TY - JOUR
T1 - Type I interferon suppression-negative and host mRNA nuclear retention-negative mutation in nsp1β confers attenuation of porcine reproductive and respiratory syndrome virus in pigs
AU - Ke, Hanzhong
AU - Han, Mingyuan
AU - Zhang, Qingzhan
AU - Rowland, Raymond
AU - Kerrigan, Maureen
AU - Yoo, Dongwan
N1 - Funding Information:
The authors would like to thank Dr. Wei Yu Chen for his help on porcine IFN-α ELISA assay. We would also like to thank Dr. Wan Liang for her kind help with tonsil RNA isolation experiments. This work was supported by Agriculture and Food Research Initiative (AFRI) Competitive Grant (No. 2013-67015-21243 ) from US Department of Agriculture (USDA)- National Institute of Food and Agriculture (NIFA), and USDA HATCH and Multistate Funds ( ILLU-888-363 ).
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/4
Y1 - 2018/4
N2 - Porcine reproductive and respiratory syndrome virus (PRRSV) has the ability to suppress the type I interferons (IFNs-α/β) induction to facilitate its survival during infection, and the nsp1 protein of PRRSV has been identified as the potent IFN antagonist. The nsp1β subunit of nsp1 has also been shown to block the host mRNA nuclear export as one of the mechanisms to suppress host antiviral protein production. The SAP motif in nsp1β is the functional motif for both IFN suppression and host mRNA nuclear retention, and using infectious clones, two mutant viruses vL126A and vL135A have been generated. These mutants retain the infectivity, but the phenotype is negative for both IFN suppression and host mRNA nuclear retention due to the loss of the SAP motif. To examine the pathogenic role of IFN suppression in pigs, 40 piglets were allotted to four groups and each group was intramuscularly infected with vL126A, vL135A, wild-type (WT) PRRSV, and placebo. Pigs infected with vL126A or vL135A exhibited mild clinical signs with low viral titers and short duration of viremia. The levels of PRRSV-specific antibody remained comparable in all infected groups but the neutralizing antibody titers were high in vL126A-infected or vL135A-infected pigs. The IFN-α concentration was also high in pigs infected with the SAP mutants. Reversion to WT sequence was observed in the SAP motif in some animals, and the revertants regained the function to suppress IFN production and host mRNA nuclear export, indicating strong selection pressure in the SAP motif of nsp1β. Together, our data demonstrate that the IFN antagonism and host mRNA nuclear retention mediated by nsp1β contributes to viral virulence, and loss of these functions confers PRRSV attenuation.
AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has the ability to suppress the type I interferons (IFNs-α/β) induction to facilitate its survival during infection, and the nsp1 protein of PRRSV has been identified as the potent IFN antagonist. The nsp1β subunit of nsp1 has also been shown to block the host mRNA nuclear export as one of the mechanisms to suppress host antiviral protein production. The SAP motif in nsp1β is the functional motif for both IFN suppression and host mRNA nuclear retention, and using infectious clones, two mutant viruses vL126A and vL135A have been generated. These mutants retain the infectivity, but the phenotype is negative for both IFN suppression and host mRNA nuclear retention due to the loss of the SAP motif. To examine the pathogenic role of IFN suppression in pigs, 40 piglets were allotted to four groups and each group was intramuscularly infected with vL126A, vL135A, wild-type (WT) PRRSV, and placebo. Pigs infected with vL126A or vL135A exhibited mild clinical signs with low viral titers and short duration of viremia. The levels of PRRSV-specific antibody remained comparable in all infected groups but the neutralizing antibody titers were high in vL126A-infected or vL135A-infected pigs. The IFN-α concentration was also high in pigs infected with the SAP mutants. Reversion to WT sequence was observed in the SAP motif in some animals, and the revertants regained the function to suppress IFN production and host mRNA nuclear export, indicating strong selection pressure in the SAP motif of nsp1β. Together, our data demonstrate that the IFN antagonism and host mRNA nuclear retention mediated by nsp1β contributes to viral virulence, and loss of these functions confers PRRSV attenuation.
KW - Host mRNA nuclear export
KW - Immune evasion-negative virus
KW - PRRS
KW - Porcine reproductive and respiratory syndrome virus
KW - Type I interferons
KW - Viral attenuation
KW - nsp1
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U2 - 10.1016/j.virol.2018.01.016
DO - 10.1016/j.virol.2018.01.016
M3 - Article
C2 - 29402432
AN - SCOPUS:85041593274
SN - 0042-6822
VL - 517
SP - 177
EP - 187
JO - Virology
JF - Virology
ER -