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Medical Microbiology and Immunology

, Volume 207, Issue 5–6, pp 271–286 | Cite as

Vaccine adjuvants CpG (oligodeoxynucleotides ODNs), MPL (3-O-deacylated monophosphoryl lipid A) and naloxone-enhanced Th1 immune response to the Plasmodium vivax recombinant thrombospondin-related adhesive protein (TRAP) in mice

  • Saeed Nazeri
  • Sedigheh Zakeri
  • Akram A. Mehrizi
  • Navid D. Djadid
  • Georges Snounou
  • Chiara Andolina
  • François Nosten
Original Investigation

Abstract

Despite considerable efforts toward vaccine development over decades, there is no available effective vaccine against Plasmodium vivax. Thrombospondin-related adhesive protein of P. vivax (PvTRAP) is essential for sporozoite motility and invasions into mosquito’s salivary gland and vertebrate’s hepatocyte; hence, it is a promising target for pre-erythrocytic vaccine. In the current investigation, the role of antibodies and cellular immune responses induced by purified recombinant PvTRAP (rPvTRAP) delivered in three adjuvants, naloxone (NLX), CpG oligodeoxynucleotides ODN1826 (CpG-ODN), and 3-O-deacylated monophosphoryl lipid A (MPL), alone and in combination was evaluated in immunized C57BL/6 mice. The highest level and the avidity of anti-PvTRAP IgG (mean OD490nm 2.55), IgG2b (mean OD490nm 1.68), and IgG2c (mean OD490nm 1.466) were identified in the group received rPvTRA/NLX–MPL–CpG. This group also presented the highest IgG2c/IgG1 (2.58) and IgG2b/IgG1 (2.95) ratio when compared to all other groups, and among the adjuvant groups, the lowest IgG2c/IgG1 (1.86) and IgG2b/IgG1 (2.25) ratio was observed in mice receiving rPvTRAP/NLX. Mice receiving rPvTRAP/adjuvants induced significantly the higher levels of interferon gamma (IFN-γ), low level of detectable IL-10, and no detectable IL-4 production. The present result revealed that PvTRAP is immunogenic and its administration with CPG, MPL, and NLX in C57BL/6 mice induced Th1 immune response. Besides, the rPvTRAP delivery in the mixed formulation of those adjuvants had more potential to increase the level, avidity, and persistence of anti-TRAP antibodies. However, it warrants further assessment to test the blocking activity of the produced antibodies in immunized mice with different adjuvant formulations.

Keywords

Malaria Plasmodium vivax Vaccine TRAP Adjuvant 

Notes

Acknowledgements

We would like to thank Dr. Amir Amanzadeh for his technical advice in HepG2 culturing. This study was funded by a grant (No. 747) from Pasteur Institute of Iran to S. Zakeri and also by Ph.D. scholarship to S. Nazeri.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal handling was in accordance with the ethical standards of the Laboratory Animal Science Department, Pasteur Institute of Iran.

Supplementary material

430_2018_545_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 KB)
430_2018_545_MOESM2_ESM.docx (15 kb)
Supplementary material 2 (DOCX 15 KB)

References

  1. 1.
    Cotter C, Sturrock HJ, Hsiang MS, Liu J, Phillips AA, Hwang J, Gueye CS, Fullman N, Goslin RD, Feachem RG (2013) The changing epidemiology of malaria elimination: new strategies for new challenges. Lancet 382(9895):900–911CrossRefGoogle Scholar
  2. 2.
    Guerra CA, Howes RE, Patil AP, Gething PW, van Boeckel TP, Temperley WH, Kabaria CW, Tatem AJ, Manh BH, Elyazar IR, Baird JK, Snow RW, Hay SI (2010) The international limits and population at risk of Plasmodium vivax transmission in 2009. PLoS Negl Trop Dis 4(8):e774CrossRefGoogle Scholar
  3. 3.
    Genton B, Dacremonte V, Rare L, Baea K, Reeder JC, Alpers MP, Muller I (2008) Plasmodium vivax and mixed infections are associated with severe malaria in children: a prospective cohort study from Papua New Guinea. PLoS Med 5(6):e127CrossRefGoogle Scholar
  4. 4.
    Price RN, Douglas NM, Anstey NM (2009) New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance. Curr Opin Infect Dis 22(5):430–435CrossRefGoogle Scholar
  5. 5.
    Alexandre MA, Ferreira CO, Siqueira AM, Magalhães BL, Mourão MP, Lacerda MV, Alecrim Md (2010) Severe Plasmodium vivax malaria, Brazilian Amazon. Emerg Infect Dis 16(10):1611–1614CrossRefGoogle Scholar
  6. 6.
    Feachem RGA, Phillips AA, Hwang J, Cotter Ch, Wielgosz B, Greenwood BM, Sabot O, Rodriguez MH, Abeyasinghe RR, Ghebreyesus TA, Snow RW (2010) Shrinking the malaria map: progress and prospects. Lancet 376(9752):1566–1578CrossRefGoogle Scholar
  7. 7.
    Polley SD, McRobert L, Sutherland CJ (2004) Vaccination for vivax malaria: targeting the invaders. Trends Parasitol 20(3):99–102CrossRefGoogle Scholar
  8. 8.
    Chitnis CE, Sharma A (2008) Targeting the Plasmodium vivax Duffy-binding protein. Trends Parasitol 24(1):29–34CrossRefGoogle Scholar
  9. 9.
    Herrera S, Corradin G, Arevalo-Herrera M (2007) An update on the search for a Plasmodium vivax vaccine. Trends Parasitol 23(3):122–128CrossRefGoogle Scholar
  10. 10.
    Remarque EJ, Faber BW, Kocken CH, Thomas AW (2008) Apical membrane antigen 1: a malaria vaccine candidate in review. Trends Parasitol 24(2):74–84CrossRefGoogle Scholar
  11. 11.
    Reed SG, Bertholet S, Coler RN, Friede M (2009) New horizons in adjuvants for vaccine development. Trends Immunol 30(1):23–32CrossRefGoogle Scholar
  12. 12.
    Reed SG, Orr MT, Fox ChB (2013) Key roles of adjuvants in modern vaccines. Nat Med 19(12):1597–1608CrossRefGoogle Scholar
  13. 13.
    Pashine A, Valiante NM, Ulmer JB (2005) Targeting the innate immune response with improved vaccine adjuvants. Nat Med 11(4):S63–S68CrossRefGoogle Scholar
  14. 14.
    Vogel FR (2000) Improving vaccine performance with adjuvants. Clin Infect Dis 30(3):S266–S270CrossRefGoogle Scholar
  15. 15.
    Perez-Mazliah D, Langhorne J (2015) CD4 T-cell subsets in malaria: TH1/TH2 revisited. Front Immunol 5:671CrossRefGoogle Scholar
  16. 16.
    Stoute JA, Slaoui M, Heppner DG, Momin P, Kester KE, Desmons P, Wellde BT, Garçon N, Krzych U, Marchand M (1997) A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. N Engl J Med 336(2):86–91CrossRefGoogle Scholar
  17. 17.
    Stewart VA, McGrath SM, Walsh DS, Davis S, Hess AS, Ware LA, Kester KE, Cummings JF, Burge JR, Voss G, Delchambre M, Garcon N, Tang DB, Cohen JD, Heppner DG (2006) Pre-clinical evaluation of new adjuvant formulations to improve the immunogenicity of the malaria vaccine RTS,S/AS02A. Vaccine 24(42–43):6483–6492CrossRefGoogle Scholar
  18. 18.
    Mettens P, Dubois PM, Demoitié MA, Bayat B, Donner MN, Bourguignon P, Stewart VA, Heppner DG Jr, Garçon N, Cohen J (2008) Improved T cell responses to Plasmodium falciparum circumsporozoite protein in mice and monkeys induced by a novel formulation of RTS,S vaccine antigen. Vaccine 26(8):1072–1082CrossRefGoogle Scholar
  19. 19.
    Kester KE, Cummings JF, Ofori-Anyinam O, Ockenhouse CF, Krzych U, Moris P, Schwenk R, Nielsen RA, Debebe Z, Pinelis E, Juompan L, Williams J, Dowler M, Stewart VA, Wirtz RA, Dubois MC, Lievens M, Cohen J, Ballou WR, Heppner DG Jr, RTS,S Vaccine Evaluation Group (2009) Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naïve adults: safety, efficacy, and immunologic associates of protection. J Infect Dis 200(3):337–346CrossRefGoogle Scholar
  20. 20.
    Agnandji ST, Fernandes JF, Bache EB, Ramharter M (2015) Clinical development of RTS, S/AS malaria vaccine: a systematic review of clinical phase I–III trials. Future Microbiol 10(10):1553–1578CrossRefGoogle Scholar
  21. 21.
    Gosling R, von Seidlein L (2016) The future of the RTS,S/AS01 malaria vaccine: an alternative development plan. PLoS Med 13(4):e1001994CrossRefGoogle Scholar
  22. 22.
    Ajua A, Lell B, Agnandji ST, Asante KP, Owusu-Agyei S, Mwangoka G, Mpina M, Salim N, Tanner M, Abdulla S, Vekemans J, Jongert E, Lievens M, Cambron P, Ockenhouse CF, Kremsner PG, Mordmüller B (2015) The effect of immunization schedule with the malaria vaccine candidate RTS,S/AS01E on protective efficacy and anti-circumsporozoite protein antibody avidity in African infants. Malar J 14:72CrossRefGoogle Scholar
  23. 23.
    Kester KE, Gray Heppner D Jr, Moris P, Ofori-Anyinam O, Krzych U, Tornieporth N, McKinney D, Delchambre M, Ockenhouse CF, Voss G, Holland C, Beckey JP, Ballou WR, Cohen J (2014) RTS,S/TRAP Group. Sequential phase 1 and phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults. Vaccine 32(49):6683–6691CrossRefGoogle Scholar
  24. 24.
    Schwarz TF, Spaczynski M, Schneider A, Wysocki J, Galaj A, Perona P, Poncelet S, Zahaf T, Hardt K, Descamps D, Dubin G (2009) Immunogenicity and tolerability of an HPV-6/18 AS04-adjuvanted prophylactic cervical cancer vaccine in women aged 15–55 years. Vaccine 27(4):581–587CrossRefGoogle Scholar
  25. 25.
    Toubaji A, Hill S, Terabe M, Qian J, Floyd T, Simpson RM, Berzofsky JA, Khleif SN (2007) The combination of GM-CSF and IL-2 as local adjuvant shows synergy in enhancing peptide vaccines and provides long term tumor protection. Vaccine 25(31):5882–5891CrossRefGoogle Scholar
  26. 26.
    Sui Y, Zhu Q, Gagnon S, Dzutsev A, Terabe M, Vaccari M, Venzon D, Klinman D, Strober W, Kelsall B, Franchini G, Belyakov IM, Berzofsky JA (2010) Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques. Proc Natl Acad Sci USA 107(21):9843–9848CrossRefGoogle Scholar
  27. 27.
    Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, Fourneau MA, Colau B, Suzich J, Losonksy G, Martin MT, Dubin G, Wettendorff MA (2006) Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine 24(33–34):5937–5949CrossRefGoogle Scholar
  28. 28.
    Wack A, Baudner BC, Hilbert AK, Manini I, Nuti S, Tavarini S, Scheffczik H, Ugozzoli M, Singh M, Kazzaz J, Montomoli E, Del Giudice G, Rappuoli R, O’Hagan DT (2008) Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice. Vaccine 26(4):552–561CrossRefGoogle Scholar
  29. 29.
    Singh M, Kazzaz J, Ugozzoli M, Baudner B, Pizza M, Giuliani M, Hawkins LD, Otten G, O’Hagan DT (2012) MF59 oil-in-water emulsion in combination with a synthetic TLR4 agonist (E6020) is a potent adjuvant for a combination Meningococcus vaccine. Hum Vaccin Immunother 8(4):486–490CrossRefGoogle Scholar
  30. 30.
    Sacerdote P, di San Secondo VE, Sirchia G, Manfredi B, Panerai AE (1998) Endogenous opioids modulate allograft rejection time in mice: possible relation with Th1/Th2 cytokines. Clin Exp Immunol 113(3):465–469CrossRefGoogle Scholar
  31. 31.
    Sacerdote P, Gaspani L, Panerai AE (2000) The opioid antagonist naloxone induces a shift from type 2 to type 1 cytokine pattern in normal and skin-grafted mice. Ann N Y Acad Sci 917:755–763CrossRefGoogle Scholar
  32. 32.
    Sacerdote P, Manfredi B, Gaspani L, Panerai AE (2000) The opioid antagonist naloxone induces a shift from type 2 to type 1 cytokine pattern in BALB/cJ mice. Blood 95(6):2031–2036PubMedGoogle Scholar
  33. 33.
    Jamali A, Mahdavi M, Shahabi S, Hassan ZM, Sabahi F, Javan M, Farsani MJ, Parsania M, Bamdad T (2007) Naloxone, an opioid receptor antagonist, enhances induction of protective immunity against HSV-1 infection in BALB/c mice. Microb Pathog 43(5–6):217–223CrossRefGoogle Scholar
  34. 34.
    Jamali A, Mahdavi M, Hassan ZM, Sabahi F, Farsani MJ, Bamdad T, Soleimanjahi H, Motazakker M, Shahabi S (2009) A novel adjuvant, the general opioid antagonist naloxone, elicits a robust cellular immune response for a DNA vaccine. Int Immunol 21(3):217–225CrossRefGoogle Scholar
  35. 35.
    Jazani NH, Parsania S, Sohrabpour M, Mazloomi E, Karimzad M, Shahabi S (2010) Naloxone and alum synergistically augment adjuvant activities of each other in a mouse vaccine model of Salmonella typhimurium infection. Immunobiology 216(6):744–751CrossRefGoogle Scholar
  36. 36.
    Motaharinia Y, Rezaee MA, Rashidi A, Jalili A, Rezaie MJ, Shapouri R, Hossieni W, Rahmani MR (2013) Induction of protective immunity against brucellosis in mice by vaccination with a combination of naloxone, alum, and heat-killed Brucella melitensis 16 M. J Microbiol Immunol Infect 46(4):253–258CrossRefGoogle Scholar
  37. 37.
    McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ (2001) Opioids, opioid receptors, and the immune response. Drug Alcohol Depend 62(2):111–123CrossRefGoogle Scholar
  38. 38.
    O’Neill LAJ, Bowie AG (2007) The family of five: TIR domain-containing adaptors in toll-like receptor signaling. Nat Rev Immunol 7(5):353–364CrossRefGoogle Scholar
  39. 39.
    Casares S, Brumeanu TD, Richie TL (2010) The RTS,S malaria vaccine. Vaccine 28(31):4880–4894CrossRefGoogle Scholar
  40. 40.
    Tielemans CL, lasak JV, Kosaetal D (2011) Immunogenicity and safety of an investigational AS02v-adjuvanted hepatitis B vaccine in patients with renal insufficiency who failed to respond or to maintain antibody levels after prior vaccination: results of two open, randomized, comparative trials. Vaccine 29(6):1159–1166CrossRefGoogle Scholar
  41. 41.
    Cluf CW (2010) Monophosphoryl lipid a (MPL) as an adjuvant for anti-cancer vaccines: clinical results. Adv Exp Med Biol 667:111–123CrossRefGoogle Scholar
  42. 42.
    Gillard P, Yang PC, Danilovits M, Su WJ, Cheng SL, Pehme L, Bollaerts A, Jongert E, Moris P, Ofori-Anyinam O, Demoitié MA, Castro M (2016) Safety and immunogenicity of the M72/AS01E candidate tuberculosis vaccine in adults with tuberculosis: a phase II randomised study. Tuberculosis (Edinb) 100:118–127CrossRefGoogle Scholar
  43. 43.
    Van Braeckel E, Bourguignon P, Koutsoukos M, Clement F, Janssens M, Carletti I, Collard A, Demoitié MA, Voss G, Leroux-Roels G, McNally L (2011) An adjuvanted polyprotein HIV-1 vaccine induces polyfunctional cross-reactive CD4+ T cell responses in seronegative volunteers. Clin Infect Dis 52(4):522–531CrossRefGoogle Scholar
  44. 44.
    Krieg AM (2002) CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709–760CrossRefGoogle Scholar
  45. 45.
    Harandi AM, Holmgren J (2004) CpG DNA as a potent inducer of mucosal immunity: implications for immune prophylaxis and immunotherapy of mucosal infections. Curr Opin Investig Drugs 5(2):141–145PubMedGoogle Scholar
  46. 46.
    Krieg AM (2004) Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 6(2):88–95CrossRefGoogle Scholar
  47. 47.
    Gupta GK, Agrawal DK (2010) CpG oligodeoxynucleotides as TLR9 agonists: therapeutic application in allergy and asthma. Bio Drugs 24(4):225–235Google Scholar
  48. 48.
    Vanderberg J, Nussenzweig R, Most H (1969) Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei. V. In vitro effects of immune serum on sporozoites. Mil Med 134(10):1183–1190CrossRefGoogle Scholar
  49. 49.
    Schwenk R, Asher LV, Chalom I, Lanar D, Sun P, White K, Keil D, Kester KE, Stoute J, Heppner DG, Krzych U (2003) Opsonization by antigen-specific antibodies as a mechanism of protective immunity induced by Plasmodium falciparum circumsporozoite protein-based vaccine. Parasite Immunol 25(1):17–25CrossRefGoogle Scholar
  50. 50.
    Muller H, Reckmann I, Hollingdale MR, Bujard H, Robson KJ, Crisanti A (1993) Thrombospondin related adhesion protein (TRAP) of Plasmodium falciparum binds specifically to sulfated glycoconjugates and to HepG2 hepatoma cells suggesting a role for this molecule in sporozoite invasion of hepatocytes. EMBO J 12(7):2881–2889CrossRefGoogle Scholar
  51. 51.
    Sinnis P, Sim BK (1997) Cell invasion by the vertebrate stages of Plasmodium. Trends Microbiol 5(2):52–58CrossRefGoogle Scholar
  52. 52.
    Nazeri S, Mehrizi AA, Djadid ND, Zakeri S (2015) A comparative study on worldwide genetic diversity and population structure analysis of Plasmodium vivax thrombospondin-related adhesive protein (PvTRAP) and its implications for the vivax vaccine design. Infect Genet Evol 36:410–423CrossRefGoogle Scholar
  53. 53.
    Nazeri S, Zakeri S, Mehrizi AA, Djadid ND (2017) Naturally acquired immune responses to thrombospondin-related adhesion protein (TRAP) of Plasmodium vivax in patients from areas of unstable malaria transmission. Acta Trop 173:45–54CrossRefGoogle Scholar
  54. 54.
    Yadava A, Sattabongkot J, Washington MA, Ware LA, Majam V, Zheng H, Kumar S, Ockenhouse CF (2007) A novel chimeric Plasmodium vivax circumsporozoite protein induces biologically functional antibodies that recognize both VK210 and VK247 sporozoites. Infect Immun 75(3):1177–1185CrossRefGoogle Scholar
  55. 55.
    Andolina C, Landier J, Carrara V, Chu CS, Franetich JF, Roth A, Rénia L, Roucher C, White NJ, Snounou G, Nosten F (2015) The suitability of laboratory-bred Anopheles cracens for the production of Plasmodium vivax sporozoites. Malar J 14:312CrossRefGoogle Scholar
  56. 56.
    Someabozorg MA, Mirkazemi S, Mehrizi AA, Shokri F, Djadid ND, Zakeri S (2015) Administration of naloxone in combination with recombinant Plasmodium vivax AMA-1 in BALB/c mice induces mixed Th1/Th2 immune responses. Parasite Immunol 37(10):521–532CrossRefGoogle Scholar
  57. 57.
    Hedman K, Lappalainen M, Seppaia I, Makela O (1989) Recent primary toxoplasma infection indicated by a low avidity of specific IgG. J Infect Dis 159(4):736–740CrossRefGoogle Scholar
  58. 58.
    Herrington DA, Clyde DF, Losonsky G, Cortesia M, Murphy JR, Davis J, Baqar S, Felix AM, Heimer EP, Gillessen D (1987) Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature 328(6127):257–259CrossRefGoogle Scholar
  59. 59.
    Garcon N, Leroux-Roels G, Cheng WF (2011) Vaccine adjuvants. Perspect Vaccinol 1(1):89–113CrossRefGoogle Scholar
  60. 60.
    Eng NF, Bhardwaj N, Mulligan R, Diaz-Mitoma F (2013) The potential of 1018 ISS adjuvant in hepatitis B vaccines. Hum Vaccin Immunother 9(8):1661–1672CrossRefGoogle Scholar
  61. 61.
    Fransen F, Boog CJ, van Putten JP, van der Ley P (2007) Agonists of toll-like receptors 3, 4, 7, and 9 are candidates for use as adjuvants in an outer membrane vaccine against Neisseria meningitidis serogroup. Infect Immun 75(12):5939–5946CrossRefGoogle Scholar
  62. 62.
    Rhee EG, Kelley RP, Agarwal I, Lynch DM, La Porte A, Simmons NL, Clark SL, Barouch DH (2010) TLR4 ligands augment antigen-specific CD8+ T lymphocyte responses elicited by a viral vaccine vector. J Virol 84(19):10413–10419CrossRefGoogle Scholar
  63. 63.
    Sugai T, Mori M, Nakazawa M, Ichino M, Naruto T, Kobayashi N, Kobayashi Y, Minami M, Yokota S (2005) A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria–tetanus–pertussis vaccine. Vaccine 23(46–47):5450–5456CrossRefGoogle Scholar
  64. 64.
    Fogg CN, Americo JL, Lustig S, Huggins JW, Smith SK, Damon I, Resch W, Earl PL, Klinman DM, Moss B (2007) Adjuvant-enhanced antibody responses to recombinant proteins correlates with protection of mice and monkeys to orthopoxvirus challenges. Vaccine 25(15):2787–2799CrossRefGoogle Scholar
  65. 65.
    Thomas HI, Wilson S, O’Toole CM, Lister CM, Saeed AM, Watkins P, Morgan-Capner P (1996) Differential maturation of avidity of IgG antibodies to gp41, p24 and p17 following infection with HIV-1. Clin Exp Immunol 103(2):185–191CrossRefGoogle Scholar
  66. 66.
    Varikuti S, Oghumu S, Natarajan G, Kimble J, Sperling RH, Moretti E, Kaplan MH, Satoskar AR (2016) STAT4 is required for the generation of Th1 and Th2, but not Th17 immune responses during monophosphoryl lipid A adjuvant activity. Int Immunol 28(11):565–570CrossRefGoogle Scholar
  67. 67.
    Krug A, Rothenfusser S, Hornung V, Jahrsdörfer B, Blackwell S, Ballas ZK, Endres S, Krieg AM, Hartmann G (2001) Identification of CpG oligonucleotide sequences with high induction of IFN-α/β in plasmacytoid dendritic cells. Eur J Immunol 31(7):2154–2163CrossRefGoogle Scholar
  68. 68.
    Chace JH, Hooker NA, Midlenstein KL, Krieg AM, Cowdery JS (1997) Bacterial DNA-induced NK cell IFN-g production is dependent on macrophage secretion of IL-12. Clin Immunol Immunopathol 84(2):185–193CrossRefGoogle Scholar
  69. 69.
    Yamamoto S, Yamamoto T, Shimada S, Kuramoto E, Yano O, Kataoka T, Tokunaga T (1992) DNA from bacteria, but not from vertebrates, induces interferons, activates natural killer cells and inhibits tumor growth. Microbiol Immunol 36(9):983–997CrossRefGoogle Scholar
  70. 70.
    Ballas ZK, Rasmussen WL, Krieg AM (1996) Induction of NK activity in murine and human cells by CpG motifs in oligodeoxynucleotides and bacterial DNA. J Immunol 157(5):1840–1845PubMedGoogle Scholar
  71. 71.
    Cowdery JS, Chace JH, Yi AK, Krieg AM (1996) Bacterial DNA induces NK cells to produce IFN-g in vivo and increases the toxicity of lipopolysaccharides. J Immunol 156(12):4570–4575PubMedGoogle Scholar
  72. 72.
    Shi Y, Felder MA, Sondel PM, Rakhmilevich AL (2015) Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages. Mol Immunol 66(2):208–215CrossRefGoogle Scholar
  73. 73.
    Vilaysane A, Muruve DA (2009) The innate immune response to DNA. Semin Immunol 21(4):208–214CrossRefGoogle Scholar
  74. 74.
    Kumagai Y, Takeuchi O, Aaira S (2008) TLR9 as a key receptor for the recognition of DNA. Adv Drug Deliv Rev 60(7):795–804CrossRefGoogle Scholar
  75. 75.
    Cooper CL, Ahluwalia NK, Efler SM, Vollmer J, Krieg AM, Davis HL (2008) Immunostimulatory effects of three classes of CpG oligodeoxynucleotides on PBMC from HCV chronic carriers. J Immune Based Ther Vaccines 6:3CrossRefGoogle Scholar
  76. 76.
    Amsen D, Spilianakis CG, Flavell RA (2009) How are T(H)1 and T(H)2 effector cells made? Curr Opin Immunol 21(2):153–160CrossRefGoogle Scholar
  77. 77.
    Ansel KM, Djuretic I, Tanasa B, Rao A (2006) Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol 24:607–656CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Malaria and Vector Research Group (MVRG), Biotechnology Research Center (BRC)Pasteur Institute of IranTehranIran
  2. 2.Sorbonne Universités, UPMC Univ Paris 06, Inserm (Institut National de la Santé et de la Recherche Medicale), Centre d’Immunologie et des Maladies Infectieuses (Cimi-Paris), UMR 1135, ERL CNRS 8255 (Centre National de la Recherche Scientifique)ParisFrance
  3. 3.Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical MedicineMahidol UniversityMae SotThailand
  4. 4.Centre for Tropical Medicine and Global Health, Nuffield Department of MedicineUniversity of OxfordOxfordUK

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