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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
Respiratory syncytial virus nonstructural proteins decrease levels of multiple members of the cellular interferon
Samer Swedan1, Alla Musiyenko, Sailen Barik
1Department of Biochemistry and Molecular Biology, University of South Alabama, College of Medicine, 307 University Blvd., Mobile, AL 36688-0002, USA.
Journal of Virology
|July 24, 2009
Summary
Respiratory syncytial virus (RSV) nonstructural (NS) proteins NS1 and NS2 target key interferon (IFN) pathway proteins, including TRAF3, IKKepsilon, and STAT2, to suppress innate immunity for viral replication.
Area of Science:
- Virology and Immunology
- Innate Immune Response Modulation
Background:
- Paramyxoviridae viruses, including respiratory syncytial virus (RSV), evade host innate immunity by suppressing type I interferon (IFN) production and function.
- The specific molecular targets of RSV nonstructural (NS) proteins NS1 and NS2 in suppressing the IFN pathway remain largely uncharacterized.
Purpose of the Study:
- To investigate the impact of RSV NS1 and NS2 proteins on the steady-state levels of critical components within the type I IFN signaling pathway.
- To elucidate the roles of individual and combined NS1 and NS2 proteins in modulating IFN activation and response pathways.
Main Methods:
- Analysis of steady-state protein levels of key IFN pathway members (TRAF3, IKKepsilon, STAT2) in the presence of RSV NS1 and NS2.
- Investigation of protein degradation mechanisms (proteasomal vs. nonproteasomal).
- Preliminary mapping of functional domains within NS1 and NS2 proteins using C-terminal deletions.
- Coimmunoprecipitation assays to determine NS1-NS2 heterodimerization.
Main Results:
- Both NS1 and NS2 proteins reduced TRAF3 levels, with NS1 being more potent.
- NS1 significantly reduced IKKepsilon levels, while NS2 modestly increased them. Loss of TRAF3 and IKKepsilon involved nonproteasomal mechanisms.
- NS2 decreased STAT2 levels, a crucial factor for antiviral gene expression. The C-termini of NS1 and NS2 were critical for their respective effects on IKKepsilon and STAT2.
- NS1 and NS2 were found to form a heterodimer.
Conclusions:
- RSV NS1 and NS2 proteins individually and collectively regulate key signaling molecules in both the IFN activation and response pathways.
- These findings reveal specific targets of RSV NS proteins, providing insights into viral immune evasion strategies and potential therapeutic targets.
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