Abstract
Several live attenuated rotavirus (RV) vaccines have been licensed, but the mechanisms of protective immunity are still poorly understood. The most frequent human B cell response is directed to the internal protein VP6 on the surface of double-layered particles, which is normally exposed only in the intracellular environment. Here, we show that the canonical VP6 antibodies secreted by humans bind to such particles and inhibit viral transcription. Polymeric IgA RV antibodies mediated an inhibitory effect against virus replication inside cells during IgA transcytosis. We defined the recognition site on VP6 as a quaternary epitope containing a high density of charged residues. RV human mAbs appear to bind to a negatively-charged patch on the surface of the Type I channel in the transcriptionally active particle, and they sterically block the channel. This unique mucosal mechanism of viral neutralization, which is not apparent from conventional immunoassays, may contribute significantly to human immunity to RV.
Highlights
Rotaviruses, double-stranded RNA viruses that belong to the Reoviridae family, are the major causative agents for acute gastroenteritis in infants and young children worldwide [1]
We found that a 1:2 ratio of a to J chain DNA enabled the formation of the highest proportion of dimers (Figure 1A), and); higher amounts of J chain did not offer any additional benefit in dimerization efficiency
When we examined the arrangement of the epitope regions A and B from each protomer in the configuration of VP6 trimers on the double-layered particle (DLP), it was clear that the Fab could only bind to regions A and B when they formed a continuous epitope at the junction of two protomers (Figure 4D & E); an Fab could not bind to region A and B on a single protomer
Summary
Rotaviruses, double-stranded RNA viruses that belong to the Reoviridae family, are the major causative agents for acute gastroenteritis in infants and young children worldwide [1]. There are 12 Type I channels located at the icosahedral five-fold axes that have narrow openings through which nascent viral mRNA egresses out of the particle during viral transcription [4]. The Type II channels located at the quasi-six-fold axes directly adjacent to the Type I channels have larger openings than the Type I channels. The Type III channels have larger openings than the Type I channels and are located at the quasi-six-fold axes not directly adjacent to the Type I channels and close to the icosahedral threefold axes. The viral transcription machinery, composed of VP1 and VP3, is located near the icosahedral five-fold axis below the VP2 layer [4]
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