Mechanism of Gram-positive Shock: Identification of Peptidoglycan and Lipoteichoic Acid Moieties Essential in the Induction of Nitric Oxide Synthase, Shock, and Multiple Organ Failure

Abstract

The incidence of septic shock caused by gram-positive bacteria has risen markedly in the last few years. It is largely unclear how gram-positive bacteria (which do not contain endotoxin) cause shock and multiple organ failure. We have discovered recently that two cell wall fragments of the pathogenic gram-positive bacterium Staphylococcus aureus, lipoteichoic acid (LTA) and peptidoglycan (PepG), synergize to cause the induction of nitric oxide (NO) formation, shock, and organ injury in the rat. We report here that a specific fragment of PepG, N-acetylglucosamine-β-[1→ 4]-N-acetylmuramyl-l-alanine–d-isoglutamine, is the moiety within the PepG polymer responsible for the synergism with LTA (or the cytokine interferon γ) to induce NO formation in the murine macrophage cell line J774.2. However, this moiety is also present in the PepG of the nonpathogenic bacterium Bacillus subtilis. We have discovered subsequently that S. aureus LTA synergizes with PepG from either bacterium to cause enhanced NO formation, shock, and organ injury in the rat, whereas the LTA from B. subtilis does not synergize with PepG of either bacterium. Thus, we propose that the structure of LTA determines the ability of a particular bacterium to cause shock and multiple organ failure (pathogenicity), while PepG acts to amplify any response induced by LTA.

A Myeloid Hypoxia-inducible Factor 1α-Krüppel-like Factor 2 Pathway Regulates Gram-positive Endotoxin-mediated Sepsis

“…However, this response is truly a double-edged sword because if this induction of HIF-1 is not carefully controlled, excessive myeloid cell activation can ensue and lead to a systemic cytokine storm and endotoxic shock. Indeed, previous studies indicate that Grampositive bacterial endotoxins can induce shock and multiple organ failure (10,11). Consistent with this observation, we also observed dramatic mortality in response to LTA.…”

Lipoteichoic Acid Isolated from Lactobacillus plantarum Inhibits Lipopolysaccharide-Induced TNF-α Production in THP-1 Cells and Endotoxin Shock in Mice

“…However, most bacterial cell walls used in tolerance-induction tests were isolated from pathogenic bacteria, making them harmful for use in clinical applications. The reason for this is that it is difficult to decide the proper concentration to induce the tolerance, and the composition of these bacterial cell walls can cause synergistical inflammation or septic shock (17,18). In our present experiments, the treatment of LPS or aLTA in THP-1 cells induced excessive proinflammatory cytokine production, and the mouse survival rate was reduced by 50% in the LPS-induced tolerance as compared with endotoxin shock mice, indicating the risk of pathogenic bacterial cell walls as a clinical material.…”

Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels

“…Catheters were placed in the inferior vena cava (through the left jugular vein) for administration of drugs and in abdominal aorta (through the left carotid artery) for the monitoring of blood pressure. Gram-positive sepsis was achieved by single administration of S. aureus LTA 3 mg/kg as described (Kengatharan et al 1998).…”