LPS recognition, a complex process with complex consequences

Thursday, September 21, 2017

LPS (lipopolysaccharide), also known as endotoxins, are large heat-resistant and resilient molecules found on the outer membrane of Gram-negative bacteria and play an important role in the structural integrity of these bacteria. LPS triggers a strong immune response as Toll-like receptors (more specifically the CD14/TLR4/MD2 receptor complex) recognize LPS. They are an essential component of Gram-negative bacteria, making LPS a relevant target for new antimicrobial agents.

LPS comprises of three parts:

  1. Lipid A: a highly conserved lipid component
  2. The core oligosaccharide: attaches directly to lipid A and common to most variants
  3. The O antigen: a repetitive glycan polymer which maintain the hydrophilic properties of the molecule.

The recognition of LPS is a complex process that starts with the binding to LBP (LPS binding protein). This protein catalyzes the monomerization of LPS and transfers it to CD14 on the cell membrane and to lipoproteins. This in turn transfers it to MD-2, a non-anchored protein that is associated with the extracellular domain of TLR4. The triggering of TLR4 initiates a signaling cascade (MyD88) for cells to secrete pro-inflammatory cytokines and nitric oxide. TLR4 is commonly found on leukocytes and dendritic cells and generates an inflammatory response when exposed to LPS that includes but is not limited to:

  • Production of cytokines such as IL’s and TNF’s
  • Activation of the alternative complement pathway
  • Activation of the coagulation cascade

These reactions can result in a physiological, pathological and clinical effects, such as fever, shock, leukopenia, hypoglycemia and even death. In the past it was thought that LPS exposure is the main cause for pathological conditions, such as sepsis and autoimmune diseases. Advancing insights demonstrate that also the host pathogen interaction plays an important role as it can cause disease due to disruption of the homeostatic state. There are many scientific publications that underline this theory with topics such as:

  • The gut microbiome in conjunction with microbial translocation
  • Periodontal disease in relation to the development of heart disease

Even though it is one of the most widely described molecules in scientific literature, its role in both homeostasis and pathology keeps expanding.

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