Resistance to Endotoxin Shock and Reduced Dissemination of Gram-Negative Bacteria in CD14-Deficient Mice

Abstract

Endotoxin shock is the result of activation of the immune system by endotoxin/LPS, a component of Gram-negative bacteria. CD14, a GPI-anchored glycoprotein expressed strongly by monocyte/macrophages, is one of several receptors for endotoxin/LPS. The role of CD14 in bacterial-induced and LPS-induced shock was tested in CD14-deficient mice produced by gene targeting in embryonic stem cells. CD14-deficient mice were found to be highly resistant to shock induced by either live Gram-negative bacteria or LPS; however, at very high concentrations of LPS or bacteria, responses through non-CD14 receptors could be detected. Surprisingly, CD14-deficient mice also showed dramatically reduced levels of bacteremia, suggesting an unexpected role for CD14 in the dissemination of Gram-negative bacteria.

The common functional C(−159)T polymorphism within the promoter region of the lipopolysaccharide receptor CD14 is not associated with sepsis development or mortality

“…TT homozygotes express about 40% more mCD14 compared to carriers of the C allele. Although mouse models indicate a correlation of CD14 overexpression to LPS responsiveness, 29 another in vivo study in mice 11 suggests that such a difference is probably not sufficient to play a role in sepsis development, supporting the results of our study. Contrary to these data, however, recently a disequilibrium of a polymorphism in a plasma protein facilitating LPS dependent activation of CD14 has been detected between sepsis patients and controls.…”

“…Transgenic mice which express human CD14 develop increased sensitivity to LPS 10 while CD14-deficient mice were found to be highly resistant to shock induced by either live Gram-negative bacteria or LPS. 11 Controversially, the application of soluble CD14 has been shown to protect mice from lethality in LPS-induced shock. 12 The genomic organisation of CD14 13 is well known, and the precise cDNA sequence has recently been verified.…”

Genetic regulation of host responses to Salmonella infection in mice

“…This increased resistance correlated with markedly decreased expression of cytokines such as TNFa and IL6. 118 Interestingly, Cd14-deficient mice were also more resistant to Gram-negative (Escherichia coli) bacterial challenge with a decreased level of bacteremia, suggesting a role for Cd14 in bacterial dissemination. 120 However, in the case of the Gramnegative intracellular pathogen Salmonella Typhimurium, Cd14, as for Tlr4, is essential to improve survival to infection.…”

Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS‐induced lethality

“…It is believed to be composed of TLR4 [1], the main transducer of signals from LPS, the GPI-linked receptor CD14 [2] and a small exteriorized adaptor known as MD-2 [3]. All three molecules are believed to form a stable complex during LPS signaling and, based on germ-line targeting [4][5][6], each is indispensable for LPS responses. However, a precise mechanism of LPS recognition by this complex is unknown and is a subject of vigorous research.…”