Removal of the Erns RNase Activity and of the 3' Untranslated Region Polyuridine Insertion in a Low-Virulence Classical Swine Fever Virus Triggers a Cytokine Storm and Lethal Disease
Wang, M. (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)
Bohórquez Garzón, José Alejandro (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)
Muñoz-González, Sara (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)
Gerber, M. (University of Bern. Department of Infectious Diseases and Pathobiology)
Alberch, Mònica (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)
Pérez-Simó, Marta (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)
Abad Morejón de Girón, Xavier (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Liniger, M. (Department of Infectious Diseases and Pathobiology. University of Bern)
Ruggli, N. (Department of Infectious Diseases and Pathobiology. University of Bern)
Ganges, Llilianne (Unitat mixta d'investigació IRTA-UAB en Sanitat Animal. Centre de Recerca en Sanitat Animal)

Fecha:	2022
Resumen:	In this study, we assessed the potential synergistic effect of the E RNase activity and the poly-U insertion in the 3' untranslated region (UTR) of the low-virulence classical swine fever virus (CSFV) isolate Pinar de Rio (PdR) in innate and adaptive immunity regulation and its relationship with classical swine fever (CSF) pathogenesis in pigs. We knocked out the E RNase activity of PdR and replaced the long polyuridine sequence of the 3' UTR with 5 uridines found typically at this position, resulting in a double mutant, vPdR-HK-5U. This mutant induced severe CSF in 5-day-old piglets and 3-week-old pigs, with higher lethality in the newborn (89. 5%) than in the older (33. 3%) pigs. However, the viremia and viral excretion were surprisingly low, while the virus load was high in the tonsils. Only alpha interferon (IFN-a) and interleukin 12 (IL-12) were highly and consistently elevated in the two groups. Additionally, high IL-8 levels were found in the newborn but not in the older pigs. This points toward a role of these cytokines in the CSF outcome, with age-related differences. The disproportional activation of innate immunity might limit systemic viral spread from the tonsils and increase virus clearance, inducing strong cytokine-mediated symptoms. Infection with vPdR-HK-5U resulted in poor neutralizing antibody responses compared with results obtained previously with the parent and RNase knockout PdR. This study shows for the first time the synergistic effect of the 3' UTR and the E RNase function in regulating innate immunity against CSFV, favoring virus replication in target tissue and thus contributing to disease severity.
Ayudas:	Ministerio de Ciencia e Innovación FPI 2016 Ministerio de Ciencia e Innovación RTI2018-100887-B-I00
Nota:	This research was supported by Ministerio de Ciencia, Innovación y Universidades, of the Spanish government under grant RTI2018-100887-B-I00. M.W. has a predoctoral fellowship CSC scholarship (2017) from the Chinese government. J.A.B. has a predoctoral fellowship, FPI 2016, from the Ministerio de Ciencia, Innovación y Universidades, of the Spanish government. IRTA is supported by CERCA Program/Generalitat de Catalunya.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Classical swine fever virus ; Virulence factors ; Innate and adaptive immunity ; Disease severity ; Pigs ; Vaccine designs ; Cytokine-mediated symptoms ; Diagnostic tools and vaccine strategies ; Tonsil ; Viral replication ; Viral spread
Publicado en:	Journal of Virology, Vol. 96 Núm. 14 (july 2022) , ISSN 1098-5514

DOI: 10.1128/jvi.00438-22
PMID: 35758667

15 p, 2.6 MB

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