Endomembrane targeting of human OAS1 p46 augments antiviral activity
- The University of Washington, United States
- Benaroya Research Institute, United States
- University of Edinburgh, United Kingdom
- The University of New Mexico, United States
- The Ohio State University, United States
- University of Washington, United States
- Charles Sturt University, United States
- The University of Washingon, United States
- The University of Texas, Galveston, United States
- Touro University Nevada, United States
- Benaroya Research Institute at Virginia Mason, United States
- The University of Pittsburgh, United States
- University of Texas Medical Branch Galveston, United States
- University of Pittsburgh, United States
- Roslin Institute, University of Edinburgh, United Kingdom
Abstract
Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.
Data availability
All data generated during this study are provided in the manuscript, supporting files, and source data files.Raw PLINK results for the association analysis of local subjects are provided in Supplementary File 5; association data for the GenOMICC replication cohort is available as described in the primary publication (Pairo-Castineira et al., 2020).Additional data on our local COVID-19 cohort is available upon request (KCerosaletti@benaroyaresearch.org). This is being done to protect the privacy of the subjects in this study as the data were obtained from samples recovered from the hospital clinical laboratory with IRB approval but without written consent. For commercial entities, availability of these data will be assessed on a case-by-case basis in conjunction with the Benaroya Research Institute business development office.
Article and author information
Author details
Katharina Esser-Nobis
Jonathan M Clingan
Eileen T McAnarney
Saumendra N Sarkar
John Kenneth Baillie
Funding
National Institutes of Health (AI145974,AI108765,AI135437)
- Ram Savan
National Institutes of Health (AI104002,AI118916,AI145296,AI127463,AI100625)
- Frank W Soveg
National Institutes of Health (AI106677,GM007270,AI140530)
- Frank W Soveg
National Institutes of Health (T32 HL007312)
- Adriana Forero
Office of the Director of the National Institutes of Health (S10OD026741)
- Ram Savan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: A cohort of 99 healthy control subjects matched for ancestry (self-reported) was assembled from participants in the 1310 healthy control registry at Benaroya Research Institute. Both studies were approved by the Institutional Review Board at Benaroya Research Institute (IRB20-036 and IRB07109respectively).
Copyright
© 2021, Soveg et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 5,375
- views
-
- 623
- downloads
-
- 59
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Endomembrane targeting of human OAS1 p46 augments antiviral activity
eLife 10:e71047.
https://doi.org/10.7554/eLife.71047
Further reading
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.
