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

Jason E. McDermott, Hugh D. Mitchell, Lisa E. Gralinski, Amie J. Eisfeld, Laurence Josset, Armand Bankhead, Gabriele Neumann, Susan C. Tilton, Alexandra Schäfer, Chengjun Li, Shufang Fan, Shannon McWeeney, Ralph S. Baric, Michael G. Katze, Katrina M. Waters

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: The complex interplay between viral replication and host immune response during infection remains poorly understood. While many viruses are known to employ anti-immune 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. Results: 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, presumably through excessive inflammation. Conclusions: The current study provides validation of network modeling approaches for identifying important players in virus infection pathogenesis, and a step forward in understanding the host response to an important infectious disease. The results presented here suggest the role of Kepi in the host response to SARS-CoV, as well as inflammatory activity driving pathogenesis through TNFα signaling in SARS-CoV infections. Though we have reported the utility of this approach in bacterial and cell culture studies previously, this is the first comprehensive study to confirm that network topology can be used to predict phenotypes in mice with experimental validation.

Original languageEnglish (US)
Article number93
JournalBMC Systems Biology
Volume10
Issue number1
DOIs
StatePublished - Sep 23 2016

Fingerprint

SARS Virus
Severe Acute Respiratory Syndrome
Enzyme inhibition
Tumor Necrosis Factor
Protein Phosphatase 1
Phosphatases
Viruses
Infection
Virus Diseases
Tumor Necrosis Factor-alpha
Coronavirus
Proteins
Protein
Coronavirus Infections
Virus
Immune Response
Mouse
Topology
Network Topology
Replication

Keywords

  • Network
  • Pathogenicity
  • SARS coronavirus
  • Systems biology

ASJC Scopus subject areas

  • Structural Biology
  • Modeling and Simulation
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

Cite this

McDermott, J. E., Mitchell, H. D., Gralinski, L. E., Eisfeld, A. J., Josset, L., Bankhead, A., ... Waters, K. M. (2016). The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus. BMC Systems Biology, 10(1), [93]. https://doi.org/10.1186/s12918-016-0336-6

The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus. / 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.

In: BMC Systems Biology, Vol. 10, No. 1, 93, 23.09.2016.

Research output: Contribution to journalArticle

McDermott, JE, Mitchell, HD, Gralinski, LE, Eisfeld, AJ, Josset, L, Bankhead, A, Neumann, G, Tilton, SC, Schäfer, A, Li, C, Fan, S, McWeeney, S, Baric, RS, Katze, MG & Waters, KM 2016, 'The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus', BMC Systems Biology, vol. 10, no. 1, 93. https://doi.org/10.1186/s12918-016-0336-6
McDermott JE, Mitchell HD, Gralinski LE, Eisfeld AJ, Josset L, Bankhead A et al. The effect of inhibition of PP1 and TNFα signaling on pathogenesis of SARS coronavirus. BMC Systems Biology. 2016 Sep 23;10(1). 93. https://doi.org/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. In: BMC Systems Biology. 2016 ; Vol. 10, No. 1.
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