Abstract
Sepsis, a life-threatening syndrome with increasing incidence worldwide, is triggered by an overwhelming inflammation induced by microbial toxins released into the bloodstream during infection. A well-known sepsis-inducing factor is the membrane constituent of Gram-negative bacteria, lipopolysaccharide (LPS), signalling via Toll-like receptor-4. Although sepsis is caused in more than 50% cases by Gram-positive and mycoplasma cells, the causative compounds are still poorly described. In contradicting investigations lipoproteins/-peptides (LP), lipoteichoic acids (LTA), and peptidoglycans (PGN), were made responsible for eliciting this pathology. Here, we used human mononuclear cells from healthy donors to determine the cytokine-inducing activity of various LPs from different bacterial origin, synthetic and natural, and compared their activity with that of natural LTA and PGN. We demonstrate that LP are the most potent non-LPS pro-inflammatory toxins of the bacterial cell walls, signalling via Toll-like receptor-2, not only in vitro, but also when inoculated into mice: A synthetic LP caused sepsis-related pathological symptoms in a dose-response manner. Additionally, these mice produced pro-inflammatory cytokines characteristic of a septic reaction. Importantly, the recently designed polypeptide Aspidasept® which has been proven to efficiently neutralize LPS in vivo, inhibited cytokines induced by the various non-LPS compounds protecting animals from the pro-inflammatory activity of synthetic LP.
Highlights
Sepsis strikes more than a million Americans and it is estimated that 28–50% of them die—far more than the number of U.S deaths from prostate cancer, breast cancer and AIDS combined[5,6]
Observations that purified or synthetic lipoteichoic acids (LTA) or PGN were devoid of such activity likely indicates that previous preparations could be contaminated with LP and that this compound may be responsible for their TLR2 activating properties[12]
Studies using purified LTA from lgt-mutants[15] as well as synthetic LTA16, or PGN part structures[18] did not show any TLR2-mediated activity. This indicated again a possible LP contamination in the previously used LTA and PGN preparations responsible for the originally determined bioactivity, proving that TLR2 is most likely a specific receptor for LP13. The mechanism of this immune activation in humans was determined at the atomic level in several X-ray diffraction studies, namely the signaling induced by triacylated LP occurs via a TLR2/TLR1-heterodimer[19], whereas diacylated LP signals via a TLR2/ TLR6-heterodimer[20]
Summary
Sepsis strikes more than a million Americans and it is estimated that 28–50% of them die—far more than the number of U.S deaths from prostate cancer, breast cancer and AIDS combined[5,6]. Recent studies provided substantial evidence that cell-envelope LP from Gram-positive and Gram-negative bacteria trigger inflammatory responses by activation of Toll-like receptor TLR29,10 at minute concentrations and seem to be important sepsis-inducing factors beyond LPS. Studies using purified LTA from lgt-mutants[15] as well as synthetic LTA16, (reviewed by Schmidt et al.17) or PGN part structures[18] did not show any TLR2-mediated activity This indicated again a possible LP contamination in the previously used LTA and PGN preparations responsible for the originally determined bioactivity, proving that TLR2 is most likely a specific receptor for LP13. Some further investigations are necessary outside the scope of this paper regarding the application of the SALP in more detailed models of Gram-positive bacteremia
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