Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity

English version České info

Nearly 1 million deaths occur annually as a result of complications associated with P. falciparum infection, with children younger than 5 being the most susceptible age group. Earlier studies have demonstrated that children co-infected with P. falciparum and Epstein-Barr virus (EBV) have impaired immune responses to control EBV, and this can result in the development of a jaw tumor called endemic Burkitt’s lymphoma (eBL). It is not known if there is any impact of acute EBV infection on the generation of anti-malarial immunity. We have used mouse models of EBV [murine gammaherpesvirus 68 (MHV68)] and malaria (P. yoelii XNL) to demonstrate that acute gammaherpesvirus infection can impair the generation of antibodies that control Plasmodium parasitemia, in turn causing a non-lethal P. yoelii XNL infection to become lethal. We identify a critical role for the MHV68 M2 protein in mediating the suppressive effect of acute MHV68 infection on the generation of humoral immunity to a secondary malaria infection. This work demonstrates that gammaherpesvirus infections can suppress the generation of an effective anti-malaria immune response and suggests that acute EBV infection should be investigated as a risk factor for the development of severe malaria in young children.

Vyšlo v časopise: Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity. PLoS Pathog 11(5): e32767. doi:10.1371/journal.ppat.1004858
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004858

Souhrn

Zdroje

1. World Health Organization. Global Malaria Programme. (2012) World malaria report 2012. Geneva: World Health Organization. xxxiv, 249 p. p.

2. Gupta S, Snow RW, Donnelly CA, Marsh K, Newbold C (1999) Immunity to non-cerebral severe malaria is acquired after one or two infections. Nat Med 5 : 340–343. 10086393

3. Miller LH, Baruch DI, Marsh K, Doumbo OK (2002) The pathogenic basis of malaria. Nature 415 : 673–679. 11832955

4. Greenwood B, Marsh K, Snow R (1991) Why do some African children develop severe malaria? Parasitol Today 7 : 277–281. 15463389

5. Speck SH, Ganem D (2010) Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe 8 : 100–115. doi: 10.1016/j.chom.2010.06.014 20638646

6. 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

7. Rochford R, Cannon MJ, Moormann AM (2005) Endemic Burkitt's lymphoma: a polymicrobial disease? Nat Rev Microbiol 3 : 182–187. 15685227

8. Whittle HC, Brown J, Marsh K, Greenwood BM, Seidelin P, et al. (1984) T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. Nature 312 : 449–450. 6095104

9. 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

10. Moormann AM, Chelimo K, Sumba PO, Tisch DJ, Rochford R, et al. (2007) Exposure to holoendemic malaria results in suppression of Epstein-Barr virus-specific T cell immunosurveillance in Kenyan children. J Infect Dis 195 : 799–808. 17299709

11. Moormann AM, Heller KN, Chelimo K, Embury P, Ploutz-Snyder R, et al. (2009) Children with endemic Burkitt lymphoma are deficient in EBNA1-specific IFN-gamma T cell responses. Int J Cancer 124 : 1721–1726. doi: 10.1002/ijc.24014 19089927

12. Cohen S, Mc GI, Carrington S (1961) Gamma-globulin and acquired immunity to human malaria. Nature 192 : 733–737. 13880318

13. Sabchareon A, Burnouf T, Ouattara D, Attanath P, Bouharoun-Tayoun H, et al. (1991) Parasitologic and clinical human response to immunoglobulin administration in falciparum malaria. Am J Trop Med Hyg 45 : 297–308. 1928564

14. Osier FH, Fegan G, Polley SD, Murungi L, Verra F, et al. (2008) Breadth and magnitude of antibody responses to multiple Plasmodium falciparum merozoite antigens are associated with protection from clinical malaria. Infect Immun 76 : 2240–2248. doi: 10.1128/IAI.01585-07 18316390

15. Rono J, Osier FH, Olsson D, Montgomery S, Mhoja L, et al. (2013) Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria. Clin Infect Dis 57 : 1409–1416. doi: 10.1093/cid/cit556 23983244

16. Rovira-Vallbona E, Moncunill G, Bassat Q, Aguilar R, Machevo S, et al. (2012) Low antibodies against Plasmodium falciparum and imbalanced pro-inflammatory cytokines are associated with severe malaria in Mozambican children: a case-control study. Malar J 11 : 181. doi: 10.1186/1475-2875-11-181 22646809

17. Dobano C, Rogerson SJ, Mackinnon MJ, Cavanagh DR, Taylor TE, et al. (2008) Differential antibody responses to Plasmodium falciparum merozoite proteins in Malawian children with severe malaria. J Infect Dis 197 : 766–774. doi: 10.1086/527490 18260767

18. Henle G, Henle W (1970) Observations on childhood infections with the Epstein-Barr virus. J Infect Dis 121 : 303–310. 4313278

19. Bowen TJ, Wedgwood RJ, Ochs HD, Henle W (1983) Transient immunodeficiency during asymptomatic Epstein-Barr virus infection. Pediatrics 71 : 964–967. 6304613

20. Junker AK, Ochs HD, Clark EA, Puterman ML, Wedgwood RJ (1986) Transient immune deficiency in patients with acute Epstein-Barr virus infection. Clin Immunol Immunopathol 40 : 436–446. 3015461

21. Provisor AJ, Iacuone JJ, Chilcote RR, Neiburger RG, Crussi FG, et al. (1975) Acquired agammaglobulinemia after a life threatening illness with clinical and laboratory features of Infectious Mononucleosis in three related male children. The New England Journal of Medicine 293 : 62–65. 165416

22. Getahun A, Smith MJ, Kogut I, van Dyk LF, Cambier JC (2012) Retention of anergy and inhibition of antibody responses during acute gamma herpesvirus 68 infection. J Immunol 189 : 2965–2974. doi: 10.4049/jimmunol.1201407 22904300

23. van der Heyde HC, Huszar D, Woodhouse C, Manning DD, Weidanz WP (1994) The resolution of acute malaria in a definitive model of B cell deficiency, the JHD mouse. J Immunol 152 : 4557–4562. 8157969

24. Haque A, Rachinel N, Quddus MR, Haque S, Kasper LH, et al. (2004) Co-infection of malaria and gamma-herpesvirus: exacerbated lung inflammation or cross-protection depends on the stage of viral infection. Clin Exp Immunol 138 : 396–404. 15544614

25. Weck KE, Kim SS, Virgin HI, Speck SH (1999) B cells regulate murine gammaherpesvirus 68 latency. J Virol 73 : 4651–4661. 10233924

26. Grun JL, Weidanz WP (1983) Antibody-independent immunity to reinfection malaria in B-cell-deficient mice. Infect Immun 41 : 1197–1204. 6350181

27. Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29 : 621–663. doi: 10.1146/annurev-immunol-031210-101400 21314428

28. Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6 : 353–360. 15785761

29. Couper KN, Blount DG, Wilson MS, Hafalla JC, Belkaid Y, et al. (2008) IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLoS Pathog 4: e1000004. doi: 10.1371/journal.ppat.1000004 18401464

30. Rasheed MA, Latner DR, Aubert RD, Gourley T, Spolski R, et al. (2013) Interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells. J Virol 87 : 7737–7746. doi: 10.1128/JVI.00063-13 23637417

31. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26 : 677–704. doi: 10.1146/annurev.immunol.26.021607.090331 18173375

32. Liang X, Collins CM, Mendel JB, Iwakoshi NN, Speck SH (2009) Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLoS Pathog 5: e1000677. doi: 10.1371/journal.ppat.1000677 19956661

33. Siegel AM, Herskowitz JH, Speck SH (2008) The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. PLoS Pathog 4: e1000039. doi: 10.1371/journal.ppat.1000039 18389062

34. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19 : 683–765. 11244051

35. de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, et al. (1991) Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 174 : 915–924. 1655948

36. Jacoby MA, Virgin HWt, Speck SH (2002) Disruption of the M2 gene of murine gammaherpesvirus 68 alters splenic latency following intranasal, but not intraperitoneal, inoculation. J Virol 76 : 1790–1801. 11799175

37. Rangaswamy US, Speck SH (2014) Murine Gammaherpesvirus M2 Protein Induction of IRF4 via the NFAT Pathway Leads to IL-10 Expression in B Cells. PLoS Pathog 10: e1003858. doi: 10.1371/journal.ppat.1003858 24391506

38. Biggar RJ, Henle W, Fleisher G, Bocker J, Lennette ET, et al. (1978) Primary Epstein-Barr virus infections in African infants. I. Decline of maternal antibodies and time of infection. Int J Cancer 22 : 239–243. 212369

39. Moss DJ, Burrows SR, Castelino DJ, Kane RG, Pope JH, et al. (1983) A comparison of Epstein-Barr virus-specific T-cell immunity in malaria-endemic and-nonendemic regions of Papua New Guinea. Int J Cancer 31 : 727–732. 6305850

40. Whittle HC, Brown J, Marsh K, Blackman M, Jobe O, et al. (1990) The effects of Plasmodium falciparum malaria on immune control of B lymphocytes in Gambian children. Clin Exp Immunol 80 : 213–218. 1972671

41. Lam KM, Syed N, Whittle H, Crawford DH (1991) Circulating Epstein-Barr virus-carrying B cells in acute malaria. Lancet 337 : 876–878. 1672968

42. Chene A, Nylen S, Donati D, Bejarano MT, Kironde F, et al. (2011) Effect of acute Plasmodium falciparum malaria on reactivation and shedding of the eight human herpes viruses. PLoS One 6: e26266. doi: 10.1371/journal.pone.0026266 22039454

43. 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

44. Wedderburn N, Davies DR, Mitchell GH, Desgranges C, de The G (1988) Glomerulonephritis in common marmosets infected with Plasmodium brasilianum and Epstein-Barr virus. J Infect Dis 158 : 789–794. 2844917

45. Leoratti FM, Durlacher RR, Lacerda MV, Alecrim MG, Ferreira AW, et al. (2008) Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria. Malar J 7 : 186. doi: 10.1186/1475-2875-7-186 18816374

46. Su Z, Stevenson MM (2000) Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection. Infect Immun 68 : 4399–4406. 10899836

47. De Souza JB, Williamson KH, Otani T, Playfair JH (1997) Early gamma interferon responses in lethal and nonlethal murine blood-stage malaria. Infect Immun 65 : 1593–1598. 9125535

48. Langhorne J, Mombaerts P, Tonegawa S (1995) alpha beta and gamma delta T cells in the immune response to the erythrocytic stages of malaria in mice. Int Immunol 7 : 1005–1011. 7577794

49. Sayles PC, Rakhmilevich L (1996) Exacerbation of Plasmodium chabaudi malaria in mice by depletion of TCR alpha beta+ T cells, but not TCR gamma delta+ T cells. Immunology 87 : 29–33. 8666432

50. Nutt SL, Tarlinton DM (2011) Germinal center B and follicular helper T cells: siblings, cousins or just good friends? Nat Immunol 12 : 472–477. 21739669

51. Vinuesa CG, Linterman MA, Goodnow CC, Randall KL (2010) T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol Rev 237 : 72–89. doi: 10.1111/j.1600-065X.2010.00937.x 20727030

52. Cubas RA, Mudd JC, Savoye AL, Perreau M, van Grevenynghe J, et al. (2013) Inadequate T follicular cell help impairs B cell immunity during HIV infection. Nat Med 19 : 494–499. doi: 10.1038/nm.3109 23475201

53. Paludan SR, Bowie AG, Horan KA, Fitzgerald KA (2011) Recognition of herpesviruses by the innate immune system. Nat Rev Immunol 11 : 143–154. doi: 10.1038/nri2937 21267015

54. Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, et al. (1999) Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 286 : 300–303. 10514374

55. Caldwell RG, Wilson JB, Anderson SJ, Longnecker R (1998) Epstein-Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9 : 405–411. 9768760

56. Pires de Miranda M, Alenquer M, Marques S, Rodrigues L, Lopes F, et al. (2008) The Gammaherpesvirus m2 protein manipulates the Fyn/Vav pathway through a multidocking mechanism of assembly. PLoS One 3: e1654. doi: 10.1371/journal.pone.0001654 18301737

57. Pires de Miranda M, Lopes FB, McVey CE, Bustelo XR, Simas JP (2013) Role of Src homology domain binding in signaling complexes assembled by the murid gamma-herpesvirus M2 protein. J Biol Chem 288 : 3858–3870. doi: 10.1074/jbc.M112.439810 23258536

58. Hausler M, Sellhaus B, Scheithauer S, Engler M, Alberg E, et al. (2005) Murine gammaherpesvirus-68 infection of mice: A new model for human cerebral Epstein-Barr virus infection. Ann Neurol 57 : 600–603. 15786475

59. Hausler M, Sellhaus B, Scheithauer S, Gaida B, Kuropka S, et al. (2007) Myocarditis in newborn wild-type BALB/c mice infected with the murine gamma herpesvirus MHV-68. Cardiovasc Res 76 : 323–330. 17658501

60. Graham AL, Lamb TJ, Read AF, Allen JE (2005) Malaria-filaria coinfection in mice makes malarial disease more severe unless filarial infection achieves patency. J Infect Dis 191 : 410–421. 15633101

61. Brooker S, Akhwale W, Pullan R, Estambale B, Clarke SE, et al. (2007) Epidemiology of plasmodium-helminth co-infection in Africa: populations at risk, potential impact on anemia, and prospects for combining control. Am J Trop Med Hyg 77 : 88–98. 18165479

62. Hasang W, Dembo EG, Wijesinghe R, Molyneux ME, Kublin JG, et al. (2014) HIV-1 infection and antibodies to Plasmodium falciparum in adults. J Infect Dis 210 : 1407–1414. doi: 10.1093/infdis/jiu262 24795481

63. Thursz MR, Kwiatkowski D, Torok ME, Allsopp CE, Greenwood BM, et al. (1995) Association of hepatitis B surface antigen carriage with severe malaria in Gambian children. Nat Med 1 : 374–375. 7585070

64. Berkley JA, Bejon P, Mwangi T, Gwer S, Maitland K, et al. (2009) HIV infection, malnutrition, and invasive bacterial infection among children with severe malaria. Clin Infect Dis 49 : 336–343. doi: 10.1086/600299 19548833

65. Otieno RO, Ouma C, Ong'echa JM, Keller CC, Were T, et al. (2006) Increased severe anemia in HIV-1-exposed and HIV-1-positive infants and children during acute malaria. AIDS 20 : 275–280. 16511422

66. Spence PJ, Jarra W, Levy P, Reid AJ, Chappell L, et al. (2013) Vector transmission regulates immune control of Plasmodium virulence. Nature 498 : 228–231. doi: 10.1038/nature12231 23719378

67. Krug LT, Evans AG, Gargano LM, Paden CR, Speck SH (2013) The absence of M1 leads to increased establishment of murine gammaherpesvirus 68 latency in IgD-negative B cells. J Virol 87 : 3597–3604. doi: 10.1128/JVI.01953-12 23302876

68. Cardiff RD, Miller CH, Munn RJ (2014) Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harb Protoc 2014 : 655–658. doi: 10.1101/pdb.prot073411 24890205

69. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, et al. (2009) Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325 : 1006–1010. doi: 10.1126/science.1175870 19608860

70. Sangster MY, Topham DJ, D'Costa S, Cardin RD, Marion TN, et al. (2000) Analysis of the virus-specific and nonspecific B cell response to a persistent B-lymphotropic gammaherpesvirus. J Immunol 164 : 1820–1828. 10657630

71. Harris JV, Bohr TM, Stracener C, Landmesser ME, Torres V, et al. (2012) Sequential Plasmodium chabaudi and Plasmodium berghei infections provide a novel model of severe malarial anemia. Infect Immun 80 : 2997–3007. doi: 10.1128/IAI.06185-11 22689817