Longevity and Composition of Cellular Immune Responses Following Experimental Malaria Infection in Humans
Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO+ CD62L- effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ+IL-2+) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.
Vyšlo v časopise:
Longevity and Composition of Cellular Immune Responses Following Experimental Malaria Infection in Humans. PLoS Pathog 7(12): e32767. doi:10.1371/journal.ppat.1002389
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002389
Souhrn
Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only ‘adaptive’ but also ‘innate’ lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO+ CD62L- effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ+IL-2+) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.
Zdroje
1. World Health Organization 2008 World Malaria Report 2008. WHO/HTM/GMP/2008.1
2. MarshKKinyanjuiS 2006 Immune effector mechanisms in malaria. Parasite Immunol 28 51 60
3. SchofieldLMuellerI 2006 Clinical immunity to malaria. Curr Mol Med 6 205 221
4. CockburnIAZavalaF 2007 T cell memory in malaria. Curr Opin Immunol 19 424 429
5. DoolanDLDobanoCBairdJK 2009 Acquired immunity to malaria. Clin Microbiol Rev 22 13 36
6. StruikSSRileyEM 2004 Does malaria suffer from lack of memory? Immunol Rev 201 268 290
7. AchtmanAHBullPCStephensRLanghorneJ 2005 Longevity of the immune response and memory to blood-stage malaria infection. Curr Top Microbiol Immunol 297 71 102
8. MigotFChougnetCRaharimalalaLAstagneauPLepersJP 1993 Human immune responses to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) after a decrease in malaria transmission in Madagascar. Am J Trop Med Hyg 48 432 439
9. WipasaJOkellLSakkhachornphopSSuphavilaiCChawansuntatiK 2011 Short-lived IFN-gamma effector responses, but long-lived IL-10 memory responses, to malaria in an area of low malaria endemicity. PLoS Pathog 7 e1001281
10. ZeveringYKhamboonruangCRungruengthanakitKTungviboonchaiLRuengpipattanapanJ 1994 Life-spans of human T-cell responses to determinants from the circumsporozoite proteins of Plasmodium falciparum and Plasmodium vivax. Proc Natl Acad Sci U S A 91 6118 6122
11. BejonPMwacharoJKaiOTodrykSKeatingS 2007 The induction and persistence of T cell IFN-gamma responses after vaccination or natural exposure is suppressed by Plasmodium falciparum. J Immunol 179 4193 4201
12. DentAEChelimoKSumbaPOSpringMDCrabbBS 2009 Temporal stability of naturally acquired immunity to Merozoite Surface Protein-1 in Kenyan adults. Malar J 8 162
13. FlanaganKLMwangiTPlebanskiMOdhiamboKRossA 2003 Ex vivo interferon-gamma immune response to thrombospondin-related adhesive protein in coastal Kenyans: longevity and risk of Plasmodium falciparum infection. Am J Trop Med Hyg 68 421 430
14. MoormannAMSumbaPOTischDJEmburyPKingCH 2009 Stability of interferon-gamma and interleukin-10 responses to Plasmodium falciparum liver stage antigen 1 and thrombospondin-related adhesive protein immunodominant epitopes in a highland population from Western Kenya. Am J Trop Med Hyg 81 489 495
15. RileyEMMorris-JonesSBlackmanMJGreenwoodBMHolderAA 1993 A longitudinal study of naturally acquired cellular and humoral immune responses to a merozoite surface protein (MSP1) of Plasmodium falciparum in an area of seasonal malaria transmission. Parasite Immunol 15 513 524
16. HviidLTheanderTGJakobsenPHbu-ZeidYAAbdulhadiNH 1990 Cell-mediated immune responses to soluble Plasmodium falciparum antigens in residents from an area of unstable malaria transmission in the Sudan. APMIS 98 594 604
17. WylerDJOppenheimJJ 1974 Lymphocyte transformation in human Plasmodium falciparum malaria. J Immunol 113 449 454
18. TodrykSMWaltherMBejonPHutchingsCThompsonFM 2009 Multiple functions of human T cells generated by experimental malaria challenge. Eur J Immunol 39 3042 3051
19. McCallMBSauerweinRW 2010 Interferon-gamma--central mediator of protective immune responses against the pre-erythrocytic and blood stage of malaria. J Leukoc Biol 88 1131 1143
20. SauerweinRWRoestenbergMMoorthyVS 2011 Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol 11 57 64
21. PomboDJLawrenceGHirunpetcharatCRzepczykCBrydenM 2002 Immunity to malaria after administration of ultra-low doses of red cells infected with Plasmodium falciparum. Lancet 360 610 617
22. RoestenbergMTeirlinckACMcCallMBTeelenKMakamdopKN 2011 Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377 1770 1776
23. RoestenbergMMcCallMHopmanJWiersmaJLutyAJv etal 2009 Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 361 468 477
24. DodooDOmerFMToddJAkanmoriBDKoramKA 2002 Absolute levels and ratios of proinflammatory and anti-inflammatory cytokine production in vitro predict clinical immunity to Plasmodium falciparum malaria. J Infect Dis 185 971 979
25. D'OmbrainMCRobinsonLJStanisicDITaraikaJBernardN 2008 Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children. Clin Infect Dis 47 1380 1387
26. LutyAJLellBSchmidt-OttRLehmanLGLucknerD 1999 Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children. J Infect Dis 179 980 988
27. McCallMBHopmanJDaouMMaigaBDaraV 2010 Early interferon-gamma response against Plasmodium falciparum correlates with interethnic differences in susceptibility to parasitemia between sympatric Fulani and Dogon in Mali. J Infect Dis 201 142 152
28. Artavanis-TsakonasKRileyEM 2002 Innate immune response to malaria: rapid induction of IFN-gamma from human NK cells by live Plasmodium falciparum-infected erythrocytes. J Immunol 169 2956 2963
29. BaratinMRoetynckSLepolardCFalkCSawadogoS 2005 Natural killer cell and macrophage cooperation in MyD88-dependent innate responses to Plasmodium falciparum. Proc Natl Acad Sci U S A 102 14747 14752
30. McCallMBRoestenbergMPloemenITeirlinckAHopmanJ 2010 Memory-like IFN-gamma response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum. Eur J Immunol 40 3472 3477
31. HensmannMKwiatkowskiD 2001 Cellular basis of early cytokine response to Plasmodium falciparum. Infect Immun 69 2364 2371
32. WaterfallMBlackARileyE 1998 Gammadelta+ T cells preferentially respond to live rather than killed malaria parasites. Infect Immun 66 2393 2398
33. D'OmbrainMCHansenDSSimpsonKMSchofieldL 2007 gammadelta-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-gamma response to Plasmodium falciparum malaria. Eur J Immunol 37 1864 1873
34. CurrierJSattabongkotJGoodMF 1992 ‘Natural’ T cells responsive to malaria: evidence implicating immunological cross-reactivity in the maintenance of TCR alpha beta+ malaria-specific responses from non-exposed donors. Int Immunol 4 985 994
35. ZeveringYAmanteFSmillieACurrierJSmithG 1992 High frequency of malaria-specific T cells in non-exposed humans. Eur J Immunol 22 689 696
36. RoussilhonCAgrapartMGuglielmiPBensussanABrasseurP 1994 Human TcR gamma delta+ lymphocyte response on primary exposure to Plasmodium falciparum. Clin Exp Immunol 95 91 97
37. RzepczykCMStamatiouSAndersonKStowersAChengQ 1996 Experimental human Plasmodium falciparum infections: longitudinal analysis of lymphocyte responses with particular reference to gamma delta T cells. Scand J Immunol 43 219 227
38. HviidLKurtzhalsJADodooDRodriguesORonnA 1996 The gamma/delta T-cell response to Plasmodium falciparum malaria in a population in which malaria is endemic. Infect Immun 64 4359 4362
39. BehrCDuboisP 1992 Preferential expansion of V gamma 9 V delta 2 T cells following stimulation of peripheral blood lymphocytes with extracts of Plasmodium falciparum. Int Immunol 4 361 366
40. BehrCPoupotRPeyratMAPoquetYConstantP 1996 Plasmodium falciparum stimuli for human gammadelta T cells are related to phosphorylated antigens of mycobacteria. Infect Immun 64 2892 2896
41. HorowitzANewmanKCEvansJHKorbelDSDavisDM 2010 Cross-talk between T cells and NK cells generates rapid effector responses to Plasmodium falciparum-infected erythrocytes. J Immunol 184 6043 6052
42. JungTMGallatinWMWeissmanILDaileyMO 1988 Down-regulation of homing receptors after T cell activation. J Immunol 141 4110 4117
43. SallustoFGeginatJLanzavecchiaA 2004 Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22 745 763
44. DarrahPAPatelDTDe LucaPMLindsayRWDaveyDF 2007 Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13 843 850
45. BejonPKeatingSMwacharoJKaiOKDunachieS 2006 Early gamma interferon and interleukin-2 responses to vaccination predict the late resting memory in malaria-naive and malaria-exposed individuals. Infect Immun 74 6331 6338
46. SederRADarrahPARoedererM 2008 T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 8 247 258
47. ChizzoliniCGrauGEGeinozASchrijversD 1990 T lymphocyte interferon-gamma production induced by Plasmodium falciparum antigen is high in recently infected non-immune and low in immune subjects. Clin Exp Immunol 79 95 99
48. RheeMSAkanmoriBDWaterfallMRileyEM 2001 Changes in cytokine production associated with acquired immunity to Plasmodium falciparum malaria. Clin Exp Immunol 126 503 510
49. Ocana-MorgnerCMotaMMRodriguezA 2003 Malaria blood stage suppression of liver stage immunity by dendritic cells. J Exp Med 197 143 151
50. KempKAkanmoriBDAdabayeriVGokaBQKurtzhalsJA 2002 Cytokine production and apoptosis among T cells from patients under treatment for Plasmodium falciparum malaria. Clin Exp Immunol 127 151 157
51. RiccioEKJuniorINRiccioLRdas GracasAMCorte-RealS 2003 Malaria associated apoptosis is not significantly correlated with either parasitemia or the number of previous malaria attacks. Parasitol Res 90 9 18
52. OtooLNRileyEMMenonAByassPGreenwoodBM 1989 Cellular immune responses to Plasmodium falciparum antigens in children receiving long term anti-malarial chemoprophylaxis. Trans R Soc Trop Med Hyg 83 778 782
53. BrustoskiKMollerUKramerMHartgersFCKremsnerPG 2006 Reduced cord blood immune effector-cell responsiveness mediated by CD4+ cells induced in utero as a consequence of placental Plasmodium falciparum infection. J Infect Dis 193 146 154
54. FinneyOCNwakanmaDConwayDJWaltherMRileyEM 2009 Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission. Eur J Immunol 39 1288 1300
55. TorciaMGSantarlasciVCosmiLClementeAMaggiL 2008 Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria. Proc Natl Acad Sci U S A 105 646 651
56. WaltherMTongrenJEAndrewsLKorbelDKingE 2005 Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23 287 296
57. BairdJK 1998 Age-dependent characteristics of protection v. susceptibility to Plasmodium falciparum. Ann Trop Med Parasitol 92 367 390
58. SchaibleUEKaufmannSH 2007 Malnutrition and infection: complex mechanisms and global impacts. PLoS Med 4 e115
59. HartgersFCObengBBKruizeYCDijkhuisAMcCallM 2009 Responses to malarial antigens are altered in helminth-infected children. J Infect Dis 199 1528 1535
60. WammesLJHamidFWiriaAEdeGBSartonoE 2010 Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum. Eur J Immunol 40 437 442
61. SiegristCA 2001 Neonatal and early life vaccinology. Vaccine 19 3331 3346
62. ZolaH 1997 The development of antibody responses in the infant. Immunol Cell Biol 75 587 590
63. BroenKBrustoskiKEngelmannILutyAJ 2007 Placental Plasmodium falciparum infection: causes and consequences of in utero sensitization to parasite antigens. Mol Biochem Parasitol 151 1 8
64. BucciKKastensWHollingdaleMRShankarAAlpersMP 2000 Influence of age and HLA type on interferon-gamma (IFN-gamma) responses to a naturally occurring polymorphic epitope of Plasmodium falciparum liver stage antigen-1 (LSA-1). Clin Exp Immunol 122 94 100
65. JohnCCMoormannAMSumbaPOOfullaAVPregibonDC 2004 Gamma interferon responses to Plasmodium falciparum liver-stage antigen 1 and thrombospondin-related adhesive protein and their relationship to age, transmission intensity, and protection against malaria. Infect Immun 72 5135 5142
66. RamharterMWinklerHKremsnerPGAdegnikaAAWillheimM 2005 Age-dependency of Plasmodium falciparum-specific and non-specific T cell cytokine responses in individuals from a malaria-endemic area. Eur Cytokine Netw 16 135 143
67. WinklerSWillheimMBaierKSchmidDAichelburgA 1999 Frequency of cytokine-producing T cells in patients of different age groups with Plasmodium falciparum malaria. J Infect Dis 179 209 216
68. KidgellCVolkmanSKDailyJBorevitzJOPlouffeD 2006 A systematic map of genetic variation in Plasmodium falciparum. PLoS Pathog 2 e57
69. SauerweinRWBijkerEMRichieTL 2010 Empowering malaria vaccination by drug administration. Curr Opin Immunol 22 367 373 S0952-7915(10)00065-8 [pii];10.1016/j.coi.2010.04.001 [doi]
70. RivadeneiraEMWassermanMEspinalCT 1983 Separation and concentration of schizonts of Plasmodium falciparum by Percoll gradients. J Protozool 30 367 370
71. PonnuduraiTLensenAHvan GemertGJBensinkMPBolmerM 1989 Infectivity of cultured Plasmodium falciparum gametocytes to mosquitoes. Parasitology 98 Pt 2 165 173
72. StewartMJVanderbergJP 1988 Malaria sporozoites leave behind trails of circumsporozoite protein during gliding motility. J Protozool 35 389 393
73. VerhageDFTelgtDSBousemaJTHermsenCCvan GemertGJv etal 2005 Clinical outcome of experimental human malaria induced by Plasmodium falciparum-infected mosquitoes. Neth J Med 63 52 58
74. NardinEHOliveiraGACalvo-CalleJMWetzelKMaierC 2004 Phase I testing of a malaria vaccine composed of hepatitis B virus core particles expressing Plasmodium falciparum circumsporozoite epitopes. Infect Immun 72 6519 6527
75. FlueckCFrankGSmithTJafarshadANebieI 2009 Evaluation of two long synthetic merozoite surface protein 2 peptides as malaria vaccine candidates. Vaccine 27 2653 2661
76. MeraldiVNebieIMoretRCuzin-OuattaraNThioconeA 2002 Recognition of synthetic polypeptides corresponding to the N- and C-terminal fragments of Plasmodium falciparum Exp-1 by T-cells and plasma from human donors from African endemic areas. Parasite Immunol 24 141 150
77. AudranRCachatMLuratiFSoeSLeroyO 2005 Phase I malaria vaccine trial with a long synthetic peptide derived from the merozoite surface protein 3 antigen. Infect Immun 73 8017 8026
78. HermsenCCVerhageDFTelgtDSTeelenKBousemaJT 2007 Glutamate-rich protein (GLURP) induces antibodies that inhibit in vitro growth of Plasmodium falciparum in a phase 1 malaria vaccine trial. Vaccine 25 2930 2940
79. HillierCJWareLABarbosaAAngovELyonJA 2005 Process development and analysis of liver-stage antigen 1, a preerythrocyte-stage protein-based vaccine for Plasmodium falciparum. Infect Immun 73 2109 2115
80. RoestenbergMRemarqueEdeJEHermsenRBlythmanH 2008 Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02. PLoS One 3 e3960
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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