Inhibition of type III interferon activity by orthopoxvirus immunomodulatory proteins.
The type III interferon (IFN) family elicits an antiviral response that is nearly identical to that evoked by IFN-alpha/beta. However, these cytokines (known as IFN-lambda1, 2, and 3) signal through a distinct receptor, and thus may be resistant to the evasion strategies used by some viruses to avoid the IFN-alpha/beta response. Orthopoxviruses are highly resistant to IFN-alpha/beta because they encode well-characterized immunomodulatory proteins that inhibit IFN activity. These include a secreted receptor (B18R) that neutralizes IFN-alpha/beta, and a cytoplasmic protein (E3L) that blocks IFN-alpha/beta effector functions in infected cells. We therefore determined the ability of these immunomodulators to abrogate the IFN-lambda-induced antiviral response. We found that (i) vaccinia virus (VACV) replication is resistant to IFN-lambda antiviral activity; (ii) neither VACV B18R nor the variola virus homolog B20R neutralizes IFN-lambda; (iii) VACV E3L inhibits the IFN-lambda-mediated antiviral response through a PKR-dependent pathway; (iv) VACV infection inhibits IFN-lambdaR-mediated signal transduction and gene expression. These results demonstrate differential sensitivity of IFN-lambda to multiple distinct evasion mechanisms employed by a single virus.
Bandi
Prasanthi
P
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA.
Pagliaccetti
Nicole E
NE
Robek
Michael D
MD
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000378:metabolism*; D007372:Interferons / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D016601:RNA-Binding Proteins / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014615:Vaccinia / Q000503:physiopathology; D014616:Vaccinia virus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012901:Variola virus / Q000378:metabolism; D018116:Vesiculovirus / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
C081374:E3L protein, Vaccinia virus; D007155:Immunologic Factors; D016601:RNA-Binding Proteins; D050791:STAT Transcription Factors; D014764:Viral Proteins; C067853:B18R protein, Vaccinia virus; D053633:Receptor, Interferon alpha-beta; D007372:Interferons