Inhibiting XBP1s production as a novel therapeutic strategy in sepsis

Sepsis accounts for over 18 million deaths annually and is characterised by a severe/hyper activation of the immune system, also referred to as a cytokine storm, which is triggered by infection. In its most severe form sepsis manifests as septic shock and can lead to hypotension and multi-organ failure leading to death. The incidence of sepsis is rising and is expected to further increase over the coming years due to a combination of an aging population and increased levels of antibiotic resistant bacteria. Currently, there is no approved effective therapy available for the treatment of sepsis.
The excessive and prolonged production of cytokines characteristic of sepsis produces an overwhelming inflammatory response which is more deadly than the original infection, causing tissue injury and multiple organ failure. This level of cytokine production requires the activity of a protein IRE1. IRE1 functions by producing XBP1s, a transcription factor recently linked to cytokine/chemokine production. In this proposal we aim to dampen the cytokine storm by blocking IRE1 signalling. Inhibiting IRE1 will prevent production of XBP1s and prevent the increase in cytokine production. We will use patient samples and an animal model of sepsis to show that blocking IRE1/XBP1s provides a novel means by which to reduce cytokine production and the inflammation associated with sepsis. Reducing cytokine production would halt the progression towards septic shock and organ failure. Such a targeted approach would be ideal for the treatment of sepsis and could work effectively in conjunction with antibiotics.

Award Date
20 June 2014
Award Value
€327,116
Principal Investigator
Professor Afshin Samali
Host Institution
National University of Ireland, Galway
Scheme
Health Research Awards