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Publications of the Week

Endomembrane Targeting of Human OAS1 p46 Augments Antiviral Activity

By August 23, 2021August 24th, 2021No Comments

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This week we profile a recent publication in eLife from the laboratory of Dr. Ram Savan (pictured, top row third from left) at UW and Center for Innate Immunity and Immune Disease.

Can you provide a brief overview of your lab’s current research focus?

Our laboratory’s research is focused on investigating the underlying molecular mechanisms leading to the heterogeneous immune responses against virus infections, with a primary emphasis on human genetic variations affecting non-coding regulatory regions in antiviral proteins. We use interdisciplinary approaches that include human genetics, virology, RNA regulation, microscopy, biochemical, and bioinformatic techniques.  Major highlights from my lab are identifying genes and their variants with genome-wide significance that affect our immune responses against viral pathogens including the hepatitis C virus, human immunodeficiency virus-1, West Nile virus, and recently SARS-CoV-2.

What is the significance of the findings in this publication?

Interferon and interferon-induced genes emerged over 550 million years ago and ever since have been a hallmark of the host’s early defense against viruses. The pathogenic viruses currently around are only a blip in the timescale of the evolutionary history of all the pathogens we might have encountered. Although interferon-stimulated genes, being the host’s primary antiviral defenders, have been studied for several decades, we only know the direct functions of a handful. Our lab has been invested in identifying their functions, discovering novel pan-antiviral effectors that control virus replication and spread, and engineering location-specific targeting of antiviral effectors to interfere with the virus life cycle. In this study, which was published at eLife, lead authors Frank Soveg and Johannes Schwerk identified a membrane-targeted gene, OAS1 p46, with strong pan-antiviral activity against a subset of viral pathogens. This protein is active against several positive-stranded RNA viruses including picornaviruses, flaviviruses, and SARS-CoV-2. Mechanistically, we show this protein is targeted to host subcellular membranes that the viruses use to hide their replication components. Using this trick, OAS1 p46 gains access to the virus and activates RNaseL that chews up viral RNA to restrict viral replication.

Most interestingly, OAS1 p46 production is controlled by a single nucleotide variation in our genome. One of the advantages of the post-genome sequencing era is the availability of human genome data at the population level across the continents to investigate genetic variability and disease susceptibility.  In collaboration with Karen Cerosaletti from the Benaroya Research Institute, we uncovered that OAS1 p46 producing genetic variant protected patients against severe COVID-19. Our genetic data show patients producing OAS1p46 protein-producing patients are protected from severe COVID-19 disease. We have also replicated this study using a larger European cohort in collaboration with Kenneth Baillie’s group at the University of Edinburgh. We propose that the genetic association with protection against severe COVID-19 can be partly explained by the enhanced antiviral activity of OAS1 p46 against SARS-CoV-2 contributing to the early control of viral replication. However, OAS1 is only a part of the puzzle, and I am sure many other genes in this pathway might also play a role in early control of the virus. Nevertheless, we have found a critical role for OAS1 p46 in cell-intrinsic antiviral immunity against important human viral pathogens including SARS-CoV-2 causing the current pandemic.

What are the next steps for this research?

We are currently interrogating genomic variations in genes of the interferon pathway that could potentially affect the expression of OAS1 p46 modulating its activity in the early control of viral infections. We are also interested in carrying out genetic association studies of the variation that produces OAS1 p46 in patients infected with newer variants of SARS-CoV-2, patients who suffer from long COVID, and disease susceptibility to flaviviruses. More broadly, our focus in the future is to provide a broader conceptual framework on how interferon-stimulated genes protect us from viruses.

If you’d like us to mention your funding sources, please list them.

This work would not have been possible without the efforts of several amazing collaborators. We thank the Benaroya Research Institute COVID-19 research team for collecting the samples for genetic analysis. This project was partially funded by National Institutes of Health grants, research fellowships from the German Research Foundation, and the Cancer Research Institute Irvington Fellowship program.

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