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Unique Properties of the Chicken TLR4/MD-2 Complex: Selective Lipopolysaccharide Activation of the MyD88-Dependent Pathway¹

Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands

During evolution, mammals have evolved a powerful innate immune response to LPS. Chickens are much more resistant to LPS-induced septic shock. Herein we report that chickens sense LPS via orthologs of mammalian TLR4 and myeloid differentiation protein-2 (MD-2) rather than the previously implicated chicken TLR2 isoform type 2 (chTLR2t2) receptor. Cloning and expression of recombinant chTLR4 and chMD-2 in HeLa 57A cells activated NF-B at concentrations of LPS as low as 100 pg/ml. Differential pairing of chicken and mammalian TLR4 and MD-2 indicated that the protein interaction was species-specific in contrast to the formation of functional human and murine chimeric complexes. The chicken LPS receptor responded to a wide variety of LPS derivatives and to the synthetic lipid A compounds 406 and 506. The LPS specificity resembled the functionality of the murine rather than the human TLR4/MD-2 complex. Polymorphism in chTLR4 (Tyr³⁸³His and Gln⁶¹¹Arg) did not influence the LPS response. Interestingly, LPS consistently failed to activate the MyD88-independent induction of IFN-β in chicken cells, in contrast to the TLR3 agonist poly(I:C) that yielded a potent IFN-β response. These results suggest that chicken lack a functional LPS-specific TRAM-TRIF (TRIF-related adapter molecule/TIR-domain-containing adapter-inducing IFN-β) signaling pathway, which may explain their aberrant response to LPS compared with the mammalian species.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants of the Netherlands Organization for Health Research and Development (grant numbers Zon-MW 912-03-007 and Zon-MW 9120.6150).

² Address correspondence and reprint requests to Dr. Jos P. M. van Putten, Department of Infectious Diseases and Immunology, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands. E-mail address: j.vanputten{at}uu.nl

³ Abbreviations used in this paper: LBP, LPS-binding protein; chTLR2t2, chicken TLR2 isoform type 2; IRF3, IFN regulatory factor 3; MD-2, myeloid differentiation protein-2; MPL, monophosphoryl lipid A; SE, S. Enteritidis; S. Enteritidis, Salmonella enterica serovar Enteritidis; SG, S. Gallinarum; S. Gallinarum, Salmonella enterica serovar Gallinarum strain 9R; TIR, Toll/IL-1R; TIRAP, TIR-domain containing adapter protein; TRAM, TRIF-related adapter molecule; TRIF, TIR-domain-containing adapter-inducing IFN-β.