Host species-specific usage of the TLR4-LPS receptor complex

Abstract

Recognition of LPS depends on the interaction of at least three molecules forming the LPS-receptor complex. The most important ones, CD14, MD2 and Toll-like receptor (TLR) 4 share a high degree of homology between species. In the present study, we investigated the importance of species-specific restriction on the recognition of LPS using stably transfected HEK293 cell lines expressing either human or bovine LPS-receptor complex components. Species-specific MD2 appeared to confer LPS recognition, whereas species-specific CD14 only appeared to play a minor role. In addition to the recognition of LPS, there is evidence that the fusion (F) protein of respiratory syncytial virus (RSV), which is the most common viral respiratory pathogen during infancy world-wide, interacts with TLR4, and plays an important role in the initiation of the innate immune response. Our findings suggest that human and bovine RSV may activate human and bovine TLR4 receptors, respectively, in the presence of both MD2 and CD14. However, no clear role for the RSV F protein of either human or bovine RSV alone in stimulating TLR4-dependent NF-κB activation was observed.

Keywords

Bovine CD14 MD2 RSV TLR4

References

Werling D. , Coffey TJ

Pattern recognition receptors in companion and farm animals - the key to unlocking the door to animal disease?

Vet J 2007; 174: 240-251.

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: 2085-2088.

Frey EA , Miller DS , Jahr TG et al. Soluble CD14 participates in the response of cells to lipopolysaccharide . J Exp Med 1992; 176: 1665-1671.

Pugin J. , Schurer-Maly CC , Leturcq D. , Moriarty A. , Ulevitch RJ , Tobias PS Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14 . Proc Natl Acad Sci USA 1993; 90: 2744-2748.

Schumann RR , Leong SR , Flaggs GW et al. Structure and function of lipopolysaccharide binding protein . Science 1990; 249: 1429-1431.

Shimazu R. , Akashi S. , Ogata H. et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4 . J Exp Med 1999; 189: 1777-1782.

Hoshino K. , Takeuchi O. , Kawai T. et al. Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product . J Immunol 1999; 162: 3749-3752.

Haziot A. , Ferrero E. , Lin XY , Stewart CL , Goyert SM CD14-deficient mice are exquisitely insensitive to the effects of LPS . Prog Clin Biol Res 1995; 392: 349-351.

Nagai Y. , Akashi S. , Nagafuku M. et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution . Nat Immunol 2002; 3: 667-672.

10.

Hamann L. , Kumpf O. , Muller M. et al. A coding mutation within the first exon of the human MD-2 gene results in decreased lipopolysaccharide-induced signaling . Genes Immun 2004; 5: 283-288.

11.

Kurt-Jones EA , Popova L. , Kwinn L. et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus . Nat Immunol 2000; 1: 398-401.

12.

Haeberle HA , Takizawa R. , Casola A. et al. Respiratory syncytial virus-induced activation of nuclear factor-kappaB in the lung involves alveolar macrophages and Toll-like receptor 4-dependent pathways . J Infect Dis 2002; 186: 1199-1206.

13.

Awomoyi AA , Rallabhandi P. , Pollin TI et al. Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children . J Immunol 2007; 179: 3171-3177.

14.

Valarcher JF , Taylor G. Bovine respiratory syncytial virus infection . Vet Res 2007; 38: 153-180.

15.

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: 92-104.

16.

Stott EJ , Thomas LH , Taylor G. , Collins AP , Jebbett J. , Crouch S. A comparison of three vaccines against respiratory syncytial virus in calves . J Hygiene (Camb) 1984; 93: 251-261.

17.

Thomas LH , Slott EJ , Collins AP , Jebbett J. Experimental pneumonia in gnotobiotic calves produced by respiratory syncytial virus . Br J Exp Pathol 1984; 65: 19-28.

18.

Lewis FA , Rae ML , Lehman NI , Ferris AA A syncytial virus associated with epidemic disease of the lower respiratory tract in infants and young children . Med J Aust 1961; 48: 932-933.

19.

Calder LJ , Gonzalez-Reyes L. , Garcia-Barreno B. et al. Electron microscopy of the human respiratory syncytial virus fusion protein and complexes that it forms with monoclonal antibodies . Virology 2000; 271: 122-131.

20.

Taylor G. , Stott EJ , Furze J. , Ford J. , Sopp P. Protective epitopes on the fusion protein of respiratory syncytial virus recognized by murine and bovine monoclonal antibodies . J Gen Virol 1992; 73: 2217-2223.

21.

Triantafilou M. , Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster . Trends Immunol 2002; 23: 301-304.

22.

Anand AR , Cucchiarini M. , Terwilliger EF , Ganju RK The tyrosine kinase Pyk2 mediates lipopolysaccharide-induced IL-8 expression in human endothelial cells . J Immunol 2008 ; 180: 5636-5644.

23.

Ohnishi T. , Muroi M. , Tanamoto K. MD-2 is necessary for the Toll-like receptor 4 protein to undergo glycosylation essential for its translocation to the cell surface . Clin Diagn Lab Immunol 2003; 10: 405-410.

24.

Kim HM , Park BS , Kim JI et al. Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran . Cell 2007; 130: 906-917.

25.

Matsushima N. , Tanaka T. , Enkhbayar P. et al. Comparative sequence analysis of leucine-rich repeats (LRRs) within vertebrate Toll-like receptors . BMC Genomics 2007; 8: 124 .

26.

Werling D. , Piercy J. , Coffey TJ

Expression of Toll-like receptors (TLR) by bovine antigen presenting cells-potential role in pathogen discrimination?

Vet Immunol Immunopathol 2006; 112: 2-11.

27.

Bryant CE , Ouellette A. , Lohmann K. et al. The cellular Toll-like receptor 4 antagonist E5531 can act as an agonist in horse whole blood . Vet Immunol Immunopathol 2007; 116: 182-189.

28.

Muroi M. , Tanamoto K. Structural regions of MD-2 that determine the agonist-antagonist activity of lipid IVa . J Biol Chem 2006; 281: 5484-5491.

29.

Lien E. , Means TK , Heine H. et al. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide . J Clin Invest 2000; 105: 497-504.

30.

Poltorak A. , Ricciardi-Castagnoli P. , Citterio S. , Beutler B. Physical contact between lipopolysaccharide and Toll-like receptor 4 revealed by genetic complementation . Proc Natl Acad Sci USA 2000; 97: 2163-2167.

31.

Visintin A. , Latz E. , Monks BG , Espevik T. , Golenbock DT Lysines 128 and 132 enable lipopolysaccharide binding to MD-2, leading to Toll-like receptor-4 aggregation and signal transduction . J Biol Chem 2003; 278: 48313-48320.

32.

da Silva Correia J. , Soldau K. , Christen U. , Tobias PS , Ulevitch RJ Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2 . J Biol Chem 2001; 276: 21129-21135.

33.

Haynes LM , Moore DD , Kurt-Jones EA , Finberg RW , Anderson LJ , Tripp RA Involvement of Toll-like receptor 4 in innate immunity to respiratory syncytial virus . J Virol 2001; 75: 10730-10737.

34.

Jain V. , Halle A. , Halmen KA et al. Phagocytosis and intracellular killing of MD-2 opsonized Gram-negative bacteria depend on TLR4 signaling . Blood 2008 ; 111: 4637-4645.

35.

Ehl S. , Bischoff R. , Ostler T. et al. The role of Toll-like receptor 4 versus interleukin-12 in immunity to respiratory syncytial virus . Eur J Immunol 2004; 34: 1146-1153.