Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Publisher: BioMed Central
Journal: Parasites & Vectors
Types: Article
Subjects: qx_70, Lipophosphoglycan, wr_350, qw_571, Research, Leishmania major, Leishmania mexicana, TLR2

Classified by OpenAIRE into

mesheuropmc: parasitic diseases
Background Leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. Despite several studies reporting involvement of the innate immune receptor Toll-like receptor 2 (TLR2) in the recognition of surface glycolipids from Leishmania parasites in vitro, the role of TLR2 and its co-receptors during cutaneous leishmaniasis infection in vivo is unknown. Methods To explore the role of TLR2 and its co-receptors in cutaneous leishmaniasis, mice deficient in either TLR2, 4, 1 or 6, or wild-type (WT) controls, were infected with either Leishmania major promastigotes, L. mexicana promastigotes, L. mexicana amastigotes, or LPG1 ?/? L. mexicana promastigotes. For each infection, lesion sizes were monitored and parasite burden was assessed at various time points. To assess immune responses, draining lymph node (DLN) cells were re-stimulated with parasite antigens and the production of cytokines and parasite-specific antibody isotypes in blood was determined by ELISA. Results Mice deficient in TLR2 and TLR4 presented with larger lesions and higher parasite burdens than WT controls. Mice lacking TLR2 co-receptors TLR1 or TLR6 did not show exacerbated infection, suggesting that TLR2 does not require either co-receptor in the recognition of Leishmania infection. Furthermore, it appears that lipophosphoglycan (LPG) is not the major mediator of TLR2 activation during infection with L. mexicana, as parasites lacking LPG (axenic amastigotes and LPG1 ?/? promastigotes) also resulted in exacerbated disease in TLR2?/? mice. Infected TLR2?/? mice show a skewed Th2 immune response to Leishmania parasites, as demonstrated by elevated IL-4, IL-13 and IL-10 production by DLN cells from L. mexicana infected mice in response to antigen. Furthermore, L. major infected TLR2?/? mice have elevated antigen-specific IgG1 antibodies. Conclusions TLR2 deficiency leads to exacerbation of disease and parasite burden through promotion of Th2 immunity. TLR2 activation in vivo occurs independently of parasite LPG, suggesting other parasite ligands are involved in TLR2 recognition of Leishmania. Electronic supplementary material The online version of this article (doi:10.1186/s13071-016-1807-8) contains supplementary material, which is available to authorized users.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. WHO. Control of the leishmaniases: Report of a meeting of the WHO Expert Committee on the control of leishmaniases. In: WHO Technical Report Series. Geneva: WHO; 2010.
    • 2. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One. 2012;7(5):e35671.
    • 3. Sacks D, Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol. 2002;2(11):845-58.
    • 4. Scott P. IFN-gamma modulates the early development of Th1 and Th2 responses in a murine model of cutaneous leishmaniasis. J Immunol. 1991;147(9):3149-55.
    • 5. Park AY, Hondowicz BD, Scott P. IL-12 is required to maintain a Th1 response during Leishmania major infection. J Immunol. 2000;165(2):896-902.
    • 6. Sypek JP, Chung CL, Mayor SE, Subramanyam JM, Goldman SJ, Sieburth DS, et al. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993;177(6):1797-802.
    • 7. Wei X-Q, Charles IG, Smith A, Ure J, Feng G-J, Huang F-P, et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature. 1995;375(6530):408-11.
    • 8. Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993;178(2):567-77.
    • 9. Muraille E, De Trez C, Brait M, De Baetselier P, Leo O, Carlier Y. Genetically resistant mice lacking MyD88-adapter protein display a high Susceptibility to Leishmania major Infection Associated with a Polarized Th2 Response. J Immunol. 2003;170(8):4237-41.
    • 10. De Veer MJ, Curtis JM, Baldwin TM, DiDonato JA, Sexton A, McConville MJ, Handman E, Schofield L. MyD88 is essential for clearance of Leishmania major: possible role for lipophosphoglycan and Toll-like receptor 2 signaling. Eur J Immunol. 2003;33(10):2822-31.
    • 11. Debus A, Glasner J, Rollinghoff M, Gessner A. High levels of susceptibility and T helper 2 response in MyD88-deficient mice infected with Leishmania major are interleukin-4 dependent. Infect Immun. 2003;71(12):7215-8.
    • 12. Kropf P, Freudenberg N, Kalis C, Modolell M, Herath S, Galanos C, et al. Infection of C57BL/10ScCr and C57BL/10ScNCr mice with Leishmania major reveals a role for Toll-like receptor 4 in the control of parasite replication. J Leukoc Biol. 2004;76(1):48-57.
    • 13. Kropf P, Freudenberg MA, Modolell M, Price HP, Herath S, Antoniazi S, et al. Toll-like receptor 4 contributes to efficient control of infection with the protozoan parasite Leishmania major. Infect Immun. 2004;72(4):1920-8.
    • 14. Abou Fakher FH, Rachinel N, Klimczak M, Louis J, Doyen N. TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors Th1 cell development and the resolution of lesions. J Immunol. 2009;182(3):1386-96.
    • 15. Liese J, Schleicher U, Bogdan C. TLR9 signaling is essential for the innate NK cell response in murine cutaneous leishmaniasis. Eur J Immunol. 2007;37(12):3424-34.
    • 16. Becker I, Salaiza N, Aguirre M, Delgado J, Carrillo-Carrasco N, Kobeh LG, et al. Leishmania lipophosphoglycan (LPG) activates NK cells through toll-like receptor-2. Mol Biochem Parasitol. 2003;130(2):65-74.
    • 17. Kavoosi G, Ardestani SK, Kariminia A, Alimohammadian MH. Leishmania major lipophosphoglycan: discrepancy in Toll-like receptor signaling. Exp Parasitol. 2010;124(2):214-8.
    • 18. Kavoosi G, Ardestani SK, Kariminia A. The involvement of TLR2 in cytokine and reactive oxygen species (ROS) production by PBMCs in response to Leishmania major phosphoglycans (PGs). Parasitology. 2009;136(10):1193-9.
    • 19. Jones DE, Buxbaum LU, Scott P. IL-4-independent inhibition of IL-12 responsiveness during Leishmania amazonensis infection. J Immunol. 2000;165(1):364-72.
    • 20. Thomas BN, Buxbaum LU. Fc{gamma}RIII mediates immunoglobulin G-induced interleukin-10 and is required for chronic Leishmania mexicana lesions. Infect Immun. 2008;76(2):623-31.
    • 21. Nicolas L, Prina E, Lang T, Milon G. Real-time PCR for detection and quantitation of Leishmania in mouse tissues. J Clin Microbiol. 2002;40(5):1666-9.
    • 22. Kwakye-Nuako G, Mosore M-T, Duplessis C, Bates MD, Puplampu N, Mensah-Attipoe I, et al. First isolation of a new species of Leishmania responsible for human cutaneous leishmaniasis in Ghana and classification in the Leishmania enriettii complex. Int J Parasitol. 2015;45(11):679-84.
    • 23. Ilg T. Lipophosphoglycan is not required for infection of macrophages or mice by Leishmania mexicana. EMBO J. 2000;19(9):1953-62.
    • 24. Finkelman FD, Holmes J, Katona IM, Urban JF, Beckmann MP, Park LS, et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990;8(1):303-33.
    • 25. Murray HW, Zhang Y, Raman VS, Reed SG, Ma X. Regulatory actions of Toll-like receptor 2 (TLR2) and TLR4 in Leishmania donovani infection in the liver. Infect Immun. 2013;81(7):2318-26.
    • 26. Vargas-Inchaustegui DA, Tai W, Xin L, Hogg AE, Corry DB, Soong L. Distinct roles for MyD88 and Toll-like receptor 2 during Leishmania braziliensis infection in mice. Infect Immun. 2009;77(7):2948-56.
    • 27. Schamber-Reis BL, Petritus PM, Caetano BC, Martinez ER, Okuda K, Golenbock D, et al. UNC93B1 and nucleic acid-sensing Toll-like receptors mediate host resistance to infection with Leishmania major. J Biol Chem. 2013;288(10):7127-36.
    • 28. Kavoosi G, Ardestani SK, Kariminia A, Alimohammadian MH: Leishmania major lipophosphoglycan: Discrepancy in toll-like receptor signaling. ExpParasitol, In Press, Corrected Proof.
    • 29. Osanya A, Song EH, Metz K, Shimak RM, Boggiatto PM, Huffman E, et al. Pathogen-derived oligosaccharides improve innate immune response to intracellular parasite infection. Am J Pathol. 2011;179(3):1329-37.
    • 30. Takeuchi O, Kawai T, Mühlradt PF, Morr M, Radolf JD, Zychlinsky A, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol. 2001;13(7):933-40.
    • 31. Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, et al. Cutting edge: Role of toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol. 2002;169(1):10-4.
    • 32. Omueti KO, Beyer JM, Johnson CM, Lyle EA, Tapping RI. Domain exchange between human toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination. J Biol Chem. 2005;280(44):36616-25.
    • 33. Buwitt-Beckmann U, Heine H, Wiesmüller K-H, Jung G, Brock R, Akira S, Ulmer AJ. TLR1- and TLR6-independent recognition of bacterial lipopeptides. J Biol Chem. 2006;281(14):9049-57.
    • 34. Jin MS, Kim SE, Heo JY, Lee ME, Kim HM, Paik S-G, Lee H, Lee J-O. Crystal structure of the TLR1-TLR2 heterodimer induced by binding of a tri-acylated lipopeptide. Cell. 2007;130(6):1071-82.
    • 35. Jin MS, Lee JO. Structures of the toll-like receptor family and its ligand complexes. Immunity. 2008;29(2):182-91.
    • 36. Farhat K, Riekenberg S, Heine H, Debarry J, Lang R, Mages J, et al. Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling. J Leukoc Biol. 2008;83(3):692-701.
    • 37. Ribeiro-Gomes FL, Moniz-de-Souza MC, Alexandre-Moreira MS, Dias WB, Lopes MF, Nunes MP, et al. Neutrophils activate macrophages for intracellular killing of Leishmania major through recruitment of TLR4 by neutrophil elastase. J Immunol. 2007;179(6):3988-94.
    • 38. Huang L, Hinchman M, Mendez S. Coinjection with TLR2 agonist Pam3CSK4 reduces the pathology of leishmanization in mice. PLoS Negl Trop Dis. 2015;9(3):e0003546.
    • 39. Miles SA, Conrad SM, Alves RG, Jeronimo SMB, Mosser DM. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania. J Exp Med. 2005;201(5):747-54.
    • 40. Kima PE, Constant SL, Hannum L, Colmenares M, Lee KS, Haberman AM, et al. Internalization of Leishmania mexicana complex amastigotes via the Fc receptor is required to sustain infection in murine cutaneous leishmaniasis. J Exp Med. 2000;191(6):1063-8.
    • 41. Buxbaum LU, Scott P. Interleukin 10- and Fcγ receptor-deficient mice resolve Leishmania mexicana lesions. Infect Immun. 2005;73(4):2101-8.
    • 42. Revaz-Breton M, Ronet C, Ives A, Torre YH-L, Masina S, Tacchini-Cottier F, Launois P. The MyD88 protein 88 pathway is differently involved in immune responses induced by distinct substrains of Leishmania major. Eur J Immunol. 2010;40(6):1697-707.
    • 43. Trinchieri G, Sher A. Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7(3):179-90.
    • 44. Bafica A, Santiago HC, Goldszmid R, Ropert C, Gazzinelli RT, Sher A. Cutting Edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J Immunol. 2006;177(6):3515-9.
    • 45. Faria MS, Reis FC, Lima AP. Toll-like receptors in Leishmania infections: guardians or promoters? J Parasitol Res. 2012;2012:930257.
    • 46. Liu D, Kebaier C, Pakpour N, Capul AA, Beverley SM, Scott P, Uzonna JE. Leishmania major phosphoglycans influence the host early immune response by modulating dendritic cell functions. Infect Immun. 2009;77(8):3272-83.
    • 47. Olivier M, Gregory DJ, Forget G. Subversion mechanisms by which Leishmania parasites can escape the host immune response: a signaling point of view. Clin Microbiol Rev. 2005;18(2):293-305.
    • 48. Späth GF, Epstein L, Leader B, Singer SM, Avila HA, Turco SJ, Beverley SM. Lipophosphoglycan is a virulence factor distinct from related glycoconjugates in the protozoan parasite Leishmania major. Proc Natl Acad Sci U S A. 2000;97(16):9258-63.
    • 49. Spath GF, Garraway LA, Turco SJ, Beverley SM. The role(s) of lipophosphoglycan (LPG) in the establishment of Leishmania major infections in mammalian hosts. Proc Natl Acad Sci U S A. 2003;100(16):9536-41.
    • 50. Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, et al. Compartmentalized control of skin immunity by resident commensals. Science. 2012;337(6098):1115-9.
  • Inferred research data

    The results below are discovered through our pilot algorithms. Let us know how we are doing!

    Title Trust
  • Discovered through pilot similarity algorithms. Send us your feedback.

Share - Bookmark

Cite this article