Seminars in Immunopathology

, Volume 30, Issue 1, pp 41–51 | Cite as

Role of TLRs/MyD88 in host resistance and pathogenesis during protozoan infection: lessons from malaria

  • Catherine Ropert
  • Bernardo S. Franklin
  • Ricardo T. Gazzinelli
Review

Abstract

Toll-like receptors (TLRs) are important to initiate the innate immune response to a wide variety of pathogens. The protective role of TLRs during infection with protozoan parasites has been established. In this regard, malaria represents an exception where activation of TLRs seems to be deleterious to the host. In this article, we review the recent findings indicating the contrasting role of Myeloid Differentiation Primary-Response gene 88 (MyD88) and TLRs during malaria and infection with other protozoa. These findings suggest that MyD88 may represent an Achilles’ heel during Plasmodium infection.

Keywords

Innate immunity Toll-like receptors MyD88 Protozoan parasites Cytokines Dendritic cells 

Notes

Acknowledgements

The R.T.G. laboratory is funded by Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), the US National Institutes of Health (NIH), the World Health Organization, and the Millenium Institute for Vaccine Technology and Development. R.T.G. is a recipient of fellowships from Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico and the John Simon Guggenheim Memorial Foundation. C.R. and B.S.F. received research fellowships from FAPEMIG and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), respectively.

References

  1. 1.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedCrossRefGoogle Scholar
  2. 2.
    Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511PubMedCrossRefGoogle Scholar
  3. 3.
    Beutler B (2004) Inferences, questions and possibilities in Toll-like receptor signalling. Nature 430:257–263PubMedCrossRefGoogle Scholar
  4. 4.
    Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32PubMedCrossRefGoogle Scholar
  5. 5.
    Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedCrossRefGoogle Scholar
  6. 6.
    Gazzinelli RT, Ropert C, Campos MA (2004) Role of the Toll/interleukin-1 receptor signaling pathway in host resistance and pathogenesis during infection with protozoan parasites. Immunol Rev 201:9–25PubMedCrossRefGoogle Scholar
  7. 7.
    Gazzinelli RT, Denkers EY (2006) Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat Rev Immunol 6:895–906PubMedCrossRefGoogle Scholar
  8. 8.
    Michailowsky V, Silva NM, Rocha CD, Vieira LQ, Lannes-Vieira J, Gazzinelli RT (2001) Pivotal role of interleukin-12 and interferon-gamma axis in controlling tissue parasitism and inflammation in the heart and central nervous system during Trypanosoma cruzi infection. Am J Pathol 159:1723–1733PubMedGoogle Scholar
  9. 9.
    Holscher C, Kohler G, Muller U, Mossmann H, Schaub GA, Brombacher F (1998) Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma interferon receptor or inducible nitric oxide synthase. Infect Immun 66:1208–1215PubMedGoogle Scholar
  10. 10.
    Castanos-Velez E, Maerlan S, Osorio LM, Aberg F, Biberfeld P, Orn A, Rottenberg ME (1998) Trypanosoma cruzi infection in tumor necrosis factor receptor p55-deficient mice. Infect Immun 66:2960–2968PubMedGoogle Scholar
  11. 11.
    Torrico F, Heremans H, Rivera MT, Van Marck E, Billiau A, Carlier Y (1991) Endogenous IFN-gamma is required for resistance to acute Trypanosoma cruzi infection in mice. J Immunol 146:3626–3632PubMedGoogle Scholar
  12. 12.
    Yap GS, Scharton-Kersten T, Charest H, Sher A (1998) Decreased resistance of TNF receptor p55- and p75-deficient mice to chronic toxoplasmosis despite normal activation of inducible nitric oxide synthase in vivo. J Immunol 160:1340–1345PubMedGoogle Scholar
  13. 13.
    Yap G, Pesin M, Sher A (2000) Cutting edge: IL-12 is required for the maintenance of IFN-gamma production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J Immunol 165:628–631PubMedGoogle Scholar
  14. 14.
    Scharton-Kersten TM, Yap G, Magram J, Sher A (1997) Inducible nitric oxide is essential for host control of persistent but not acute infection with the intracellular pathogen Toxoplasma gondii. J Exp Med 185:1261–1273PubMedCrossRefGoogle Scholar
  15. 15.
    Scharton-Kersten TM, Wynn TA, Denkers EY, Bala S, Grunvald E, Hieny S, Gazzinelli RT, Sher A (1996) In the absence of endogenous IFN-gamma, mice develop unimpaired IL-12 responses to Toxoplasma gondii while failing to control acute infection. J Immunol 157:4045–4054PubMedGoogle Scholar
  16. 16.
    Hunter CA, Ellis-Neyes LA, Slifer T, Kanaly S, Grunig G, Fort M, Rennick D, Araujo FG (1997) IL-10 is required to prevent immune hyperactivity during infection with Trypanosoma cruzi. J Immunol 158:3311–3316PubMedGoogle Scholar
  17. 17.
    Gazzinelli RT, Wysocka M, Hieny S, Scharton-Kersten T, Cheever A, Kuhn R, Muller W, Trinchieri G, Sher A (1996) In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+T cells and accompanied by overproduction of IL-12, IFN-gamma and TNF-alpha. J Immunol 157:798–805PubMedGoogle Scholar
  18. 18.
    Rivas L, Moreno J, Canavate C, Alvar J (2004) Virulence and disease in leishmaniasis: what is relevant for the patient? Trends Parasitol 20:297–301PubMedCrossRefGoogle Scholar
  19. 19.
    Sacks D, Anderson C (2004) Re-examination of the immunosuppressive mechanisms mediating non-cure of Leishmania infection in mice. Immunol Rev 201:225–238PubMedCrossRefGoogle Scholar
  20. 20.
    Rogers KA, Titus RG (2004) The human cytokine response to Leishmania major early after exposure to the parasite in vitro. J Parasitol 90:557–563PubMedCrossRefGoogle Scholar
  21. 21.
    Walther M, Woodruff J, Edele F, Jeffries D, Tongren JE, King E, Andrews L, Bejon P, Gilbert SC, de Souza JB, Sinden R, Hill AV, Riley EM (2006) Innate immune responses to human malaria: heterogeneous cytokine responses to blood-stage Plasmodium falciparum correlate with parasitological and clinical outcomes. J Immunol 177:5736–5745PubMedGoogle Scholar
  22. 22.
    Ringwald P, Peyron F, Vuillez JP, Touze JE, Le Bras J, Deloron P (1991) Levels of cytokines in plasma during Plasmodium falciparum malaria attacks. J Clin Microbiol 29:2076–2078PubMedGoogle Scholar
  23. 23.
    Koch O, Awomoyi A, Usen S, Jallow M, Richardson A, Hull J, Pinder M, Newport M, Kwiatkowski D (2002) IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria. J Infect Dis 185:1684–1687PubMedCrossRefGoogle Scholar
  24. 24.
    Amani V, Vigario AM, Belnoue E, Marussig M, Fonseca L, Mazier D, Renia L (2000) Involvement of IFN-gamma receptor-medicated signaling in pathology and anti-malarial immunity induced by Plasmodium berghei infection. Eur J Immunol 30:1646–1655PubMedCrossRefGoogle Scholar
  25. 25.
    Grau GE, Piguet PF, Vassalli P, Lambert PH (1989) Tumor-necrosis factor and other cytokines in cerebral malaria: experimental and clinical data. Immunol Rev 112:49–70PubMedCrossRefGoogle Scholar
  26. 26.
    McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371:508–510PubMedCrossRefGoogle Scholar
  27. 27.
    Omer FM, Riley EM (1998) Transforming growth factor beta production is inversely correlated with severity of murine malaria infection. J Exp Med 188:39–48PubMedCrossRefGoogle Scholar
  28. 28.
    Esamai F, Ernerudh J, Janols H, Welin S, Ekerfelt C, Mining S, Forsberg P (2003) Cerebral malaria in children: serum and cerebrospinal fluid TNF-alpha and TGF-beta levels and their relationship to clinical outcome. J Trop Pediatr 49:216–223PubMedCrossRefGoogle Scholar
  29. 29.
    Korbel DS, Finney OC, Riley EM (2004) Natural killer cells and innate immunity to protozoan pathogens. Int J Parasitol 34:1517–1528PubMedCrossRefGoogle Scholar
  30. 30.
    Kossodo S, Monso C, Juillard P, Velu T, Goldman M, Grau GE (1997) Interleukin-10 modulates susceptibility in experimental cerebral malaria. Immunology 91:536–540PubMedCrossRefGoogle Scholar
  31. 31.
    Li C, Sanni LA, Omer F, Riley E, Langhorne J (2003) Pathology of Plasmodium chabaudi chabaudi infection and mortality in interleukin-10-deficient mice are ameliorated by anti-tumor necrosis factor alpha and exacerbated by anti-transforming growth factor beta antibodies. Infect Immun 71:4850–4856PubMedCrossRefGoogle Scholar
  32. 32.
    Li C, Corraliza I, Langhorne J (1999) A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect Immun 67:4435–4442PubMedGoogle Scholar
  33. 33.
    Palsson-McDermott EM, O'Neill LA (2004) Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 113:153–162PubMedCrossRefGoogle Scholar
  34. 34.
    Triantafilou M, Gamper FG, Haston RM, Mouratis MA, Morath S, Hartung T, Triantafilou K (2006) Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J Biol Chem 281:31002–31011PubMedCrossRefGoogle Scholar
  35. 35.
    McCartney-Francis N, Jin W, Wahl SM (2004) Aberrant Toll receptor expression and endotoxin hypersensitivity in mice lacking a functional TGF-beta 1 signaling pathway. J Immunol 172:3814–3821PubMedGoogle Scholar
  36. 36.
    Liew FY, Xu D, Brint EK, O'Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458PubMedCrossRefGoogle Scholar
  37. 37.
    Ferguson MA (1999) The structure, biosynthesis and functions of glycosylphosphatidylinositol anchors, and the contributions of trypanosome research. J Cell Sci 112(Pt 17):2799–2809PubMedGoogle Scholar
  38. 38.
    Tachado SD, Mazhari-Tabrizi R, Schofield L (1999) Specificity in signal transduction among glycosylphosphatidylinositols of Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. Parasite Immunol 21:609–617PubMedCrossRefGoogle Scholar
  39. 39.
    Ropert C, Gazzinelli RT (2000) Signaling of immune system cells by glycosylphosphatidylinositol (GPI) anchor and related structures derived from parasitic protozoa. Curr Opin Microbiol 3:395–403PubMedCrossRefGoogle Scholar
  40. 40.
    Lodge R, Descoteaux A (2005) Modulation of phagolysosome biogenesis by the lipophosphoglycan of Leishmania. Clin Immunol 114:256–265PubMedCrossRefGoogle Scholar
  41. 41.
    Camargo MM, Andrade AC, Almeida IC, Travassos LR, Gazzinelli RT (1997) Glycoconjugates isolated from Trypanosoma cruzi but not from Leishmania species membranes trigger nitric oxide synthesis as well as microbicidal activity in IFN-gamma-primed macrophages. J Immunol 159:6131–6139PubMedGoogle Scholar
  42. 42.
    Camargo MM, Almeida IC, Pereira ME, Ferguson MA, Travassos LR, Gazzinelli RT (1997) Glycosylphosphatidylinositol-anchored mucin-like glycoproteins isolated from Trypanosoma cruzi trypomastigotes initiate the synthesis of proinflammatory cytokines by macrophages. J Immunol 158:5890–5901PubMedGoogle Scholar
  43. 43.
    Ropert C, Ferreira LR, Campos MA, Procopio DO, Travassos LR, Ferguson MA, Reis LF, Teixeira MM, Almeida IC, Gazzinelli RT (2002) Macrophage signaling by glycosylphosphatidylinositol-anchored mucin-like glycoproteins derived from Trypanosoma cruzi trypomastigotes. Microbes Infect 4:1015–1025PubMedCrossRefGoogle Scholar
  44. 44.
    Almeida IC, Gazzinelli RT (2001) Proinflammatory activity of glycosylphosphatidylinositol anchors derived from Trypanosoma cruzi: structural and functional analyses. J Leukoc Biol 70:467–477PubMedGoogle Scholar
  45. 45.
    Schofield L, Hackett F (1993) Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. J Exp Med 177:145–153PubMedCrossRefGoogle Scholar
  46. 46.
    Tachado SD, Gerold P, McConville MJ, Baldwin T, Quilici D, Schwarz RT, Schofield L (1996) Glycosylphosphatidylinositol toxin of Plasmodium induces nitric oxide synthase expression in macrophages and vascular endothelial cells by a protein tyrosine kinase-dependent and protein kinase C-dependent signaling pathway. J Immunol 156:1897–1907PubMedGoogle Scholar
  47. 47.
    Debierre-Grockiego F, Azzouz N, Schmidt J, Dubremetz JF, Geyer H, Geyer R, Weingart R, Schmidt RR, Schwarz RT (2003) Roles of glycosylphosphatidylinositols of Toxoplasma gondii. Induction of tumor necrosis factor-alpha production in macrophages. J Biol Chem 278:32987–32993PubMedCrossRefGoogle Scholar
  48. 48.
    Ropert C, Almeida IC, Closel M, Travassos LR, Ferguson MA, Cohen P, Gazzinelli RT (2001) Requirement of mitogen-activated protein kinases and I kappa B phosphorylation for induction of proinflammatory cytokines synthesis by macrophages indicates functional similarity of receptors triggered by glycosylphosphatidylinositol anchors from parasitic protozoa and bacterial lipopolysaccharide. J Immunol 166:3423–3431PubMedGoogle Scholar
  49. 49.
    Campos MA, Almeida IC, Takeuchi O, Akira S, Valente EP, Procopio DO, Travassos LR, Smith JA, Golenbock DT, Gazzinelli RT (2001) Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J Immunol 167:416–423PubMedGoogle Scholar
  50. 50.
    Ropert C, Ferreira LR, Campos MA, Procopio DO, Travassos LR, Ferguson MA, Reis LF, Teixeira MM, Almeida IC, Gazzinelli RT (2002) Macrophage signaling by glycosylphosphatidylinositol-anchored mucin-like glycoproteins derived from Trypanosoma cruzi trypomastigotes. Microbes Infect 4:1015–1025PubMedCrossRefGoogle Scholar
  51. 51.
    Oliveira AC, Peixoto JR, de Arruda LB, Campos MA, Gazzinelli RT, Golenbock DT, Akira S, Previato JO, Mendonca-Previato L, Nobrega A, Bellio M (2004) Expression of functional TLR4 confers proinflammatory responsiveness to Trypanosoma cruzi glycoinositolphospholipids and higher resistance to infection with T. cruzi. J Immunol 173:5688–5696PubMedGoogle Scholar
  52. 52.
    Becker I, Salaiza N, Aguirre M, Delgado J, Carrillo-Carrasco N, Kobeh LG, Ruiz A, Cervantes R, Torres AP, Cabrera N, Gonzalez A, Maldonado C, Isibasi A (2003) Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Mol Biochem Parasitol 130:65–74PubMedCrossRefGoogle Scholar
  53. 53.
    Krishnegowda G, Hajjar AM, Zhu JZ, Douglass EJ, Uematsu S, Akira S, Woods AS, Gowda DC (2005) Induction of proinflammatory responses in macrophages by the Glycosylphosphatidylinositols of Plasmodium falciparum—cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem 280:8606–8616PubMedCrossRefGoogle Scholar
  54. 54.
    Naik RS, Branch OH, Woods AS, Vijaykumar M, Perkins DJ, Nahlen BL, Lal AA, Cotter RJ, Costello CE, Ockenhouse CF, Davidson EA, Gowda DC (2000) Glycosylphosphatidylinositol anchors of Plasmodium falciparum: molecular characterization and naturally elicited antibody response that may provide immunity to malaria pathogenesis. J Exp Med 192:1563–1576PubMedCrossRefGoogle Scholar
  55. 55.
    Debierre-Grockiego F, Campos MA, Azzouz N, Schmidt J, Bieker U, Resende MG, Mansur DS, Weingart R, Schmidt RR, Golenbock DT, Gazzinelli RT, Schwarz RT (2007) Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from Toxoplasma gondii. J Immunol 179:1129–1137PubMedGoogle Scholar
  56. 56.
    Shoda LK, Kegerreis KA, Suarez CE, Roditi I, Corral RS, Bertot GM, Norimine J, Brown WC (2001) DNA from protozoan parasites Babesia bovis, Trypanosoma cruzi, and T. brucei is mitogenic for B lymphocytes and stimulates macrophage expression of interleukin-12, tumor necrosis factor alpha, and nitric oxide. Infect Immun 69:2162–2171PubMedCrossRefGoogle Scholar
  57. 57.
    Brown WC, Suarez CE, Shoda LK, Estes DM (1999) Modulation of host immune responses by protozoal DNA. Vet Immunol Immunopathol 72:87–94PubMedCrossRefGoogle Scholar
  58. 58.
    Brown WC, Corral RS (2002) Stimulation of B lymphocytes, macrophages, and dendritic cells by protozoan DNA. Microbes Infect 4:969–974PubMedCrossRefGoogle Scholar
  59. 59.
    Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A (2006) Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J Immunol 177:3515–3519PubMedGoogle Scholar
  60. 60.
    Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408:740–745PubMedCrossRefGoogle Scholar
  61. 61.
    Drennan MB, Stijlemans B, Van den AJ, Quesniaux VJ, Barkhuizen M, Brombacher F, De Baetselier P, Ryffel B, Magez S (2005) The induction of a type 1 immune response following a Trypanosoma brucei infection is MyD88 dependent. J Immunol 175:2501–2509PubMedGoogle Scholar
  62. 62.
    Coban C, Ishii KJ, Sullivan DJ, Kumar N (2002) Purified malaria pigment (hemozoin) enhances dendritic cell maturation and modulates the isotype of antibodies induced by a DNA vaccine. Infect Immun 70:3939–3943PubMedCrossRefGoogle Scholar
  63. 63.
    Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S (2005) Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med 201:19–25PubMedCrossRefGoogle Scholar
  64. 64.
    Millington OR, Di Lorenzo C, Phillips RS, Garside P, Brewer JM (2006) Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function. J Biol 5:5PubMedCrossRefGoogle Scholar
  65. 65.
    Urban BC, Todryk S (2006) Malaria pigment paralyzes dendritic cells. J Biol 5:4PubMedCrossRefGoogle Scholar
  66. 66.
    Skorokhod OA, Alessio M, Mordmuller B, Arese P, Schwarzer E (2004) Hemozoin (malarial pigment) inhibits differentiation and maturation of human monocyte-derived dendritic cells: a peroxisome proliferator-activated receptor-gamma-mediated effect. J Immunol 173:4066–4074PubMedGoogle Scholar
  67. 67.
    Taramelli D, Basilico N, Pagani E, Grande R, Monti D, Ghione M, Olliaro P (1995) The heme moiety of malaria pigment (beta-hematin) mediates the inhibition of nitric oxide and tumor necrosis factor-alpha production by lipopolysaccharide-stimulated macrophages. Exp Parasitol 81:501–511PubMedCrossRefGoogle Scholar
  68. 68.
    Jaramillo M, Gowda DC, Radzioch D, Olivier M (2003) Hemozoin increases IFN-gamma-inducible macrophage nitric oxide generation through extracellular signal-regulated kinase- and NF-kappa B-dependent pathways. J Immunol 171:4243–4253PubMedGoogle Scholar
  69. 69.
    Huy NT, Trang DTX, Kariu T, Sasai M, Saida K, Harada S, Kamei K (2006) Leukocyte activation by malarial pigment. Parasitol Int 55:75–81PubMedCrossRefGoogle Scholar
  70. 70.
    Deshpande P, Shastry P (2004) Modulation of cytokine profiles by malaria pigment—hemozoin: role of IL-10 in suppression of proliferative responses of mitogen stimulated human PBMC. Cytokine 28:205–213PubMedCrossRefGoogle Scholar
  71. 71.
    Keller CC, Yamo O, Ouma C, Ong'echa JM, Ounah D, Hittner JB, Vulule JM, Perkins DJ (2006) Acquisition of hemozoin by monocytes down-regulates interleukin-12 p40 (IL-12p40) transcripts and circulating IL-12p70 through an IL-10-dependent mechanism: in vivo and in vitro findings in severe malarial anemia. Infect Immun 74:5249–5260PubMedCrossRefGoogle Scholar
  72. 72.
    Schwarzer E, Turrini F, Ulliers D, Giribaldi G, Ginsburg H, Arese P (1992) Impairment of macrophage functions after ingestion of Plasmodium falciparum-infected erythrocytes or isolated malarial pigment. J Exp Med 176:1033–1041PubMedCrossRefGoogle Scholar
  73. 73.
    Schwarzer E, Alessio M, Ulliers D, Arese P (1998) Phagocytosis of the malarial pigment, hemozoin, impairs expression of major histocompatibility complex class II antigen, CD54, and CD11c in human monocytes. Infect Immun 66:1601–1606PubMedGoogle Scholar
  74. 74.
    Parroche P, Lauw FN, Goutagny N, Latz E, Monks BG, Visintin A, Halmen KA, Lamphier M, Olivier M, Bartholomeu DC, Gazzinelli RT, Golenbock DT (2007) Malaria hemozoin is immunologically inert but radically enhances innate responses by presenting malaria DNA to Toll-like receptor 9. Proc Natl Acad Sci USA 104:1919–1924PubMedCrossRefGoogle Scholar
  75. 75.
    Jaramillo M, Plante I, Ouellet N, Vandal K, Tessier PA, Olivier M (2004) Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection. J Immunol 172:3101–3110PubMedGoogle Scholar
  76. 76.
    Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308:1626–1629PubMedCrossRefGoogle Scholar
  77. 77.
    Ropert C, Gazzinelli RT (2004) Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi. J Endotoxin Res 10:425–430PubMedGoogle Scholar
  78. 78.
    Trinchieri G, Sher A (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179–190PubMedCrossRefGoogle Scholar
  79. 79.
    Coban C, Ishii KJ, Horii T, Akira S (2007) Manipulation of host innate immune responses by the malaria parasite. Trends Microbiol 15:271–278PubMedCrossRefGoogle Scholar
  80. 80.
    Mockenhaupt FP, Cramer JP, Hamann L, Stegemann MS, Eckert J, Oh NR, Otchwemah RN, Dietz E, Ehrhardt S, Schroder NW, Bienzle U, Schumann RR (2006) Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria. J Commun Dis 38:230–245PubMedGoogle Scholar
  81. 81.
    Mockenhaupt FP, Hamann L, von Gaertner C, Bedu-Addo G, von Kleinsorgen C, Schumann RR, Bienzle U (2006) Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis 194:184–188PubMedCrossRefGoogle Scholar
  82. 82.
    Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ, Kyrieleis O, Khan A, Aucan C, Segal S, Moore CE, Knox K, Campbell SJ, Lienhardt C, Scott A, Aaby P, Sow OY, Grignani RT, Sillah J, Sirugo G, Peshu N, Williams TN, Maitland K, Davies RJ, Kwiatkowski DP, Day NP, Yala D, Crook DW, Marsh K, Berkley JA, O'Neill LA, Hill AV (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 39:523–528PubMedCrossRefGoogle Scholar
  83. 83.
    Loharungsikul S, Troye-Blomberg M, Amoudruz P, Pichyangkul S, Yongvanitchit K, Looareesuwan S, Mahakunkijcharoen Y, Sarntivijai S, Khusmith S (2007) Expression of Toll-like receptors on antigen-presenting cells in patients with falciparum malaria. Acta Trop (in press). DOI  10.1016/j.actatropica.2007.08.002
  84. 84.
    McCall MB, Netea MG, Hermsen CC, Jansen T, Jacobs L, Golenbock D, van der Ven AJ, Sauerwein RW (2007) Plasmodium falciparum infection causes proinflammatory priming of human TLR responses. J Immunol 179:162–171PubMedGoogle Scholar
  85. 85.
    Ockenhouse CF, Hu WC, Kester KE, Cummings JF, Stewart A, Heppner DG, Jedlicka AE, Scott AL, Wolfe ND, Vahey M, Burke DS (2006) Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria. Infect Immun 74:5561–5573PubMedCrossRefGoogle Scholar
  86. 86.
    Stevenson MM, Riley EM (2004) Innate immunity to malaria. Nat Rev Immunol 4:169–180PubMedCrossRefGoogle Scholar
  87. 87.
    Perry JA, Olver CS, Burnett RC, Avery AC (2005) Cutting edge: the acquisition of TLR tolerance during malaria infection impacts T cell activation. J Immunol 174:5921–5925PubMedGoogle Scholar
  88. 88.
    Chen M, Aosai F, Norose K, Mun HS, Takeuchi O, Akira S, Yano A (2002) Involvement of MyD88 in host defense and the down-regulation of anti-heat shock protein 70 autoantibody formation by MyD88 in Toxoplasma gondii-infected mice. J Parasitol 88:1017–1019PubMedGoogle Scholar
  89. 89.
    Scanga CA, Aliberti J, Jankovic D, Tilloy F, Bennouna S, Denkers EY, Medzhitov R, Sher A (2002) Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J Immunol 168:5997–6001PubMedGoogle Scholar
  90. 90.
    Campos MA, Closel M, Valente EP, Cardoso JE, Akira S, Alvarez-Leite JI, Ropert C, Gazzinelli RT (2004) Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol 172:1711–1718PubMedGoogle Scholar
  91. 91.
    De Veer MJ, Curtis JM, Baldwin TM, DiDonato JA, Sexton A, McConville MJ, Handman E, Schofield L (2003) MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling. Eur J Immunol 33:2822–2831PubMedCrossRefGoogle Scholar
  92. 92.
    Muraille E, De Trez C, Brait M, De Baetselier P, Leo O, Carlier Y (2003) Genetically resistant mice lacking MyD88-adapter protein display a high susceptibility to Leishmania major infection associated with a polarized Th2 response. J Immunol 170:4237–4241PubMedGoogle Scholar
  93. 93.
    Adachi K, Tsutsui H, Kashiwamura S, Seki E, Nakano H, Takeuchi O, Takeda K, Okumura K, Van Kaer L, Okamura H, Akira S, Nakanishi K (2001) Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J Immunol 167:5928–5934PubMedGoogle Scholar
  94. 94.
    Coban C, Ishii KJ, Uematsu S, Arisue N, Sato S, Yamamoto M, Kawai T, Takeuchi O, Hisaeda H, Horii T, Akira S (2007) Pathological role of Toll-like receptor signaling in cerebral malaria. Int Immunol 19:67–79PubMedCrossRefGoogle Scholar
  95. 95.
    Togbe D, Schofield L, Grau GE, Schnyder B, Boissay V, Charron S, Rose S, Beutler B, Quesniaux VF, Ryffel B (2007) Murine cerebral malaria development is independent of toll-like receptor signaling. Am J Pathol 170:1640–1648PubMedCrossRefGoogle Scholar
  96. 96.
    Lepenies B, Cramer JP, Burchard GD, Wagner H, Kirschning CJ, Jacobs T (2007) Induction of experimental cerebral malaria is independent of TLR2/4/9. Med Microbiol Immunol 197:39–44PubMedCrossRefGoogle Scholar
  97. 97.
    Franklin BS, Rodrigues SO, Antonelli LR, Oliveira RV, Goncalves AM, Sales-Junior PA, Valente EP, Alvarez-Leite JI, Ropert C, Golenbock DT, Gazzinelli RT (2007) MyD88-dependent activation of dendritic cells and CD4(+) T lymphocytes mediates symptoms, but is not required for the immunological control of parasites during rodent malaria. Microbes Infect 9:881–890PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Catherine Ropert
    • 1
  • Bernardo S. Franklin
    • 1
  • Ricardo T. Gazzinelli
    • 1
    • 2
    • 3
  1. 1.Laboratory of Immunopathology, René Rachou InstituteFIOCRUZBelo HorizonteBrazil
  2. 2.Department of Biochemistry and Immunology, Institute of Biological SciencesFederal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Division of Infectious Disease and Immunology, Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

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