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Anthrax toxin receptor 1 is the cellular receptor for Seneca Valley virus
Linde A. Miles, … , John T. Poirier, Charles M. Rudin
Linde A. Miles, … , John T. Poirier, Charles M. Rudin
Published June 26, 2017
Citation Information: J Clin Invest. 2017;127(8):2957-2967. https://doi.org/10.1172/JCI93472.
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Research Article Virology

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

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Abstract

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.

Authors

Linde A. Miles, Laura N. Burga, Eric E. Gardner, Mihnea Bostina, John T. Poirier, Charles M. Rudin

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Figure 1

Identification of ANTXR1 as host dependency factor for SVV.

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Identification of ANTXR1 as host dependency factor for SVV.
(A) Depictio...
(A) Depiction of genome-scale CRISPR knockout (GeCKO) screen workflow. After lentiviral transduction of the sgRNA library, transduced cells were selected by puromycin. Cells were then challenged with SVV to select for resistant cells. (B) The screen identified ANTXR1 (blue) and TEX2 (red) as the most significant hits. Nontargeting control sgRNAs are highlighted in black. Log fold change (logFC) in selected over control pools is indicated on the vertical axis as a function of the average log counts per million reads (logCPM). (C) HAP1 cells were transduced with individual sgRNAs identified from the HAP1 GeCKO screen. Cell viability was assayed in the absence (light gray) or presence (black) of SVV. Each bar corresponds to the average of n = 6 replicates with error bars representing SD. Dashed lines indicate parental HAP1 cell viability in the absence and presence of SVV. (D) Individual sgRNAs identified in the 25 H446 GeCKO screen colonies were transduced into parental H446 cells. Cell viability was tested in the absence (light gray) or presence (black) of SVV. Parental H446 cell viability in the absence and presence of SVV is indicated with dashed lines. Each bar corresponds to the average of n = 6 replicates with error bars representing SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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