The leader proteinase of foot-and-mouth disease virus inhibits the induction of beta interferon mRNA and blocks the host innate immune response.
We have previously shown that the leader proteinase (L(pro)) of foot-and-mouth disease virus (FMDV) blocks cap-dependent mRNA translation and that a genetically engineered FMDV lacking the leader proteinase coding region (A12-LLV2) is attenuated in cell culture and susceptible animals. The attenuated phenotype apparently is a consequence of the inability of A12-LLV2 to block the expression of type I interferon (IFN-alpha/beta) protein, resulting in IFN-induced inhibition of FMDV replication. Here we show that in addition to preventing IFN-alpha/beta protein synthesis, L(pro) reduces the level of immediate-early induction of IFN-beta mRNA and IFN-stimulated gene products such as double-stranded RNA-dependent protein kinase R (PKR), 2',5'-oligoadenylate synthetase, and Mx1 mRNAs in swine cells. Down-regulation of cellular PKR by RNA interference did not affect wild-type virus yield but resulted in a higher yield of A12-LLV2, indicating a direct role of PKR in controlling FMDV replication in the natural host. The observation that L(pro) controls the transcription of genes involved in innate immunity reveals a novel role of this protein in antagonizing the cellular response to viral infection.
de Los Santos
Teresa
T
Plum Island Animal Disease Center, USDA, ARS, NAA, P.O. Box 848, Greenport, NY 11944, USA.
de Avila Botton
Sonia
S
Weiblen
Rudi
R
Grubman
Marvin J
MJ
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics; D000818:Animals; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D029544:Foot-and-Mouth Disease Virus / Q000276:immunology / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013552:Swine; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000235:genetics
D012333:RNA, Messenger; D016899:Interferon-beta; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase; D010450:Endopeptidases; C088747:leader proteinase, foot-and-mouth disease virus; D019204:GTP-Binding Proteins