Lipoproteins/peptides are sepsis-inducing toxins from bacteria that can be neutralized by synthetic anti-endotoxin peptides

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.

Bacterial lipids: powerful modifiers of the innate immune response

“…Martinez de Tejada et al . extended these studies to show that lipoproteins are the most potent stimulators of TLR2 in vitro and are capable of producing sepsis-like pathology in mice 19 . Finally, evidence even suggests that LTA can serve to dampen lipoprotein-induced immune cell stimulation and IL-8 production in intestinal epithelial cells 20 .…”

The synthetic antimicrobial peptide 19-2.5 attenuates septic cardiomyopathy and prevents down-regulation of SERCA2 in polymicrobial sepsis

“…The amino acid sequence of this 20’mer is GCKKYRRFRWKFKGKFWFWG, with a molecular weight of 2711 kDa. Pep2.5 was amidated at the C-terminal end and had a purity of >95% as measured by HPLC and MALDI-TOF mass spectrometry9.…”

“…The newly designed synthetic antimicrobial peptide 19-2.5 (Pep2.5) belongs to the class of synthetic anti-lipopolysaccharide peptides (SALP = synthetic anti-LPS peptides). However, its activity is not restricted to Gram-negative bacterial infection8, as Pep2.5 neutralizes LPS as well as lipoteichoic acid (LTA) and LPs without causing harm9.…”

Adapting Drug Approval Pathways for Bacteriophage-Based Therapeutics

“…Such issues could potentially be anticipated and avoided by the selection of phages which exhibit different properties such as lower virulence or through the combination of phages with conventional antibiotics. Although this may suggest that whole replicating phage therapies could be consigned to topical application further research is required, particularly if the issue is addressed through the incorporation of anti-endotoxin adjuvants (de Tejada et al, 2015 ; Valera et al, 2015 ).…”