4 T cell responses during acute and persistent infection. J Infect Dis 192: 1513–1524. 16206065

12. Odumade OA, Knight JA, Schmeling DO, Masopust D, Balfour HH Jr., et al. (2012) Primary Epstein-Barr virus infection does not erode preexisting CD8(+) T cell memory in humans. J Exp Med 209: 471–478. doi: 10.1084/jem.20112401 22393125

13. Long HM, Chagoury OL, Leese AM, Ryan GB, James E, et al. (2013) MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response. J Exp Med 210: 933–949. doi: 10.1084/jem.20121437 23569328

14. Callan MF, Fazou C, Yang H, Rostron T, Poon K, et al. (2000) CD8(+) T-cell selection, function, and death in the primary immune response in vivo. J Clin Invest 106: 1251–1261. 11086026

15. Steven NM, Annels NE, Kumar A, Leese AM, Kurilla MG, et al. (1997) Immediate early and early lytic cycle proteins are frequent targets of the Epstein-Barr virus-induced cytotoxic T cell response. J Exp Med 185: 1605–1617. 9151898

16. Steven NM, Leese AM, Annels NE, Lee SP, Rickinson AB (1996) Epitope focusing in the primary cytotoxic T cell response to Epstein-Barr virus and its relationship to T cell memory. J Exp Med 184: 1801–1813. 8920868

17. Catalina MD, Sullivan JL, Bak KR, Luzuriaga K (2001) Differential evolution and stability of epitope-specific CD8(+) T cell responses in EBV infection. J Immunol 167: 4450–4457. 11591771

18. Chijioke O, Muller A, Feederle R, Barros MH, Krieg C, et al. (2013) Human natural killer cells prevent infectious mononucleosis features by targeting lytic Epstein-Barr virus infection. Cell Rep 5: 1489–1498. doi: 10.1016/j.celrep.2013.11.041 24360958

19. Clute SC, Watkin LB, Cornberg M, Naumov YN, Sullivan JL, et al. (2005) Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis. J Clin Invest 115: 3602–3612. 16308574

20. Hwang AE, Hamilton AS, Cockburn MG, Ambinder R, Zadnick J, et al. (2012) Evidence of genetic susceptibility to infectious mononucleosis: a twin study. Epidemiol Infect 140: 2089–2095. 22152594

21. McAulay KA, Higgins CD, Macsween KF, Lake A, Jarrett RF, et al. (2007) HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest 117: 3042–3048. 17909631

22. Rostgaard K, Wohlfahrt J, Hjalgrim H (2014) A genetic basis for infectious mononucleosis: evidence from a family study of hospitalized cases in denmark. Clin Infect Dis 58: 1684–1689. doi: 10.1093/cid/ciu204 24696238

23. Helminen M, Lahdenpohja N, Hurme M (1999) Polymorphism of the interleukin-10 gene is associated with susceptibility to Epstein-Barr virus infection. J Infect Dis 180: 496–499. 10395868

24. Thacker EL, Mirzaei F, Ascherio A (2006) Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis. Ann Neurol 59: 499–503. 16502434

25. Hjalgrim H, Askling J, Rostgaard K, Hamilton-Dutoit S, Frisch M, et al. (2003) Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 349: 1324–1332. 14523140

26. Silins SL, Sherritt MA, Silleri JM, Cross SM, Elliott SL, et al. (2001) Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood 98: 3739–3744. 11739180

27. Fleisher G, Henle W, Henle G, Lennette ET, Biggar RJ (1979) Primary infection with Epstein-Barr virus in infants in the United States: clinical and serologic observations. J Infect Dis 139: 553–558. 220340

28. Tamaki H, Beaulieu BL, Somasundaran M, Sullivan JL (1995) Major histocompatibility complex class I-restricted cytotoxic T lymphocyte responses to Epstein-Barr virus in children. J Infect Dis 172: 739–746. 7658067

29. Holder B, Miles DJ, Kaye S, Crozier S, Mohammed NI, et al. (2010) Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants. PLoS One 5: e14013. doi: 10.1371/journal.pone.0014013 21103338

30. Slyker JA, Casper C, Tapia K, Richardson B, Bunts L, et al. (2013) Clinical and virologic manifestations of primary Epstein-Barr virus (EBV) infection in Kenyan infants born to HIV-infected women. J Infect Dis 207: 1798–1806. doi: 10.1093/infdis/jit093 23493724

31. de Martino M, Rossi ME, Azzari C, Gelli MG, Galli L, et al. (1998) Different meaning of CD38 molecule expression on CD4+ and CD8+ cells of children perinatally infected with human immunodeficiency virus type 1 infection surviving longer than five years. Pediatr Res 43: 752–758. 9621984

32. Njie R, Bell AI, Jia H, Croom-Carter D, Chaganti S, et al. (2009) The effects of acute malaria on Epstein-Barr virus (EBV) load and EBV-specific T cell immunity in Gambian children. J Infect Dis 199: 31–38. doi: 10.1086/594373 19032105

33. Moormann AM, Chelimo K, Sumba OP, Lutzke ML, Ploutz-Snyder R, et al. (2005) Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children. J Infect Dis 191: 1233–1238. 15776368

34. Piriou E, Asito AS, Sumba PO, Fiore N, Middeldorp JM, et al. (2012) Early age at time of primary Epstein-Barr virus infection results in poorly controlled viral infection in infants from Western Kenya: clues to the etiology of endemic Burkitt lymphoma. J Infect Dis 205: 906–913. doi: 10.1093/infdis/jir872 22301635

35. Donati D, Zhang LP, Chene A, Chen Q, Flick K, et al. (2004) Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infect Immun 72: 5412–5418. 15322039

36. Chattopadhyay PK, Chelimo K, Embury PB, Mulama DH, Sumba PO, et al. (2013) Holoendemic Malaria Exposure Is Associated with Altered Epstein-Barr Virus-Specific CD8+ T-Cell Differentiation. J Virol 87: 1779–1788. doi: 10.1128/JVI.02158-12 23175378

37. Ceesay SJ, Casals-Pascual C, Erskine J, Anya SE, Duah NO, et al. (2008) Changes in malaria indices between 1999 and 2007 in The Gambia: a retrospective analysis. Lancet 372: 1545–1554. doi: 10.1016/S0140-6736(08)61654-2 18984187

38. Ceesay SJ, Casals-Pascual C, Nwakanma DC, Walther M, Gomez-Escobar N, et al. (2010) Continued decline of malaria in The Gambia with implications for elimination. PLoS One 5: e12242. doi: 10.1371/journal.pone.0012242 20805878

39. Condon LM, Cederberg LE, Rabinovitch MD, Liebo RV, Go JC, et al. (2014) Age-Specific Prevalence of Epstein-Barr Virus Infection Among Minnesota Children: Effects of Race/Ethnicity and Family Environment. Clin Infect Dis.

40. Balfour HH Jr., Holman CJ, Hokanson KM, Lelonek MM, Giesbrecht JE, et al. (2005) A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J Infect Dis 192: 1505–1512. 16206064

41. Dunne PJ, Faint JM, Gudgeon NH, Fletcher JM, Plunkett FJ, et al. (2002) Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. Blood 100: 933–940. 12130505

42. Tamaru Y, Miyawaki T, Iwai K, Tsuji T, Nibu R, et al. (1993) Absence of bcl-2 expression by activated CD45RO+ T lymphocytes in acute infectious mononucleosis supporting their susceptibility to programmed cell death. Blood 82: 521–527. 8329707

43. Williams H, McAulay K, Macsween KF, Gallacher NJ, Higgins CD, et al. (2005) The immune response to primary EBV infection: a role for natural killer cells. Br J Haematol 129: 266–274. 15813855

44. Kollmann TR, Levy O, Montgomery RR, Goriely S (2012) Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37: 771–783. doi: 10.1016/j.immuni.2012.10.014 23159225

45. Horwitz CA, Henle W, Henle G, Goldfarb M, Kubic P, et al. (1981) Clinical and laboratory evaluation of infants and children with Epstein-Barr virus-induced infectious mononucleosis: report of 32 patients (aged 10–48 months). Blood 57: 933–938. 6260269

46. Junying J, Herrmann K, Davies G, Lissauer D, Bell A, et al. (2003) Absence of Epstein-Barr virus DNA in the tumor cells of European hepatocellular carcinoma. Virology 306: 236–243. 12642097

47. Yao QY, Rickinson AB, Epstein MA (1985) A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals. Int J Cancer 35: 35–42. 2981780

48. Yao QY, Rickinson AB, Gaston JS, Epstein MA (1985) In vitro analysis of the Epstein-Barr virus: host balance in long-term renal allograft recipients. Int J Cancer 35: 43–49. 2981781

49. Macsween KF, Higgins CD, McAulay KA, Williams H, Harrison N, et al. (2010) Infectious mononucleosis in university students in the United kingdom: evaluation of the clinical features and consequences of the disease. Clin Infect Dis 50: 699–706. doi: 10.1086/650456 20121570

50. Henle G, Henle W (1966) Immunofluorescence in cells derived from Burkitt's lymphoma. J Bacteriol 91: 1248–1256. 4160230

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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