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Title: A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection

Abstract

Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are nomore » treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. Lastly, these studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [1]
  1. Sandia National Lab. (SNL-CA), Livermore, CA (United States)
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Publication Date:
Research Org.:
Sandia National Lab. (SNL-CA), Livermore, CA (United States); Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA)
OSTI Identifier:
1326652
Alternate Identifier(s):
OSTI ID: 1474355
Report Number(s):
SAND-2016-6020J; LLNL-JRNL-738409
Journal ID: ISSN 0022-538X; 642583
Grant/Contract Number:  
AC04-94AL85000; AC52-07NA27344
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 90; Journal Issue: 16; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological and medical sciences

Citation Formats

Harmon, Brooke, Bird, Sara W., Schudel, Benjamin R., Hatch, Anson V., Rasley, Amy, and Negrete, Oscar A. A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection. United States: N. p., 2016. Web. doi:10.1128/JVI.00543-16.
Harmon, Brooke, Bird, Sara W., Schudel, Benjamin R., Hatch, Anson V., Rasley, Amy, & Negrete, Oscar A. A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection. United States. doi:10.1128/JVI.00543-16.
Harmon, Brooke, Bird, Sara W., Schudel, Benjamin R., Hatch, Anson V., Rasley, Amy, and Negrete, Oscar A. Wed . "A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection". United States. doi:10.1128/JVI.00543-16. https://www.osti.gov/servlets/purl/1326652.
@article{osti_1326652,
title = {A genome-wide RNA interference screen identifies a role for Wnt/β-catenin signaling during Rift Valley Fever Virus infection},
author = {Harmon, Brooke and Bird, Sara W. and Schudel, Benjamin R. and Hatch, Anson V. and Rasley, Amy and Negrete, Oscar A.},
abstractNote = {Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. Lastly, these studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.},
doi = {10.1128/JVI.00543-16},
journal = {Journal of Virology},
number = 16,
volume = 90,
place = {United States},
year = {2016},
month = {7}
}

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