Anthrax toxin receptor 1 is the cellular receptor for Seneca Valley virus

Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. It has shown promise as a cancer therapeutic in preclinical studies and early-phase clinical trials. Here, we have identified anthrax toxin receptor 1 (ANTXR1) as the receptor for SVV using geno...

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Bibliographic Details
Published in:The Journal of clinical investigation 2017-08, Vol.127 (8), p.2957-2967
Main Authors: Miles, Linde A, Burga, Laura N, Gardner, Eric E, Bostina, Mihnea, Poirier, John T, Rudin, Charles M
Format: Article
Language:English
Subjects:
Analysis
Animals
Anthrax
Apoptosis
Biomedical research
Cancer
Capsid Proteins - chemistry
Cell Line, Tumor
Cell Survival
Clinical trials
Cryoelectron Microscopy
Deoxyribonucleic acid
DNA
Female
Gene expression
Gene Expression Profiling
Genome
Genomes
Green Fluorescent Proteins - chemistry
Health aspects
Heparan sulfate
Humans
Infection
Infections
Interferon
Lung cancer
Mice
Mice, Nude
Microscopy
Neoplasm Proteins - chemistry
Neuroendocrine tumors
Oncolysis
Oncolytic Virotherapy
Oncolytic Viruses
Pediatrics
Permissive cells
Picornaviridae
Proteins
Receptors, Cell Surface - chemistry
Receptors, Virus - chemistry
Rodents
Studies
Tropism
Viruses
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Summary:Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. It has shown promise as a cancer therapeutic in preclinical studies and early-phase clinical trials. Here, we have identified anthrax toxin receptor 1 (ANTXR1) as the receptor for SVV using genome-wide loss-of-function screens. ANTXR1 is necessary for permissivity in vitro and in vivo. However, robust SVV replication requires an additional innate immune defect. We found that SVV interacts directly and specifically with ANTXR1, that this interaction is required for SVV binding to permissive cells, and that ANTXR1 expression is necessary and sufficient for infection in cell lines with decreased expression of antiviral IFN genes at baseline. Finally, we identified the region of the SVV capsid that is responsible for receptor recognition using cryoelectron microscopy of the SVV-ANTXR1-Fc complex. These studies identify ANTXR1, a class of receptor that is shared by a mammalian virus and a bacterial toxin, as the cellular receptor for SVV.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI93472