ArticlePLoS pathogens2025
Key virulence factors responsible for differences in pathogenicity between clinically proven live-attenuated Japanese encephalitis vaccine SA14-14-2 and its pre-attenuated highly virulent parent SA14.
Article in PLoS pathogens, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
2 citing papers in PubMed.
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Authors and funding
5 authors.
Funding
Abstract
Japanese encephalitis virus (JEV), a neuroinvasive and neurovirulent orthoflavivirus, can be prevented in humans with the SA14-14-2 vaccine, a live-attenuated version derived from the wild-type SA14 strain. To determine the viral factors responsible for the differences in pathogenicity between SA14 and SA14-14-2, we initially established a reverse genetics system that includes a pair of full-length infectious cDNAs for both strains. Using this cDNA pair, we then systematically exchanged genomic regions between SA14 and SA14-14-2 to generate 20 chimeric viruses and evaluated their replication capability in cell culture and their pathogenic potential in mice. Our findings revealed the following: (i) The single envelope (E) protein of SA14-14-2, which contains nine mutations (eight in the ectodomain and one in the stem region), is both necessary and sufficient to render SA14 non-neuroinvasive and non-neurovirulent. (ii) Conversely, the E protein of SA14 alone is necessary for SA14-14-2 to become highly neurovirulent, but it is not sufficient to make it highly neuroinvasive. (iii) The limited neuroinvasiveness of an SA14-14-2 derivative that contains the E gene of SA14 significantly increases (approaching that of the wild-type strain) when two viral nonstructural proteins are replaced by their counterparts from SA14: (a) NS1/1', which has four mutations on the external surface of the core β-ladder domain; and (b) NS2A, which has two mutations in the N-terminal region, including two non-transmembrane α-helices. In line with their roles in viral pathogenicity, the E, NS1/1', and NS2A genes all contribute to the enhanced spread of the virus in cell culture. Collectively, our data reveal for the first time that the E protein of JEV has a dual function: It is the master regulator of viral neurovirulence and also the primary initiator of viral neuroinvasion. After the initial E-mediated neuroinvasion, the NS1/1' and NS2A proteins act as secondary promoters, further amplifying viral neuroinvasiveness.
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