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Abstract

Enterovirus D68 (EV-D68) causes severe respiratory disease and is a strong candidate as the etiologic agent of acute flaccid myelitis. Acute flaccid myelitis is a rare neurologic disorder that typically affects adolescents less than 13 y old, manifesting as muscle paralysis or weakness. No approved antiviral compounds or vaccines exist for EV-D68. An appropriate mouse model is needed to develop therapeutics. We previously showed that the AG129 mouse strain, which has a double knockout of Ifnar1 and Ifngr1 on the 129/Sv genetic background, exhibits clear clinical signs when infected intraperitoneally with EV-D68 at postnatal day 10. The AGB6 strain, which has the same double knockout, but on the C57BL/6 (B6) genetic background, is more sensitive to dengue virus infections relative to AG129. Given the widespread use of the B6 background in mouse research, we systematically assessed EV-D68 infection in AGB6, the AB6 and GB6 strains, which have single knockouts in Ifnar1 and Ifngr1, respectively, and the parental B6 strain. AGB6 was highly susceptible to EV-D68, equivalent to AG129. No differences in susceptibility were observed between AGB6 and AB6 and GB6 and B6, suggesting that the IFNγ receptor contributes little to EV-D68 protection. Because B6 is the genetic background for many genetically modified mice, AGB6 facilitates the evaluation of the role of host genes in EV-D68 pathogenesis through genetic crosses. We introduced the knockout allele of Setd3, a gene essential for enterovirus RNA replication, into AGB6. While EV-D68 lethality was completely penetrant in AGB6-Setd3+/+ and AGB6-Setd3+/− mice, all AGB6-Setd3−/− littermates survived until the experimental endpoint. We conclude that AGB6 is well suited for testing EV-D68 therapeutics. Our study further underscores the importance of SETD3 being a promising therapeutic target for controlling EV-D68 and other enterovirus infections.

Keywords: AFM, acute flaccid myelitis; B6, C57BL/6; DKO, double knockout; dpi, days postinfection; EV-D68, enterovirus D68; KO, knockout; P10, postnatal day 10; pfu, plaque-forming unit; RD, rhabdomyosarcoma
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