Problem in the interferon program associated with more severe COVID-19
A component of the human interferon system that activates SARS-CoV-2 cellular defenses appears to be defective in a proportion of humans, new research reports. COVID-19 outcomes were more severe in hospitalized patients who exhibited this immune system deficit, the study shows. The results suggest the related interferon defense is a key component of a protective antiviral response.
The heterogeneity of COVID-19 disease makes it challenging to predict the course of infection in an individual. Following virus infection, interferons generate the initial signals for cellular defenses. Knowing that defects in interferon signaling associate with more severe COVID-19, Arthur Wickenhagen et al. used interferon-stimulated gene expression screening on human lung cells and identified a gene for an enzyme, OAS1, that reacts to interferon signals, leading the enzyme to counteract the viral attack. OAS1 has been shown to inhibit SARS-CoV-2 replication. In most mammals, OAS1 is attached to membranes by a prenyl group.
However, billions of humans do not possess the prenylated OAS1 haplotype, including many experiencing severe COVID-19. Wickenhagen studied whether the OAS1 haplotype that wasn’t prenylated possessed the same anti-SARS-CoV-2 activity as its prenylated counterpart. “Remarkably,” they write, the non-prenylated form “possessed no detectable anti-SARS-CoV-2 activity.”
After examining the transcriptomes of nearly 500 COVID-19 patients with variable disease outcomes, they report that the absence of prenylated OAS1 was associated with more severe disease. The realization that prenylation can be essential for antiviral activity prompted the researchers to investigate this aspect of OAS1 biology beyond humans.
There is currently great interest in identifying the biological characteristics of bats that might predispose them to be reservoirs of circulating viruses. Horseshoe bats do not possess the prenylated OAS1 haplotype, Wickenhagen and colleagues found. This may contribute to horseshoe bats being such prolific reservoir hosts of Sarbecoviruses, say the authors.
Wickenhagen, A., et al. (2021) A prenylated dsRNA sensor protects against severe COVID-19. Science. doi.org/10.1126/science.abj3624.
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