Cell and Tissue Research

, Volume 343, Issue 1, pp 121–130 | Cite as

Avian toll-like receptors

  • Robert Brownlie
  • Brenda Allan


Analysis of the genomes of two distantly related bird species, chicken and zebra finch (divergence of about 100 million years), indicate that there are ten avian toll-like receptors and that five of these, TLR2a, 2b, 3, 4, 5 and 7, are clear orthologs to TLRs found in mammals. Duplication of genes has led to TLR1La and 1Lb, TLR2a and 2b, and two TLR7s in the zebra finch. Avian TLR21 may be orthologous to TLR21 found in fish and amphibians, and avian TLR15, which is phylogenetically related to the TLR2 family, appears to be unique to avian species. While TLR2 is conserved between mammalian and avian species, the other TLR2 family members evolved independently. Dimerization between either of the two avian TLR2 species and TLR1La or 1Lb permits recognition of the same broad range of molecules as recognized by mammalian TLR2 dimerized with either TLR1, 6 and 10. Similarly, while TLR9 has been lost from the avian genome, DNA high in unmethylated CpG motifs is immunostimulatory through avian TLR21 which is absent in mammals. Thus, while some TLR members were commonly retained in both mammals and birds, others were separately lost or gained, or diverged independently; but broadly speaking the TLRs of the two classes of vertebrates evolved to recognize very similar spectra of microbial products. Components of downstream TLR signaling are also mostly conserved but with some losses in avian species; notably, TRAM is absent in avian genomes and, hence, the TRIF/TRAM-dependent signaling pathway utilized by mammals in LPS activation appears to be absent in birds.


Toll-like receptor Avian Innate Immunity Chicken 


  1. Abdul-Careem MF, Haq K, Shanmuganathan S, Read LR, Schat KA, Heidari M, Sharif S (2009) Induction of innate host responses in the lungs of chickens following infection with a very virulent strain of Marek's disease virus. Virology 393:250–257CrossRefPubMedGoogle Scholar
  2. Abreu MT (2010) Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10:131–144CrossRefPubMedGoogle Scholar
  3. Adler HE, DaMassa AJ (1979) Toxicity of endotoxin to chicks. Avian Dis 23:174–178CrossRefPubMedGoogle Scholar
  4. Akashi-Takamura S, Miyake K (2008) TLR accessory molecules. Curr Opin Immunol 20:420–425CrossRefPubMedGoogle Scholar
  5. Akira S (2009) Pathogen recognition by innate immunity and its signaling. Proc Jpn Acad B Phys Biol Sci 85:143–156CrossRefGoogle Scholar
  6. Ausubel FM (2005) Are innate immune signaling pathways in plants and animals conserved? Nat Immunol 6:973–979CrossRefPubMedGoogle Scholar
  7. Barber MR, Aldridge JR Jr, Webster RG, Magor KE (2010) Association of RIG-I with innate immunity of ducks to influenza. Proc Natl Acad Sci USA 107:5913–5918CrossRefPubMedGoogle Scholar
  8. Bhat A, Gomis S, Potter A, Tikoo SK (2010) Role of Hsp90 in CpG ODN mediated immunostimulation in avian macrophages. Mol Immunol 47:1337–1346CrossRefPubMedGoogle Scholar
  9. Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025–1029CrossRefPubMedGoogle Scholar
  10. Boyd A, Philbin VJ, Smith AL (2007) Conserved and distinct aspects of the avian Toll-like receptor (TLR) system: implications for transmission and control of bird-borne zoonoses. Biochem Soc Trans 35:1504–1507CrossRefPubMedGoogle Scholar
  11. Brikos C, O'Neill LA (2008) Signalling of toll-like receptors. Handb Exp Pharmacol 21–50Google Scholar
  12. Brownlie R, Zhu J, Allan B, Mutwiri GK, Babiuk LA, Potter A, Griebel P (2009) Chicken TLR21 acts as a functional homologue to mammalian TLR9 in the recognition of CpG oligodeoxynucleotides. Mol Immunol 46:3163–3170CrossRefPubMedGoogle Scholar
  13. Consortium (2004) Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432:695–716CrossRefGoogle Scholar
  14. Cormican P, Lloyd AT, Downing T, Connell SJ, Bradley D, O'Farrelly C (2009) The avian Toll-like receptor pathway–subtle differences amidst general conformity. Dev Comp Immunol 33:967–973CrossRefPubMedGoogle Scholar
  15. Crippen TL (2006) The selective inhibition of nitric oxide production in the avian macrophage cell line HD11. Vet Immunol Immunopathol 109:127–137CrossRefPubMedGoogle Scholar
  16. Dalpke A, Frank J, Peter M, Heeg K (2006) Activation of toll-like receptor 9 by DNA from different bacterial species. Infect Immun 74:940–946CrossRefPubMedGoogle Scholar
  17. de Zoete MR, Keestra AM, Roszczenko P, van Putten JP (2010) Activation of human and chicken toll-like receptors by Campylobacter spp. Infect Immun 78:1229–1238CrossRefPubMedGoogle Scholar
  18. Dil N, Qureshi MA (2002) Differential expression of inducible nitric oxide synthase is associated with differential Toll-like receptor-4 expression in chicken macrophages from different genetic backgrounds. Vet Immunol Immunopathol 84:191–207CrossRefPubMedGoogle Scholar
  19. Downing T, Lloyd AT, O'Farrelly C, Bradley DG (2010) The differential evolutionary dynamics of avian cytokine and TLR gene classes. J Immunol 184:6993–7000Google Scholar
  20. Farnell MB, Crippen TL, He H, Swaggerty CL, Kogut MH (2003a) Oxidative burst mediated by toll like receptors (TLR) and CD14 on avian heterophils stimulated with bacterial toll agonists. Dev Comp Immunol 27:423–429CrossRefPubMedGoogle Scholar
  21. Farnell MB, He H, Genovese K, Kogut MH (2003b) Pharmacological analysis of signal transduction pathways required for oxidative burst in chicken heterophils stimulated by a Toll-like receptor 2 agonist. Int Immunopharmacol 3:1677–1684CrossRefPubMedGoogle Scholar
  22. Fukui A, Inoue N, Matsumoto M, Nomura M, Yamada K, Matsuda Y, Toyoshima K, Seya T (2001) Molecular cloning and functional characterization of chicken toll-like receptors. A single chicken toll covers multiple molecular patterns. J Biol Chem 276:47143–47149CrossRefPubMedGoogle Scholar
  23. Gomis S, Babiuk L, Godson DL, Allan B, Thrush T, Townsend H, Willson P, Waters E, Hecker R, Potter A (2003) Protection of chickens against Escherichia coli infections by DNA containing CpG motifs. Infect Immun 71:857–863CrossRefPubMedGoogle Scholar
  24. Gomis S, Babiuk L, Allan B, Willson P, Waters E, Ambrose N, Hecker R, Potter A (2004) Protection of neonatal chicks against a lethal challenge of Escherichia coli using DNA containing cytosine-phosphodiester-guanine motifs. Avian Dis 48:813–822CrossRefPubMedGoogle Scholar
  25. Gomis S, Babiuk L, Allan B, Willson P, Waters E, Hecker R, Potter A (2007) Protection of chickens against a lethal challenge of Escherichia coli by a vaccine containing CpG oligodeoxynucleotides as an adjuvant. Avian Dis 51:78–83CrossRefPubMedGoogle Scholar
  26. Guan Y, Ranoa DR, Jiang S, Mutha SK, Li X, Baudry J, Tapping RI (2010) Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling. J Immunol 184:5094–5103CrossRefPubMedGoogle Scholar
  27. Hansell C, Zhu XW, Brooks H, Sheppard M, Withanage S, Maskell D, McConnell I (2007) Unique features and distribution of the chicken CD83+ cell. J Immunol 179:5117–5125PubMedGoogle Scholar
  28. Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102:2660–2669CrossRefPubMedGoogle Scholar
  29. He H, Kogut MH (2003) CpG-ODN-induced nitric oxide production is mediated through clathrin-dependent endocytosis, endosomal maturation, and activation of PKC, MEK1/2 and p38 MAPK, and NF-kappaB pathways in avian macrophage cells (HD11). Cell Signal 15:911–917CrossRefPubMedGoogle Scholar
  30. He H, Crippen TL, Farnell MB, Kogut MH (2003) Identification of CpG oligodeoxynucleotide motifs that stimulate nitric oxide and cytokine production in avian macrophage and peripheral blood mononuclear cells. Dev Comp Immunol 27:621–627CrossRefPubMedGoogle Scholar
  31. He H, Genovese KJ, Nisbet DJ, Kogut MH (2007a) Synergy of CpG oligodeoxynucleotide and double-stranded RNA (poly I:C) on nitric oxide induction in chicken peripheral blood monocytes. Mol Immunol 44:3234–3242CrossRefPubMedGoogle Scholar
  32. He H, Genovese KJ, Swaggerty CL, Nisbet DJ, Kogut MH (2007b) In vivo priming heterophil innate immune functions and increasing resistance to Salmonella enteritidis infection in neonatal chickens by immune stimulatory CpG oligodeoxynucleotides. Vet Immunol Immunopathol 117:275–283CrossRefPubMedGoogle Scholar
  33. Higgs R, Cormican P, Cahalane S, Allan B, Lloyd AT, Meade K, James T, Lynn DJ, Babiuk LA, O'Farrelly C (2006) Induction of a novel chicken Toll-like receptor following Salmonella enterica serovar Typhimurium infection. Infect Immun 74:1692–1698CrossRefPubMedGoogle Scholar
  34. Higuchi M, Matsuo A, Shingai M, Shida K, Ishii A, Funami K, Suzuki Y, Oshiumi H, Matsumoto M, Seya T (2008) Combinational recognition of bacterial lipoproteins and peptidoglycan by chicken Toll-like receptor 2 subfamily. Dev Comp Immunol 32:147–155CrossRefPubMedGoogle Scholar
  35. Hoshino K, Kaisho T (2008) Nucleic acid sensing Toll-like receptors in dendritic cells. Curr Opin Immunol 20:408–413CrossRefPubMedGoogle Scholar
  36. Iqbal M, Philbin VJ, Smith AL (2005a) Expression patterns of chicken Toll-like receptor mRNA in tissues, immune cell subsets and cell lines. Vet Immunol Immunopathol 104:117–127CrossRefPubMedGoogle Scholar
  37. Iqbal M, Philbin VJ, Withanage GS, Wigley P, Beal RK, Goodchild MJ, Barrow P, McConnell I, Maskell DJ, Young J, Bumstead N, Boyd Y, Smith AL (2005b) Identification and functional characterization of chicken toll-like receptor 5 reveals a fundamental role in the biology of infection with Salmonella enterica serovar Typhimurium. Infect Immun 73:2344–2350CrossRefPubMedGoogle Scholar
  38. Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Huber M, Kalis C, Keck S, Galanos C, Freudenberg M, Beutler B (2005) CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6:565–570CrossRefPubMedGoogle Scholar
  39. Jurk M, Schulte B, Kritzler A, Noll B, Uhlmann E, Wader T, Schetter C, Krieg AM, Vollmer J (2004) C-Class CpG ODN: sequence requirements and characterization of immunostimulatory activities on mRNA level. Immunobiology 209:141–154CrossRefPubMedGoogle Scholar
  40. Kaiser P (2007) The avian immune genome–a glass half-full or half-empty? Cytogenet Genome Res 117:221–230CrossRefPubMedGoogle Scholar
  41. Karpala AJ, Lowenthal JW, Bean AG (2008) Activation of the TLR3 pathway regulates IFNbeta production in chickens. Dev Comp Immunol 32:435–444CrossRefPubMedGoogle Scholar
  42. Kaufman J, Milne S, Göbel TW, Walker BA, Jacob JP, Auffray C, Zoorob R, Beck S (1999) The chicken B locus is a minimal essential major histocompatibility complex. Nature 401:923–925CrossRefPubMedGoogle Scholar
  43. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11:373–384CrossRefPubMedGoogle Scholar
  44. Keestra AM, van Putten JP (2008) Unique properties of the chicken TLR4/MD-2 complex: selective lipopolysaccharide activation of the MyD88-dependent pathway. J Immunol 181:4354–4362PubMedGoogle Scholar
  45. Keestra AM, de Zoete MR, van Aubel RA, van Putten JP (2007) The central leucine-rich repeat region of chicken TLR16 dictates unique ligand specificity and species-specific interaction with TLR2. J Immunol 178:7110–7119PubMedGoogle Scholar
  46. Keestra AM, de Zoete MR, van Aubel RA, van Putten JP (2008) Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin. Mol Immunol 45:1298–1307CrossRefPubMedGoogle Scholar
  47. Kogut MH, Iqbal M, He H, Philbin V, Kaiser P, Smith A (2005) Expression and function of Toll-like receptors in chicken heterophils. Dev Comp Immunol 29:791–807CrossRefPubMedGoogle Scholar
  48. Kogut MH, Genovese KJ, He H, Kaiser P (2008) Flagellin and lipopolysaccharide up-regulation of IL-6 and CXCLi2 gene expression in chicken heterophils is mediated by ERK1/2-dependent activation of AP-1 and NF-kappaB signaling pathways. Innate Immun 14:213–222CrossRefPubMedGoogle Scholar
  49. Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, Monks BG, McKnight CJ, Lamphier MS, Duprex WP, Espevik T, Golenbock DT (2007) Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8:772–779CrossRefPubMedGoogle Scholar
  50. Leulier F, Lemaitre B (2008) Toll-like receptors–taking an evolutionary approach. Nat Rev Genet 9:165–178CrossRefPubMedGoogle Scholar
  51. Leveque G, Forgetta V, Morroll S, Smith AL, Bumstead N, Barrow P, Loredo-Osti JC, Morgan K, Malo D (2003) Allelic variation in TLR4 is linked to susceptibility to Salmonella enterica serovar Typhimurium infection in chickens. Infect Immun 71:1116–1124CrossRefPubMedGoogle Scholar
  52. Lu Y, Sarson AJ, Gong J, Zhou H, Zhu W, Kang Z, Yu H, Sharif S, Han Y (2009) Expression profiles of genes in Toll-like receptor-mediated signaling of broilers infected with Clostridium perfringens. Clin Vaccine Immunol 16:1639–1647CrossRefPubMedGoogle Scholar
  53. MacDonald MR, Xia J, Smith AL, Magor KE (2008) The duck toll like receptor 7: genomic organization, expression and function. Mol Immunol 45:2055–2061CrossRefPubMedGoogle Scholar
  54. Mäkelä SM, Strengell M, Pietilä TE, Osterlund P, Julkunen I (2009) Multiple signaling pathways contribute to synergistic TLR ligand-dependent cytokine gene expression in human monocyte-derived macrophages and dendritic cells. J Leukoc Biol 85:664–672CrossRefPubMedGoogle Scholar
  55. Matsumoto M, Funami K, Oshiumi H, Seya T (2004) Toll-like receptor 3: a link between toll-like receptor, interferon and viruses. Microbiol Immunol 48:147–154PubMedGoogle Scholar
  56. Meade KG, Higgs R, Lloyd AT, Giles S, O'Farrelly C (2009) Differential antimicrobial peptide gene expression patterns during early chicken embryological development. Dev Comp Immunol 33:516–524CrossRefPubMedGoogle Scholar
  57. Nerren JR, Swaggerty CL, MacKinnon KM, Genovese KJ, He H, Pevzner I, Kogut MH (2009) Differential mRNA expression of the avian-specific toll-like receptor 15 between heterophils from Salmonella-susceptible and -resistant chickens. Immunogenetics 61:71–77CrossRefPubMedGoogle Scholar
  58. Nerren JR, He H, Genovese K, Kogut MH (2010) Expression of the avian-specific toll-like receptor 15 in chicken heterophils is mediated by Gram-negative and Gram-positive bacteria, but not TLR agonists. Vet Immunol Immunopathol 136:151–156Google Scholar
  59. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO (2009) The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex. Nature 458:1191–1195CrossRefPubMedGoogle Scholar
  60. Patel BA, Gomis S, Dar A, Willson PJ, Babiuk LA, Potter A, Mutwiri G, Tikoo SK (2008) Oligodeoxynucleotides containing CpG motifs (CpG-ODN) predominantly induce Th1-type immune response in neonatal chicks. Dev Comp Immunol 32:1041–1049CrossRefPubMedGoogle Scholar
  61. Philbin VJ, Iqbal M, Boyd Y, Goodchild MJ, Beal RK, Bumstead N, Young J, Smith AL (2005) Identification and characterization of a functional, alternatively spliced Toll-like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens. Immunology 114:507–521CrossRefPubMedGoogle Scholar
  62. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088CrossRefPubMedGoogle Scholar
  63. Rankin R, Pontarollo R, Ioannou X, Krieg AM, Hecker R, Babiuk LA, van Drunen Littel-van den Hurk S (2001) CpG motif identification for veterinary and laboratory species demonstrates that sequence recognition is highly conserved. Antisense Nucleic Acid Drug Dev 11:333–340CrossRefPubMedGoogle Scholar
  64. Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci USA 102:9577–9582CrossRefPubMedGoogle Scholar
  65. Schütt C (1999) CD14. Int J Biochem Cell Biol 31:545–549CrossRefPubMedGoogle Scholar
  66. Schwarz H, Schneider K, Ohnemus A, Lavric M, Kothlow S, Bauer S, Kaspers B, Staeheli P (2007) Chicken toll-like receptor 3 recognizes its cognate ligand when ectopically expressed in human cells. J Interferon Cytokine Res 27:97–101CrossRefPubMedGoogle Scholar
  67. Shaughnessy RG, Meade KG, Cahalane S, Allan B, Reiman C, Callanan JJ, O'Farrelly C (2009) Innate immune gene expression differentiates the early avian intestinal response between Salmonella and Campylobacter. Vet Immunol Immunopathol 132:191–198CrossRefPubMedGoogle Scholar
  68. Shimazu R, Akashi S, Ogata H, Nagai Y, Fukudome K, Miyake K, Kimoto M (1999) MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med 189:1777–1782CrossRefPubMedGoogle Scholar
  69. Smith J, Speed D, Law AS, Glass EJ, Burt DW (2004) In-silico identification of chicken immune-related genes. Immunogenetics 56:122–133CrossRefPubMedGoogle Scholar
  70. Taghavi A, Allan B, Mutwiri G, Van Kessel A, Willson P, Babiuk L, Potter A, Gomis S (2008) Protection of neonatal broiler chicks against Salmonella Typhimurium septicemia by DNA containing CpG motifs. Avian Dis 52:398–406CrossRefPubMedGoogle Scholar
  71. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820CrossRefPubMedGoogle Scholar
  72. Tanimura N, Saitoh S, Matsumoto F, Akashi-Takamura S, Miyake K (2008) Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. Biochem Biophys Res Commun 368:94–99CrossRefPubMedGoogle Scholar
  73. Temperley ND, Berlin S, Paton IR, Griffin DK, Burt DW (2008) Evolution of the chicken Toll-like receptor gene family: a story of gene gain and gene loss. BMC Genomics 9:62CrossRefPubMedGoogle Scholar
  74. Uematsu S, Akira S (2008) Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol 1–20Google Scholar
  75. Uematsu S, Jang MH, Chevrier N, Guo Z, Kumagai Y, Yamamoto M, Kato H, Sougawa N, Matsui H, Kuwata H, Hemmi H, Coban C, Kawai T, Ishii KJ, Takeuchi O, Miyasaka M, Takeda K, Akira S (2006) Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c + lamina propria cells. Nat Immunol 7:868–874CrossRefPubMedGoogle Scholar
  76. Vinkler M, Bryjova A, Albrecht T, Bryja J (2009) Identification of the first Toll-like receptor gene in passerine birds: TLR4 orthologue in zebra finch (Taeniopygia guttata). Tissue Antigens 74:32–41CrossRefPubMedGoogle Scholar
  77. Wang Y, Shan C, Ming S, Liu Y, Du Y, Jiang G (2008) Immunoadjuvant effects of bacterial genomic DNA and CpG oligodeoxynucleotides on avian influenza virus subtype H5N1 inactivated oil emulsion vaccine in chicken. Res Vet Sci 86:399–405Google Scholar
  78. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431–1433CrossRefPubMedGoogle Scholar
  79. Wu Z, Rothwell L, Hu T, Kaiser P (2009) Chicken CD14, unlike mammalian CD14, is trans-membrane rather than GPI-anchored. Dev Comp Immunol 33:97–104CrossRefPubMedGoogle Scholar
  80. Xie H, Raybourne RB, Babu US, Lillehoj HS, Heckert RA (2003) CpG-induced immunomodulation and intracellular bacterial killing in a chicken macrophage cell line. Dev Comp Immunol 27:823–834CrossRefPubMedGoogle Scholar
  81. Xing Z, Cardona CJ, Li J, Dao N, Tran T, Andrada J (2008) Modulation of the immune responses in chickens by low-pathogenicity avian influenza virus H9N2. J Gen Virol 89:1288–1299CrossRefPubMedGoogle Scholar
  82. Yang Y, Liu B, Dai J, Srivastava PK, Zammit DJ, Lefrancois L, Li Z (2007) Heat shock protein gp96 is a master chaperone for toll-like receptors and is important in the innate function of macrophages. Immunity 26:215–226CrossRefPubMedGoogle Scholar
  83. Yang Y, Jiang Y, Yin Q, Liang H, She R (2010) Chicken intestine defensins activated murine peripheral blood mononuclear cells through the TLR4-NF-kappaB pathway. Vet Immunol Immunopathol 133:59–65CrossRefPubMedGoogle Scholar
  84. Yilmaz A, Shen S, Adelson DL, Xavier S, Zhu JJ (2005) Identification and sequence analysis of chicken Toll-like receptors. Immunogenetics 56:743–753CrossRefPubMedGoogle Scholar
  85. Zähringer U, Lindner B, Inamura S, Heine H, Alexander C (2008) TLR2 -promiscuous or specific? A critical re-evaluation of a receptor expressing apparent broad specificity. Immunobiology 213:205–224CrossRefPubMedGoogle Scholar
  86. Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Vaccine and Infectious Diseases OrganizationUniversity of SaskatchewanSaskatoonCanada

Personalised recommendations