Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that causes 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 signaling 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.

Original publication

DOI

10.1111/imm.13393

Type

Journal article

Journal

Immunology

Publication Date

20/07/2021

Keywords

Iminosugar, Inflammation, Sepsis, dengue virus, unfolded protein response