Pathogen-induced inflammation is attenuated by the iminosugar MON-DNJ via modulation of the unfolded protein response.
Andrew C SayceFernando O MartínezBeatrice Ellen TyrrellNilanka PereraMichelle L HillRaymond A DwekJoanna Louise MillerNicole ZitzmannPublished in: Immunology (2021)
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.
Keyphrases
- endoplasmic reticulum stress
- oxidative stress
- endoplasmic reticulum
- diabetic rats
- small molecule
- dengue virus
- induced apoptosis
- high glucose
- endothelial cells
- protein protein
- zika virus
- acute kidney injury
- intensive care unit
- healthcare
- candida albicans
- drug induced
- palliative care
- cancer therapy
- sars cov
- septic shock
- toll like receptor
- patient safety
- genome wide
- binding protein
- aedes aegypti
- immune response
- lps induced
- health insurance
- induced pluripotent stem cells
- cell surface
- drug delivery