Evolution and species-specific conservation of toll-like receptors in terrestrial vertebrates

References

• Charles A, Janeway J, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20(1):197–216. doi:10.1146/annurev.immunol.20.083001.084359.
   PubMedGoogle Scholar
• Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4(7):499–410. 1038/nri1391.
   PubMed Web of Science ®Google Scholar
• Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science 2010;327(5963):291–295. doi: 10.1126/science.1183021.
   PubMed Web of Science ®Google Scholar
• Janeway CA. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 1989;54(0):1–13. doi: 10.1101/SQB.1989.054.01.003.
   PubMedGoogle Scholar
• Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol 2001;1(2):135. doi: 10.1038/35100529.
   PubMed Web of Science ®Google Scholar
• Gay NJ, Gangloff M. Structure and function of Toll receptors and their ligands. Annu Rev Biochem 2007;76(1):141–165. doi: 10.1146/annurev.biochem.76.060305.151318.
   PubMedGoogle Scholar
• Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 Gene. Science 1998;282(5396):2085–2088. 10.1126/science.282.5396.2085.
   PubMed Web of Science ®Google Scholar
• Barreiro LB, Ben-Ali M, Quach H, et al. Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet 2009;5(7):e1000562. doi: 10.1371/journal.pgen.1000562.
   PubMed Web of Science ®Google Scholar
• Takeda K, Akira S. TLR signaling pathways. Sem Immunol 2004;16(1):3–9. doi: 10.1016/j.smim.2003.10.003.
   PubMed Web of Science ®Google Scholar
• Jungi TW, Farhat K, Burgener IA, Werling D. Toll-like receptors in domestic animals. Cell Tissue Res 2011;343(1):107–120. doi: 10.1007/s00441-010-1047-8.
   PubMed Web of Science ®Google Scholar
• Uematsu S, Akira S. Toll-like receptors (TLRs) and their ligands. In: Bauer S, Hartmann G, editors. Toll-like receptors (TLRs) and innate immunity. Berlin, Heidelberg: Springer Berlin Heidelberg; 2008. pp 1–20. doi: 10.1007/978-3-540-72167-3_1.
   Google Scholar
• Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124(4):783–801. 10.1016/j.cell.2006.02.015.
   PubMed Web of Science ®Google Scholar
• Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol 2006;7(2):131. doi: 10.1038/ni1303.
   PubMed Web of Science ®Google Scholar
• Roach JC, Glusman G, Rowen L, et al. The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 2005;102(27):9577–9582. doi: 10.1073/pnas.0502272102.
   PubMed Web of Science ®Google Scholar
• Barreiro LB, Quintana-Murci L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 2010;11(1):17.
   PubMed Web of Science ®Google Scholar
• Das A, Guha P, Chaudhuri TK. Environmental selection influences the diversity of TLR genes in ethnic Rajbanshi population of North Bengal Region of India. J Genet Eng Biotechnol 2016;14(2):241–245.
   PubMedGoogle Scholar
• Ferrer-Admetlla A, Bosch E, Sikora M, et al. Balancing selection is the main force shaping the evolution of innate immunity genes. J Immunol 2008;181(2):1315–1322.
   PubMed Web of Science ®Google Scholar
• Netea MG, Wijmenga C, O’Neill LAJ. Genetic variation in toll-like receptors and disease susceptibility. Nat Immunol 2012;13(6):535.
   PubMed Web of Science ®Google Scholar
• Marina EZ, Lisandra ZMM, Elizabeth LR, et al. The evolution of bat nucleic acid‐sensing Toll-like receptors. Mol Ecol 2015;24(23):5899–5909.
   PubMed Web of Science ®Google Scholar
• Ishengoma E, Agaba M. Evolution of toll-like receptors in the context of terrestrial ungulates and cetaceans diversification. BMC Evol Biol 2017;17(1):54.
   PubMedGoogle Scholar
• Miller SI, Ernst RK, Bader MW. LPS, TLR4 and infectious disease diversity. Nat Rev Micro 2005;3(1):36. doi: 10.1038/nrmicro1068.
   PubMed Web of Science ®Google Scholar
• Quintana-Murci L, Clark AG. Population genetic tools for dissecting innate immunity in humans. Nat Rev Immunol 2013;13(4):280. doi: 10.1038/nri3421.
   PubMed Web of Science ®Google Scholar
• Khakoo SI, Rajalingam R, Shum BP, et al. Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity 2000;12(6):687–698. doi: 10.1016/S1074-7613(00)80219-8.
   PubMed Web of Science ®Google Scholar
• Zelus D, Robinson-Rechavi M, Delacre M, et al. Fast evolution of interleukin-2 in mammals and positive selection in ruminants. J Mol Evol 2000;51(3):234–244. doi: 10.1007/s002390010085.
   PubMed Web of Science ®Google Scholar
• The International SNPMWG. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928. doi: 10.1038/35057149.
   PubMed Web of Science ®Google Scholar
• Downing T, Cormican P, O’Farrelly C, et al. Evidence of the adaptive evolution of immune genes in chicken. BMC Res Notes 2009;2(1):254. doi: 10.1186/1756-0500-2-254.
   PubMedGoogle Scholar
• Lively CM, Dybdahl MF. Parasite adaptation to locally common host genotypes. Nature 2000;405(6787):679. doi: 10.1038/35015069.
   PubMed Web of Science ®Google Scholar
• Kuijl C, Neefjes J. New insight into the everlasting host-pathogen arms race. Nat Immunol 2009;10(8):808. doi: 10.1038/ni0809-808.
   PubMed Web of Science ®Google Scholar
• Zhang Q, Zmasek CM, Godzik A. Domain architecture evolution of pattern-recognition receptors. Immunogenetics 2010;62(5):263–272. doi: 10.1007/s00251-010-0428-1.
   PubMed Web of Science ®Google Scholar
• Jann OC, Werling D, Chang JS, et al. Molecular evolution of bovine toll-like receptor 2 suggests substitutions of functional relevance. BMC Evol Biol 2008;8(1):288.
   PubMedGoogle Scholar
• Darfour-Oduro KA, Megens HJ, Roca AL, et al. Adaptive evolution of toll-like receptors (TLRs) in the family Suidae. PLoS One 2015;10(4):e0124069. doi: 10.1371/journal.pone.0124069.
   PubMed Web of Science ®Google Scholar
• Wlasiuk G, Nachman MW. Adaptation and constraint at toll-like receptors in primates. Mol Biol Evol 2010;27(9):2172–2186. doi: 10.1093/molbev/msq104.
   PubMed Web of Science ®Google Scholar
• Fornůsková A, Vinkler M, Pagès M, et al. Contrasted evolutionary histories of two toll-like receptors (Tlr4 and Tlr7) in wild rodents (MURINAE). BMC Evol Biol 2013;13(1):194. doi: 10.1186/1471-2148-13-194.
   PubMedGoogle Scholar
• Huang Y, Temperley ND, Ren L, et al. Molecular evolution of the vertebrate TLR1 gene family - a complex history of gene duplication, gene conversion, positive selection and co-evolution. BMC Evol Biol 2011;11(1):149. doi: 10.1186/1471-2148-11-149.
   PubMedGoogle Scholar
• Babik W, Dudek K, Fijarczyk A, et al. Constraint and adaptation in newt toll-like receptor genes. Genome Biol Evol 2014;7(1):81–95.
   PubMed Web of Science ®Google Scholar
• Lau Q, Igawa T, Kosch TA, Satta Y. Selective constraint acting on TLR2 and TLR4 genes of Japanese Rana frogs. PeerJ 2018;6:e4842.
   PubMed Web of Science ®Google Scholar
• Webb AE, Gerek ZN, Morgan CC, et al. Adaptive evolution as a predictor of species-specific innate immune response. Mol Biol Evol 2015;32(7):1717–1729. doi: 10.1093/molbev/msv051.
   PubMed Web of Science ®Google Scholar
• Grueber CE, Wallis GP, Jamieson IG. Episodic positive selection in the evolution of avian toll-like receptor innate immunity genes. PLoS One 2014;9(3):e89632. doi: 10.1371/journal.pone.0089632.
   PubMed Web of Science ®Google Scholar
• Priyam M, Tripathy M, Rai U, Ghorai SM. Divergence of protein sensing (TLR 4, 5) and nucleic acid sensing (TLR 3, 7) within the reptilian lineage. Mol Phylogenet Evol 2018;119:210.
   PubMed Web of Science ®Google Scholar
• Sauter KS, Brcic M, Franchini M, Jungi TW. Stable transduction of bovine TLR4 and bovine MD-2 into LPS-nonresponsive cells and soluble CD14 promote the ability to respond to LPS. Vet Immunol Immunopathol 2007;118(1–2):92–104. doi: 10.1016/j.vetimm.2007.04.017.
   PubMed Web of Science ®Google Scholar
• Lizundia R, Sauter KS, Taylor G, Werling D. Host species-specific usage of the TLR4-LPS receptor complex. Innate Immun 2008;14(4):223–231. doi: 10.1177/1753425908095957.
   PubMed Web of Science ®Google Scholar
• Oblak A, Jerala R. Species-specific activation of TLR4 by hypoacylated endotoxins governed by residues 82 and 122 of MD-2. PLoS One 2014;9(9):e107520. doi: 10.1371/journal.pone.0107520.
   PubMed Web of Science ®Google Scholar
• Bryant CE, Monie TP. Mice, men and the relatives: cross-species studies underpin innate immunity. Open Biol 2012;2(4):120015. doi: 10.1098/rsob.120015.
   PubMedGoogle Scholar
• Steeghs L, Keestra AM, van Mourik A, et al. Differential activation of human and mouse toll-like receptor 4 by the adjuvant candidate LpxL1 of Neisseria meningitidis. Infect Immun 2008;76(8):3801–3807. doi: 10.1128/IAI.00005-08.
   PubMed Web of Science ®Google Scholar
• Gioannini TL, Teghanemt A, Zhang D, et al. Isolation of an endotoxin–MD-2 complex that produces toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc Natl Acad Sci 2004;101(12):4186–4191. doi: 10.1073/pnas.0306906101.
   PubMed Web of Science ®Google Scholar
• Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B. Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4). Genome Biol 2000;1(1):research002.1–research002.10.
   Web of Science ®Google Scholar
• Smirnova I, Hamblin MT, McBride C, Beutler B, Di Rienzo A. Excess of rare amino acid polymorphisms in the toll-like receptor 4 in humans. Genetics 2001;158(4):1657–1664.
   PubMed Web of Science ®Google Scholar
• Schroder K, Irvine KM, Taylor MS, et al. Conservation and divergence in toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proc Natl Acad Sci 2012;109(16):E944–E953. doi: 10.1073/pnas.1110156109.
   PubMed Web of Science ®Google Scholar
• Ketloy C, Engering A, Srichairatanakul U, et al. Expression and function of toll-like receptors on dendritic cells and other antigen presenting cells from non-human primates. Vet Immunol Immunopathol 2008;125(1–2):18–30. doi: 10.1016/j.vetimm.2008.05.001.
   PubMed Web of Science ®Google Scholar
• Vinkler M, Bainová H, Bryja J. Protein evolution of toll-like receptors 4, 5 and 7 within Galloanserae birds. Genet Sel Evol 2014;46(1):72. doi: 10.1186/s12711-014-0072-6.
   PubMedGoogle Scholar
• Vinkler M, Albrecht T. The question waiting to be asked: innate immunity receptors in the perspective of zoological research. Folia Zool 2009;58:15–28.
   Web of Science ®Google Scholar
• Saponaro C, Cianciulli A, Calvello R, et al. First identification of toll-like receptor-4 in avian brain: evolution of lipopolysaccharide recognition and inflammation-dependent responses. Immunopharmacol Immunotoxicol 2011;33(1):64–72.
   PubMed Web of Science ®Google Scholar
• Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000;25(2):187. doi: 10.1038/76048.
   PubMed Web of Science ®Google Scholar
• Lorenz E, Mira J, Frees KL, Schwartz DA. Relevance of mutations in the tlr4 receptor in patients with gram-negative septic shock. Arch Intern Med 2002;162(9):1028–1032. doi: 10.1001/archinte.162.9.1028.
   PubMedGoogle Scholar
• Bagheri M, Miraie-Ashtiani R, Moradi-Shahrbabak M, et al. Selective genotyping and logistic regression analyses to identify favorable SNP-genotypes for clinical mastitis and production traits in Holstein dairy cattle. Livest Sci 2013;151(2–3):140–151. doi: 10.1016/j.livsci.2012.11.018.
   Web of Science ®Google Scholar
• Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by toll-like receptor 5. Nature 2001;410:1099. doi: 10.1038/35074106.
   PubMed Web of Science ®Google Scholar
• Andersen-Nissen E, Smith KD, Strobe KL, et al. Evasion of toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A 2005;102(26):9247–9252. doi: 10.1073/pnas.0502040102.
   PubMed Web of Science ®Google Scholar
• Alcaide M, Edwards SV. Molecular evolution of the toll-like receptor multigene family in birds. Mol Biol Evol 2011;28(5):1703–1715. doi: 10.1093/molbev/msq351.
   PubMed Web of Science ®Google Scholar
• Hawn TR, Verbon A, Lettinga KD, et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J Exp Med 2003;198(10):1563–1572. doi: 10.1084/jem.20031220.
   PubMed Web of Science ®Google Scholar
• Feuillet V, Medjane S, Mondor I, et al. Involvement of toll-like receptor 5 in the recognition of flagellated bacteria. Proc Natl Acad Sci 2006;103(33):12487–12492. doi: 10.1073/pnas.0605200103.
   PubMed Web of Science ®Google Scholar
• Uematsu S, Jang MH, Chevrier N, et al. Detection of pathogenic intestinal bacteria by toll-like receptor 5 on intestinal CD11c + lamina propria cells. Nat Immunol 2006;7(8):868. doi: 10.1038/ni1362.
   PubMed Web of Science ®Google Scholar
• Andersen-Nissen E, Hawn TR, Smith KD, et al. Cutting edge: Tlr5−/− mice are more susceptible to Escherichia coli urinary tract infection. J Immunol 2007;178(8):4717–4720. doi: 10.4049/jimmunol.178.8.4717.
   PubMed Web of Science ®Google Scholar
• Wlasiuk G, Khan S, Switzer WM, Nachman MW. A history of recurrent positive selection at the Toll-Like receptor 5 in primates. Mol Biol Evol 2009;26(4):937–949. doi: 10.1093/molbev/msp018.
   PubMed Web of Science ®Google Scholar
• Keestra AM, de Zoete MR, van Aubel RAMH, van Putten JPM. The central leucine-rich repeat region of chicken TLR16 dictates unique ligand specificity and species-specific interaction with TLR2. J Immunol 2007;178(11):7110–7119. doi: 10.4049/jimmunol.178.11.7110.
   PubMed Web of Science ®Google Scholar
• Andersen-Nissen E, Smith KD, Bonneau R, et al. A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med 2007;204(2):393–403. doi: 10.1084/jem.20061400.
   PubMed Web of Science ®Google Scholar
• Kogut MH, Iqbal M, He H, et al. Expression and function of toll-like receptors in chicken heterophils. Dev Comp Immunol 2005;29(9):791–807. 10.1016/j.dci.2005.02.002.
   PubMed Web of Science ®Google Scholar
• He H, Genovese KJ, Nisbet DJ, Kogut MH. Profile of Toll-like receptor expressions and induction of nitric oxide synthesis by Toll-like receptor agonists in chicken monocytes. Mol Immunol 2006;43(7):783–789. doi: 10.1016/j.molimm.2005.07.002.
   PubMed Web of Science ®Google Scholar
• Iqbal M, Philbin VJ, Withanage GSK, et al. 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 2005;73(4):2344–2350. doi: 10.1128/IAI.73.4.2344-2350.2005.
   PubMed Web of Science ®Google Scholar
• Iqbal M, Philbin VJ, Smith AL. Expression patterns of chicken toll-like receptor mRNA in tissues, immune cell subsets and cell lines. Vet Immunol Immunopathol 2005;104(1):117–127. doi: 10.1016/j.vetimm.2004.11.003. 70.
   PubMed Web of Science ®Google Scholar
• Zarember KA, Godowski PJ. 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 2002;168(2):554–561. doi: 10.4049/jimmunol.168.2.554.
   PubMed Web of Science ®Google Scholar
• Voogdt CGP, Bouwman LI, Kik MJL, et al. Reptile Toll-like receptor 5 unveils adaptive evolution of bacterial flagellin recognition. Sci Rep 2016;6(1):19046.
   PubMedGoogle Scholar
• Blohmke CJ, Park J, Hirschfeld AF, et al. TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis. J Immunol 2010;185(12):7731–7738. doi: 10.4049/jimmunol.1001513.
   PubMed Web of Science ®Google Scholar
• West TE, Chantratita N, Chierakul W, et al. Impaired TLR5 functionality is associated with survival in melioidosis. J Immunol 2013;190(7):3373–3379. doi: 10.4049/jimmunol.1202974.
   PubMed Web of Science ®Google Scholar
• Vijay-Kumar M, Carvalho FA, Aitken JD, et al. TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin. Eur J Immunol 2010;40(12):3528–3534. doi: 10.1002/eji.201040421.
   PubMed Web of Science ®Google Scholar
• Lu J, Sun PD. The structure of the TLR5-flagellin complex: a new mode of pathogen detection, conserved receptor dimerization for signaling. Sci Signal 2012;5(216):pe11–pepe. doi: 10.1126/scisignal.2002963. 76.
   Web of Science ®Google Scholar
• Yoon SI, Kurnasov O, Natarajan V, et al. Structural basis of TLR5-flagellin recognition and signaling. Science 2012;5(216):pe11– p864. doi: 10.1126/science.1215584.
   Google Scholar
• Metcalfe HJ, La Ragione RM, Smith DGE, Werling D. Functional characterisation of bovine TLR5 indicates species-specific recognition of flagellin. Vet Immunol Immunopathol 2014;157(3–4):197–205. doi: 10.1016/j.vetimm.2013.12.006.
   PubMed Web of Science ®Google Scholar
• Reid SD, Selander RK, Whittam TS. Sequence diversity of flagellin (fliC) alleles in pathogenic Escherichia coli. J Bacteriol 1999;181(1):153–160.
   PubMed Web of Science ®Google Scholar
• Areal H, Abrantes J, Esteves PJ. Signatures of positive selection in Toll-like receptor (TLR) genes in mammals. BMC Evol Biol 2011;11(1):368. doi: 10.1186/1471-2148-11-368.
   PubMedGoogle Scholar
• Keestra AM, de Zoete MR, van Aubel RAMH, van Putten JPM. Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin. Mol Immunol 2008;45(5):1298–1307. doi: 10.1016/j.molimm.2007.09.013.
   PubMed Web of Science ®Google Scholar
• Smith SA, Jann OC, Haig D, et al. Adaptive evolution of Toll-like receptor 5 in domesticated mammals. BMC Evol Biol 2012;12(1):122. doi: 10.1186/1471-2148-12-122.
   PubMedGoogle Scholar
• Philbin VJ, Iqbal M, Boyd Y, et al. Identification and characterization of a functional, alternatively spliced toll‐like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens. Immunology 2005;114(4):507–521. doi: 10.1111/j.1365-2567.2005.02125.x.
   PubMed Web of Science ®Google Scholar
• Dowling JK, Dellacasagrande J. Toll-like receptors: ligands, cell-based models, and readouts for receptor action. In: McCoy CE, ed. Toll-like receptors: practice and methods. New York, NY: Springer New York; 2016. pp 3–27. doi: 10.1007/978-1-4939-3335-8_1
   Google Scholar
• Radstake TRDJ, Franke B, Hanssen S, et al. The Toll‐like receptor 4 Asp299Gly functional variant is associated with decreased rheumatoid arthritis disease susceptibility but does not influence disease severity and/or outcome. Arthriti Rheum 2004;50(3):999–1001. doi: 10.1002/art.20114.
   PubMedGoogle Scholar
• Tao K, Fujii M, Tsukumo SI, et al. Genetic variations of toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Ann Rheum Dis 2007;66(7):905–909. doi: 10.1136/ard.2006.065961.
   PubMed Web of Science ®Google Scholar
• Werling D, Jann OC, Offord V, et al. Variation matters: TLR structure and species-specific pathogen recognition. Trends Immunol 2009;30(3):124–130. doi: 10.1016/j.it.2008.12.001.
   PubMed Web of Science ®Google Scholar
• Kapetanovic R, Fairbairn L, Beraldi D, et al. Pig bone marrow-derived macrophages resemble human macrophages in their response to bacterial lipopolysaccharide. J Immunol 2012;188(7):3382–3394. doi: 10.4049/jimmunol.1102649.
   PubMed Web of Science ®Google Scholar
• Hajjar AM, Ernst RK, Tsai JH, et al. Human toll-like receptor 4 recognizes host-specific LPS modifications. Nat Immunol 2002;3(4):354. doi: 10.1038/ni777.
   PubMed Web of Science ®Google Scholar
• Grabiec A, Meng G, Fichte S, et al. Human but not murine toll-like receptor 2 discriminates between tri-palmitoylated and tri-lauroylated peptides. J Biol Chem 2004;279(46):48004–48012. doi: 10.1074/jbc.M405311200.
   PubMed Web of Science ®Google Scholar
• Farhat K, Riekenberg S, Jung G, et al. Identification of full length bovine TLR1 and functional characterization of lipopeptide recognition by bovine TLR2/1 heterodimer. Vet Res 2010;41(3):34. doi: 10.1051/vetres/2010006.
   PubMed Web of Science ®Google Scholar
• Morr M, Takeuchi O, Akira S, et al. Differential recognition of structural details of bacterial lipopeptides by toll‐like receptors. Eur J Immunol 2002;32(12):3337–3347. doi: 10.1002/1521-4141(2002012)32:12 < 3337::AID-IMMU3337 > 3.0.CO;2-I
   PubMed Web of Science ®Google Scholar
• Oosting M, Ter Hofstede H, Sturm P, et al. TLR1/TLR2 heterodimers play an important role in the recognition of Borrelia spirochetes. PLoS One 2011;6(10):e25998.
   PubMed Web of Science ®Google Scholar
• Naik S, Kelly EJ, Meijer L, et al. Absence of toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr 2001;32(4):449–453. doi: 10.1097/00005176-200104000-00011.
   PubMed Web of Science ®Google Scholar
• Zeng H, Wu H, Sloane V, et al. Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways. Am J Physiol Gastrointest Liver Physiol 2006;290(1):G96–G108. doi: 10.1152/ajpgi.00273.2005.
   PubMed Web of Science ®Google Scholar
• Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004;303(5663):1526–1529. doi: 10.1126/science.1093620.
   PubMed Web of Science ®Google Scholar
• Meng W, Yamazaki T, Nishida Y, Hanagata N. Nuclease-resistant immunostimulatory phosphodiester CpG oligodeoxynucleotides as human toll-like receptor 9 agonists. BMC Biotechnol 2011;11(1):88. doi: 10.1186/1472-6750-11-88.
   PubMedGoogle Scholar
• Roman M, Martin-Orozco E, Goodman JS, et al. Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants. Nat Med 1997;3(8):849. doi: 10.1038/nm0897-849.
   PubMed Web of Science ®Google Scholar