Abstract
Enterovirus (EV)-D68 has been associated with epidemics in the United Sates in 2014, 2016 and 2018. This study aims to identify potential viral virulence determinants. We found that neonatal type I interferon receptor knockout mice are susceptible to EV-D68 infection via intraperitoneal inoculation and were able to recapitulate the paralysis process observed in human disease. Among the EV-D68 strains tested, strain US/MO-14-18949 caused no observable disease in this mouse model, whereas the other strains caused paralysis and death. Sequence analysis revealed several conserved genetic changes among these virus strains: nucleotide positions 107 and 648 in the 5′-untranslated region (UTR); amino acid position 88 in VP3; 1, 148, 282 and 283 in VP1; 22 in 2A; 47 in 3A. A series of chimeric and point-mutated infectious clones were constructed to identify viral elements responsible for the distinct virulence. A single amino acid change from isoleucine to valine at position 88 in VP3 attenuated neurovirulence by reducing virus replication in the brain and spinal cord of infected mice.
Highlights
Enterovirus D68 (EV-D68), previously known as rhinovirus 87 [1], is a single-stranded, plus-senseRNA virus belonging to the genus Enterovirus of the Picornaviridae family
We tested the susceptibility of Tg21/IFNR-ko (Tg21 with type I interferon receptor knockout) mice to EV-D 68. These mice were used in our previous studies for poliovirus Sabin strains and Zikavirus [29,30,31]. We found that this mouse model is susceptible to EV-D68 and recapitulates the paralysis observed in severe human infections, and different EV-D68 isolates show distinct virulence in this model
To test the susceptibility of Tg21/IFNR-ko mice to EV-D68, 5, 8- and 10-day-old mice were inoculated with various dosages (5 × 102 –5 × 104 TCID50 per mouse) of EV-D68 strain 49129 (US/MO/14-18947) via the i.p. route
Summary
Enterovirus D68 (EV-D68), previously known as rhinovirus 87 [1], is a single-stranded, plus-sense. RNA virus belonging to the genus Enterovirus of the Picornaviridae family. The viral genome encodes a polyprotein with a single open reading frame with untranslated regions at both ends. Secondary structures form an internal ribosome entry site (IRES) in the 50 - untranslated region (UTR) and mediate virus translation [2]. The polypeptide contains a P1 region that encodes the structural proteins (VP1, VP2, VP3 and VP4) and P2 and P3 regions that encode non-structural proteins (2A, 2B, 2C, 3A, 3B, 3C and 3D) that are important to virus replication. Genetically closer to enteroviruses, EV-D68 possesses key characteristics of rhinovirus: a lower optimal growth temperature at 33 ◦ C and acid sensitivity which limits its survival through the alimentary tract. EV-D68 is regarded as a respiratory pathogen that causes symptoms including sneezing, cough, runny nose and, in some cases, wheezing and difficulty breathing
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