Abstract
Sepsis is a life‐threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non‐targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad‐spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen‐stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen‐induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis‐related inflammatory disorders associated with excess cytokine secretion.
Highlights
Recent changes to the consensus definitions of sepsis and septic shock highlight a shift in clinical risk stratification to identify patients at greater risk of mortality through a focus on dysregulation of the immune response to invading pathogens [1]
Macrophages play a central role in directing the immune response to sepsis [19] and are among the determinant cells in the outcome of dengue virus (DENV) infection in humans, as target cells of DENV and orchestrators of the innate immune response required for viral control [20]
Whereas LPS stimulation induced 8 of 12 cytokines tested by 24 h post-infection (p.i.), cytokine induction by DENV was limited to TNF-α, IFN-γ and IP-10 at 24 h suggesting a specific role of these cytokines in initiating the macrophage response to DENV
Summary
Recent changes to the consensus definitions of sepsis and septic shock highlight a shift in clinical risk stratification to identify patients at greater risk of mortality through a focus on dysregulation of the immune response to invading pathogens [1]. The complexity of dynamic immune responses complicates identification of individual proteins or signalling networks that are responsible for sepsis. There is evidence for dysregulation of several systems contributing to septic pathophysiology including excessive inflammation, coagulopathy, endothelial dysfunction, immune suppression, epigenetic alteration and metabolic dysregulation [2–4]. Approaches aimed at inhibiting expression or signalling by single molecules expressed early in the onset of inflammation (e.g. TNF- α) have failed to improve mortality in sepsis in individual trials a meta-analysis suggests potential benefit [5].
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