Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus

The innate immune system contributes to the earliest phase of the host defense against foreign organisms and has both soluble and cellular pattern recognition receptors for microbial products. Two important members of this receptor group, CD14 and the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Thus, a common receptor activation pathway can initiate innate immune responses to both bacterial and viral pathogens.

[1]  R. Ulevitch,et al.  CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. , 1990, Science.

[2]  P. Godowski,et al.  Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. , 1999, Science.

[3]  P. Openshaw,et al.  Distinct types of lung disease caused by functional subsets of antiviral T cells , 1994, The Journal of experimental medicine.

[4]  B. Graham,et al.  Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus. , 1993, Journal of immunology.

[5]  E. Walsh,et al.  Enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by prior intramuscular inoculation of formalin-inactiva ted virus. , 1986, Journal of virology.

[6]  Antony Rodriguez,et al.  The 18‐wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense , 1997, The EMBO journal.

[7]  M. Ferretti,et al.  Heterotrimeric G proteins physically associated with the lipopolysaccharide receptor CD14 modulate both in vivo and in vitro responses to lipopolysaccharide. , 1998, The Journal of clinical investigation.

[8]  C. Janeway,et al.  A human homologue of the Drosophila Toll protein signals activation of adaptive immunity , 1997, Nature.

[9]  R. Ulevitch,et al.  Recognition of bacterial endotoxins by receptor-dependent mechanisms. , 1993, Advances in immunology.

[10]  L. Larivière,et al.  Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4) , 1999, The Journal of experimental medicine.

[11]  J. Schlesinger,et al.  Purification and characterization of the respiratory syncytial virus fusion protein. , 1985, The Journal of general virology.

[12]  M. Potter The BALB/c Mouse , 1985, Current Topics in Microbiology and Immunology.

[13]  B. Monks,et al.  Cutting edge: cells that carry A null allele for toll-like receptor 2 are capable of responding to endotoxin. , 1999, Journal of immunology.

[14]  L. Anderson,et al.  Priming with live respiratory syncytial virus (RSV) prevents the enhanced pulmonary inflammatory response seen after RSV challenge in BALB/c mice immunized with formalin-inactivated RSV , 1997, Journal of virology.

[15]  A. Tomasz,et al.  CD14 is a pattern recognition receptor. , 1994, Immunity.

[16]  M. Meister,et al.  Antimicrobial peptide defense in Drosophila , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[17]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[18]  B. Trask,et al.  Cloning and characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and TIL4: evidence for a multi-gene receptor family in humans. , 1998, Blood.

[19]  L. Anderson,et al.  Involvement of Toll-Like Receptor 4 in Innate Immunity to Respiratory Syncytial Virus , 2001, Journal of Virology.

[20]  M. Perkins,et al.  Primary respiratory syncytial virus infection in mice , 1988, Journal of medical virology.

[21]  Yoshinori Nagai,et al.  MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4 , 1999, The Journal of experimental medicine.

[22]  C. Heilman From the National Institute of Allergy and Infectious Diseases and the World Health Organization. Respiratory syncytial and parainfluenza viruses. , 1990, The Journal of infectious diseases.

[23]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[24]  R. M. Wooten,et al.  Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. , 1999, Journal of immunology.

[25]  Michael P. Brown,et al.  CD40 Ligand (CD154) Enhances the Th1 and Antibody Responses to Respiratory Syncytial Virus in the BALB/c Mouse , 2000, The Journal of Immunology.

[26]  D. Golenbock,et al.  Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. , 1999, Journal of immunology.

[27]  C B Hall,et al.  Respiratory syncytial viral infection in children with compromised immune function. , 1986, The New England journal of medicine.

[28]  D. Golenbock,et al.  Toll-like Receptor 2 Functions as a Pattern Recognition Receptor for Diverse Bacterial Products* , 1999, The Journal of Biological Chemistry.

[29]  D. Golenbock,et al.  The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors. , 1999, Journal of immunology.

[30]  J. Cavaillon,et al.  Polymyxin-B inhibition of LPS-induced interleukin-1 secretion by human monocytes is dependent upon the LPS origin. , 1986, Molecular immunology.

[31]  B. Bloom,et al.  Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. , 1999, Science.

[32]  F. Gusovsky,et al.  Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction* , 1999, The Journal of Biological Chemistry.

[33]  L. J. Anderson,et al.  Protective and disease-enhancing immune responses to respiratory syncytial virus. , 1995, The Journal of infectious diseases.

[34]  S. Akira,et al.  Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. , 1999, Immunity.

[35]  A. Gurney,et al.  Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling , 1998, Nature.

[36]  K. Anderson,et al.  A conserved signaling pathway: the Drosophila toll-dorsal pathway. , 1996, Annual review of cell and developmental biology.

[37]  D. Golenbock,et al.  Mycobacterial lipoarabinomannan recognition requires a receptor that shares components of the endotoxin signaling system. , 1996, Journal of immunology.

[38]  M. Rothe,et al.  Peptidoglycan- and Lipoteichoic Acid-induced Cell Activation Is Mediated by Toll-like Receptor 2* , 1999, The Journal of Biological Chemistry.

[39]  G. Hardiman,et al.  A family of human receptors structurally related to Drosophila Toll. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Rothe,et al.  Human Toll-like Receptor 2 Confers Responsiveness to Bacterial Lipopolysaccharide , 1998, The Journal of experimental medicine.