Sepsis - History

History

Severe systemic toxicity has been recognised since before the dawn of history but it was only in the 19th century that a specific term - sepsis - was coined for this condition. By the end of the 19th century, it was widely believed that microbes produced substances that could injure the mammalian host and that soluble toxins released during infection caused the fever and shock that were commonplace during severe infections. Pfeiffer coined the term endotoxin at the beginning of the 20th century to denote the pyrogenic principle associated with Vibrio cholerae. It was soon realised that endotoxins were expressed by most and perhaps all Gram negative organisms. The lipopolysaccharide character of enteric endotoxins was elucidated in the 1944 by Shear. The molecular character of this material was determined by Luderitz et al in 1973.

It was discovered in 1965 that a strain of C3H/HeJ mice were immune to the endotoxin induced shock. The genetic locus for this effect was dubbed Lps. These mice were also found to be hypersusceptible to infection by Gram negative bacteria. These observations were finally linked in 1998 by the discovery of the Toll-like receptor gene 4 (TLR 4). Genetic mapping work, performed over a period of 5 years, showed that TLR4 was the sole candidate locus within the Lps critical region strongly implying that a mutation within TLR4 must account for the lipopolysaccharide resistance phenotype. The defect in the TLR4 gene that led to the endotoxin resistant phenotype was discovered to be due to a mutation in the cytoplasmic domain.