SIR ROBERT MUIR, SEPSIS AND SCOTTISH HEALTHCARE

Bacterial infections are typically recognised in the body by pattern recognition receptors (PRRs) on antigen presenting cells (APCs). PRRs recognise evolutionarily conserved motifs on the bacterial cell surface as being foreign, as well as endogenous mediators released by the host in response to danger, stress and trauma (called ‘danger associated molecular patterns’ (DAMPs)). ‘Pathogen associated molecular patterns' (PAMPs) are parts of the invading organism that are required for their survival, but also have no human homologue. Cells which express PRRs include macrophages, neutrophils and dendritic cells, and they respond to pathogens by secreting a range of cytokines which contribute to the inflammatory response.

Pattern recognition receptors include the family of Toll-like Receptors (TLRs), which can recognise a broad range of bacterial cell wall components, such as lipopolysaccharide, as well as elements indicative of fungal and viral infection.  TLRs detect PAMPs either at the cell surface or within lysosomal or endosomal cellular compartments. Ligation of TLRs causes induction of signalling pathways that lead to gene transcription. One important signalling pathway is that of NF-KB, which is crucial for cytokine production and cell survival. In resting cells, NF-KB components are kept in the cytoplasm, non-covalently bonding to IKB inhibitors. These inhibitors prevent NF-KB from travelling into the nucleus, interacting with DNA and transcribing products. Cell stimuli such as bacterial cell wall components elicit the degradation of the inhibitors, allowing NF-KB to move to the nucleus and transcribe inflammatory mediators. Among the many genes NF-KB can transcribe are TNFa and IL-1, which can induce further activation of NF-KB in a positive feedback loop. In addition, NF-KB induces the transcription of anti-apoptotic mediators such as A1 and A20. Thus NF-KB activation functions to increase the life span of activated cell populations, such as neutrophils, whilst simultaneously activating them to manufacture pro-inflammatory mediators. Increased activation of NF-KB can be correlated with reduced sepsis survival, and unchecked ligation of PRRs can result in systemic inflammation, tissue injury, intravascular coagulation and death from septicaemia.