Toll-like receptors: the key to the stable door?

Severe sepsis continues to lead to critical illness. Few therapeutic options exist other than antibiotic therapy and general supportive care. Large numbers of patients continue to die as a consequence of overactivation of the host inflammatory response and the resultant coagulopathy and disregulation of the normal controls of vasoactive tone. It is now known that a critical part of this host response occurs at the level of innate defence, without the need for antigen processing or the clonal expansion of cells targeted against the invading pathogen. This commentary will discuss the therapeutic targets revealed by our new understanding of the Toll-like receptor. The potential clinical difficulties that may result from intervention at this pattern-recognition receptor will also be explored.

[1]  D. Schwartz,et al.  TLR4 mutations are associated with endotoxin hyporesponsiveness in humans , 2000, Nature Genetics.

[2]  P. Detmers,et al.  Toll Receptors: a Central Element in Innate Immune Responses , 2002, Infection and Immunity.

[3]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[4]  T. Calandra,et al.  MIF regulates innate immune responses through modulation of Toll-like receptor 4 , 2001, Nature.

[5]  Douglas T. Golenbock,et al.  Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus , 2000, Nature Immunology.

[6]  S. Foster,et al.  A cell wall component from pathogenic and non-pathogenic gram-positive bacteria (peptidoglycan) synergises with endotoxin to cause the release of tumour necrosis factor-alpha, nitric oxide production, shock, and multiple organ injury/dysfunction in the rat. , 2001, Shock.

[7]  T. Michel,et al.  Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein , 2001, Nature.

[8]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[9]  S. Akira,et al.  Cutting Edge: Endotoxin Tolerance in Mouse Peritoneal Macrophages Correlates with Down-Regulation of Surface Toll-Like Receptor 4 Expression1 , 2000, The Journal of Immunology.

[10]  Reduced Release of DNA from Streptococcus pneumoniae After Treatment with Rifampin in Comparison to Spontaneous Growth and Ceftriaxone Treatment , 2001, European Journal of Clinical Microbiology and Infectious Diseases.

[11]  E. Faist,et al.  Removal of Mediators by Continuous Hemofiltration in Septic Patients , 2001, World Journal of Surgery.

[12]  A. Aderem,et al.  The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Jonathan D. G. Jones,et al.  Novel Disease Resistance Specificities Result from Sequence Exchange between Tandemly Repeated Genes at the Cf-4/9 Locus of Tomato , 1997, Cell.

[14]  R. Nau,et al.  Modulation of Release of Proinflammatory Bacterial Compounds by Antibacterials: Potential Impact on Course of Inflammation and Outcome in Sepsis and Meningitis , 2002, Clinical Microbiology Reviews.

[15]  D. Podolsky,et al.  Lipopolysaccharide Activates Distinct Signaling Pathways in Intestinal Epithelial Cell Lines Expressing Toll-Like Receptors1 , 2000, The Journal of Immunology.

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

[17]  S. Opal,et al.  High-Dose Antithrombin III in Severe Sepsis: A Randomized Controlled Trial , 2001 .

[18]  S. Opal,et al.  Bench-to-bedside review: Toll-like receptors and their role in septic shock , 2002, Critical care.

[19]  J. Cohen,et al.  Adjunctive therapy in sepsis: a critical analysis of the clinical trial programme. , 1999, British medical bulletin.

[20]  Takaaki Ohtake,et al.  Innate antimicrobial peptide protects the skin from invasive bacterial infection , 2001, Nature.

[21]  E. Beutler,et al.  Synergy between TLR2 and TLR4: a safety mechanism. , 2001, Blood cells, molecules & diseases.

[22]  M. Colonna,et al.  TREM-1 amplifies inflammation and is a crucial mediator of septic shock , 2001, Nature.

[23]  A. Aderem,et al.  The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens , 1999, Nature.

[24]  Y. Vodovotz,et al.  Hepatocyte toll-like receptor 2 expression in vivo and in vitro: role of cytokines in induction of rat TLR2 gene expression by lipopolysaccharide. , 2000, Shock.

[25]  S. Wright,et al.  Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide , 1986, The Journal of experimental medicine.

[26]  S. Opal,et al.  Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. , 2001, JAMA.

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