The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence
Open accessAbstract
Viral immune evasion strategies target key aspects of the host antiviral response. Recently, it has been recognized that Toll-like receptors (TLRs) have a role in innate defense against viruses. Here, we define the function of the vaccinia virus (VV) protein A46R and show it inhibits intracellular signalling by a range of TLRs. TLR signalling is triggered by homotypic interactions between the Toll-like–interleukin-1 resistance (TIR) domains of the receptors and adaptor molecules. A46R contains a TIR domain and is the only viral TIR domain–containing protein identified to date. We demonstrate that A46R targets the host TIR adaptors myeloid differentiation factor 88 (MyD88), MyD88 adaptor-like, TIR domain–containing adaptor inducing IFN-β (TRIF), and the TRIF-related adaptor molecule and thereby interferes with downstream activation of mitogen-activated protein kinases and nuclear factor κB. TRIF mediates activation of interferon (IFN) regulatory factor 3 (IRF3) and induction of IFN-β by TLR3 and TLR4 and suppresses VV replication in macrophages. Here, A46R disrupted TRIF-induced IRF3 activation and induction of the TRIF-dependent gene regulated on activation, normal T cell expressed and secreted. Furthermore, we show that A46R is functionally distinct from another described VV TLR inhibitor, A52R. Importantly, VV lacking the A46R gene was attenuated in a murine intranasal model, demonstrating the importance of A46R for VV virulence.
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Cites
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The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
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Self-citationInnate immune recognition of viral infection
Kawai, T., & Akira, S. (2006) · Nature Immunology · doi:10.1038/ni1303 · Cited by 1,899
Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury
Lai, Y., Di Nardo, A., Nakatsuji, T., Leichtle, A., Yang, Y., Cogen, A. L., Wu, Z.-R., Hooper, L. V., Schmidt, R. R., von Aulock, S., et al. (2009) · Nature Medicine · doi:10.1038/nm.2062 · Cited by 781
Viral evasion and subversion of pattern-recognition receptor signalling
Bowie, A. G., & Unterholzner, L. (2008) · Nature Reviews Immunology · doi:10.1038/nri2436 · Cited by 746
Self-citationMultiple Functions of BCL-2 Family Proteins
Hardwick, J. M., & Soane, L. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008722 · Cited by 564
Metadata
- Authors
- Stack, J., Haga, I. R., Schröder, M., Bartlett, N. W., Maloney, G., Reading, P. C., Fitzgerald, K. A., Smith, G. L., & Bowie, A. G.
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2005-03-14
- Volume
- 201
- Issue
- 6
- Pages
- 1007-1018
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2145243874
- Cited by
- 369
- References
- 56
- FWCI
- 12.98
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Stack, J., Haga, I. R., Schröder, M., Bartlett, N. W., Maloney, G., Reading, P. C., Fitzgerald, K. A., Smith, G. L., & Bowie, A. G. (2005). Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence. The Journal of Experimental Medicine. https://doi.org/10.1084/jem.20041442
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