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Myxoma T2 protein as a model for poxvirus TNF receptor homologs
G McFadden1, M Schreiber, L Sedger
1Department of Biochemistry, University of Alberta, Edmonton, Canada. mcfadden@rri.on.ca
Abstract:
Many poxviruses encode a plethora of immunomodulatory proteins, including homologs of cellular cytokine receptors. These receptor mimics, also referred to as viroceptors, are believed to function by binding and sequestering host cytokines thus preventing their signaling cascade prior to receptor engagement. The M-T2 protein of myxoma virus is a TNF receptor homolog that has two distinct activities: the secreted dimeric M-T2 protein binds and inhibits TNF alpha while the intracellular version permits myxoma virus replication in infected T-lymphocytes by blocking the cellular apoptosis response to the virus infection. Studies with M-T2 mutants reveal that distinct protein domains mediate these two anti-immune properties of this protein.
Insights
Myxoma virus M-T2 protein inhibits TNF alpha and blocks apoptosis, allowing viral replication in T-lymphocytes. Distinct protein domains mediate these two crucial anti-immune functions.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Poxviruses utilize immunomodulatory proteins, including viroceptors (cytokine receptor mimics), to evade host immune responses.
- Viroceptors are hypothesized to sequester host cytokines, preventing signal transduction.
- Myxoma virus M-T2 protein is a tumor necrosis factor (TNF) receptor homolog with dual anti-immune functions.
Purpose of the Study:
- To investigate the distinct roles of the M-T2 protein in myxoma virus pathogenesis.
- To elucidate the mechanisms by which M-T2 interferes with host immune signaling and viral replication.
- To identify the specific protein domains responsible for M-T2's anti-immune activities.
Main Methods:
- Analysis of M-T2 protein structure and function.
- Generation and characterization of M-T2 mutants.
- Assays to measure TNF alpha inhibition.
- Assessment of apoptosis inhibition in infected T-lymphocytes.
Main Results:
- Secreted dimeric M-T2 protein effectively binds and neutralizes TNF alpha.
- Intracellular M-T2 protein inhibits apoptosis in virus-infected T-lymphocytes, promoting viral replication.
- Mutational analysis identified distinct domains responsible for TNF alpha inhibition and apoptosis blockade.
Conclusions:
- The myxoma virus M-T2 protein possesses dual immunomodulatory functions essential for viral survival and propagation.
- M-T2 acts as both a secreted TNF alpha inhibitor and an intracellular apoptosis suppressor.
- Targeting specific M-T2 domains offers potential strategies for controlling poxvirus infections.