Abstract
In recent years, there has been a significant increase in detection of Enterovirus D-68 (EV-D68) among patients with severe respiratory infections worldwide. EV-D68 is now recognized as a re-emerging pathogen; however, due to lack of a permissive animal model for EV-D68, a comprehensive understanding of the pathogenesis and immune response against EV-D68 has been hampered. Recently, it was shown that EV-D68 has a strong affinity for α2,6-linked sialic acids (SAs) and we have shown previously that α2,6-linked SAs are abundantly present in the respiratory tract of cotton rats (Sigmodon hispidus). Thus, we hypothesized that cotton rats could be a potential model for EV-D68 infection. Here, we evaluated the ability of two recently isolated EV-D68 strains (VANBT/1 and MO/14/49), along with the historical prototype Fermon strain (ATCC), to infect cotton rats. We found that cotton rats are permissive to EV-D68 infection without virus adaptation. The different strains of EV-D68 showed variable infection profiles and the ability to produce neutralizing antibody (NA) upon intranasal infection or intramuscular immunization. Infection with the VANBT/1 resulted in significant induction of pulmonary cytokine gene expression and lung pathology. Intramuscular immunization with live VANBT/1 or MO/14/49 induced strong homologous antibody responses, but a moderate heterologous NA response. We showed that passive prophylactic administration of serum with high content of NA against VANBT/1 resulted in an efficient antiviral therapy. VANBT/1-immunized animals showed complete protection from VANBT/1 challenge, but induced strong pulmonary Th1 and Th2 cytokine responses and enhanced lung pathology, indicating the generation of exacerbated immune response by immunization. In conclusion, our data illustrate that the cotton rat is a powerful animal model that provides an experimental platform to investigate pathogenesis, immune response, anti-viral therapies and vaccines against EV-D68 infection.
Highlights
Picornaviruses of the genus Enterovirus (EV) comprise many human pathogens that cause most common infections in humans, such as EV A-D and rhinovirus (RV) A-C [1]
Induction of pulmonary cytokines and lung pathology in response to VANBT infection To determine effect of the EV-D68 infection on the induction of an inflammatory response, we focused on the lung tissue and measured the expression of cotton rat mRNA for several chemokines, Type I and Type II interferons (IFNs), cytokines, and select IFN-inducible genes following VANBT infection
The detection frequency of EV-D68 in respiratory infections has been on the rise worldwide and the 2014 USA outbreak was the largest and most widespread EV-D68 epidemic investigated to date [9, 10, 13,14,15,16,17,18,19,20,21,22,23]
Summary
Picornaviruses of the genus Enterovirus (EV) comprise many human pathogens that cause most common infections in humans, such as EV A-D and rhinovirus (RV) A-C [1]. The EVs are small, single-stranded, positive-sense RNA viruses with a genome of ~7.5 kb, encapsidated into an icosahedral capsid, forming a non-enveloped virion of around 30 nm diameter. There are total 5 types of EV-D species: EV-D70, associated with acute hemorrhagic conjunctivitis [2, 3], EV-D94, causative agent of acute flaccid paralysis [4, 5], EV-D111 and D120, identified in non-human primates [6, 7], and EV-D68. The EV-D68 genome consists of single open reading frame (ORF), encoding four structural proteins (VP1-VP4) and seven nonstructural proteins (2A-2C and 3A-3D), flanked by a long 5’ untranslated region (UTR) with a hairpin-loop secondary structure and a short 3’UTR with a poly(A) tract [11]
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