Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.
Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from gram-negative bacteria. Activation of TLR4 signaling pathways by LPS is a critical upstream event in the pathogenesis of gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in gram-negative sepsis, we first showed that TLR4(-/-) and myeloid differentiation primary response gene 88 (MyD88)(-/-) mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2(-/-) and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for gram-negative sepsis.
Roger
Thierry
T
Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
Froidevaux
Céline
C
Le Roy
Didier
D
Reymond
Marlies Knaup
MK
Chanson
Anne-Laure
AL
Mauri
Davide
D
Burns
Kim
K
Riederer
Beat Michel
BM
Akira
Shizuo
S
Calandra
Thierry
T
D000818:Animals; D004926:Escherichia coli / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006090:Gram-Negative Bacteria / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000382:microbiology* / Q000473:pathology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D007074:Immunoglobulin G; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011993:Recombinant Fusion Proteins; D051197:Toll-Like Receptor 4