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Title: The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus

Abstract

The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ antiimmune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. To investigate this dichotomy in severe acute respiratory syndrome coronavirus (SARS-CoV), we developed a transcriptional network model of SARS-CoV infection in mice and used the model to prioritize candidate regulatory targets for further investigation. We validated our predictions in 18 different knockout (KO) mouse strains, showing that network topology provides significant predictive power to identify genes that are important for viral infection. We identified a novel player in the immune response to virus infection, Kepi, an inhibitory subunit of the protein phosphatase 1 (PP1) complex, which protects against SARS-CoV pathogenesis. We also found that receptors for the proinflammatory cytokine, tumor necrosis factor alpha (TNFα), promote pathogenesis through a parallel feed-forward circuit that promotes inflammation. These results are consistent with previous studies showing the role of over-stimulation of the inflammatory response to SARS-CoV in pathogenesis. We conclude that the critical balance between immune response and inflammation can be manipulated to improve the outcome of the infection.more » Further, our study provides two potential therapeutic strategies for mitigating the effects of SARS-CoV infection, and may provide insight into treatment strategies for Middle East Respiratory Syndrome Coronavirus (MERS-CoV).« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1340835
Report Number(s):
PNNL-SA-118784
Journal ID: ISSN 1752-0509; WN9030198
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: BMC Systems Biology; Journal Volume: 10; Journal Issue: 1
Country of Publication:
United States
Language:
English
Subject:
systems biology; network inference; SARS coronavirus

Citation Formats

McDermott, Jason E., Mitchell, Hugh D., Gralinski, Lisa E., Eisfeld, Amie J., Josset, Laurence, Bankhead, Armand, Neumann, Gabriele, Tilton, Susan C., Schäfer, Alexandra, Li, Chengjun, Fan, Shufang, McWeeney, Shannon, Baric, Ralph S., Katze, Michael G., and Waters, Katrina M. The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus. United States: N. p., 2016. Web. doi:10.1186/s12918-016-0336-6.
McDermott, Jason E., Mitchell, Hugh D., Gralinski, Lisa E., Eisfeld, Amie J., Josset, Laurence, Bankhead, Armand, Neumann, Gabriele, Tilton, Susan C., Schäfer, Alexandra, Li, Chengjun, Fan, Shufang, McWeeney, Shannon, Baric, Ralph S., Katze, Michael G., & Waters, Katrina M. The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus. United States. doi:10.1186/s12918-016-0336-6.
McDermott, Jason E., Mitchell, Hugh D., Gralinski, Lisa E., Eisfeld, Amie J., Josset, Laurence, Bankhead, Armand, Neumann, Gabriele, Tilton, Susan C., Schäfer, Alexandra, Li, Chengjun, Fan, Shufang, McWeeney, Shannon, Baric, Ralph S., Katze, Michael G., and Waters, Katrina M. Fri . "The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus". United States. doi:10.1186/s12918-016-0336-6.
@article{osti_1340835,
title = {The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus},
author = {McDermott, Jason E. and Mitchell, Hugh D. and Gralinski, Lisa E. and Eisfeld, Amie J. and Josset, Laurence and Bankhead, Armand and Neumann, Gabriele and Tilton, Susan C. and Schäfer, Alexandra and Li, Chengjun and Fan, Shufang and McWeeney, Shannon and Baric, Ralph S. and Katze, Michael G. and Waters, Katrina M.},
abstractNote = {The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ antiimmune strategies to facilitate their replication, highly pathogenic virus infections can also cause an excessive immune response that exacerbates, rather than reduces pathogenicity. To investigate this dichotomy in severe acute respiratory syndrome coronavirus (SARS-CoV), we developed a transcriptional network model of SARS-CoV infection in mice and used the model to prioritize candidate regulatory targets for further investigation. We validated our predictions in 18 different knockout (KO) mouse strains, showing that network topology provides significant predictive power to identify genes that are important for viral infection. We identified a novel player in the immune response to virus infection, Kepi, an inhibitory subunit of the protein phosphatase 1 (PP1) complex, which protects against SARS-CoV pathogenesis. We also found that receptors for the proinflammatory cytokine, tumor necrosis factor alpha (TNFα), promote pathogenesis through a parallel feed-forward circuit that promotes inflammation. These results are consistent with previous studies showing the role of over-stimulation of the inflammatory response to SARS-CoV in pathogenesis. We conclude that the critical balance between immune response and inflammation can be manipulated to improve the outcome of the infection. Further, our study provides two potential therapeutic strategies for mitigating the effects of SARS-CoV infection, and may provide insight into treatment strategies for Middle East Respiratory Syndrome Coronavirus (MERS-CoV).},
doi = {10.1186/s12918-016-0336-6},
journal = {BMC Systems Biology},
number = 1,
volume = 10,
place = {United States},
year = {Fri Sep 23 00:00:00 EDT 2016},
month = {Fri Sep 23 00:00:00 EDT 2016}
}
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