Abstract
Since its identification in 1969, Enterovirus 71 (EV71) has been causing periodic outbreaks of infection in children worldwide and most prominently in the Asia-Pacific Region. Understanding the pathogenesis of Enterovirus 71 (EV71) is hampered by the virus’s inability to infect small animals and replicate in their derived in vitro cultured cells. This manuscript describes the phenotypic and genotypic characteristics of two selected EV71 strains (EV71:TLLm and EV71:TLLmv), which have been adapted to replicate in mouse-derived NIH/3T3 cells, in contrast to the original parental virus which is only able to replicate in primate cell lines. The EV71:TLLm strain exhibited productive infection in all primate and rodent cell lines tested, while EV71:TLLmv exhibited greater preference for mouse cell lines. EV71:TLLmv displayed higher degree of adaptation and temperature adaptability in NIH/3T3 cells than in Vero cells, suggesting much higher fitness in NIH/3T3 cells. In comparison with the parental EV71:BS strain, the adapted strains accumulated multiple adaptive mutations in the genome resulting in amino acid substitutions, most notably in the capsid-encoding region (P1) and viral RNA-dependent RNA polymerase (3D). Two mutations, E167D and L169F, were mapped to the VP1 canyon that binds the SCARB2 receptor on host cells. Another two mutations, S135T and K140I, were located in the VP2 neutralization epitope spanning amino acids 136–150. This is the first report of human EV71 with the ability to productively infect rodent cell lines in vitro.
Highlights
Enterovirus 71 (EV71) is a small non-enveloped virus approximately 30 nm in diameter
Human RD cells, as well as monkey Vero and COS-7 cells, exhibited full lytic cytopathic effects (CPE) within 48 hours post-infection (Figure 1A, 1J, 1 M), and viral antigens were detected in fixed infected cells (Figure 2A; data not shown for RD and Vero cells)
Sequential passage of the human EV71 isolate (EV71:BS) generated virus strains that gained the ability to infect in vitro cultured rodent cell lines
Summary
Enterovirus 71 (EV71) is a small non-enveloped virus approximately 30 nm in diameter. The viral capsid exhibits icosahedral symmetry and is comprised of 60 identical units (protomers), with each consisting of four viral structural proteins VP1–VP4. The capsid surrounds a core of a single-stranded positive-sense RNA genome of 7,450 nucleotides (nt) long. The genome contains a single open reading frame which encodes a polyprotein of 2193 amino acids (aa) and is flanked by a long 59 untranslated region (UTR) of 745 nt and a shorter 39 UTR of 85 nt with a poly-A tract of variable length at its 39 terminus. The polyprotein is divided into three regions, i.e. P1, P2 and P3. P1 encodes four viral structural proteins 1A-1D (VP4, VP2, VP3 and VP1); P2 and P3 encode seven non-structural proteins 2A-2C and 3A-3D [1,2,3]
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