Abstract
Rotavirus is a major cause of gastroenteritis in children, with infection typically inducing high levels of protective antibodies. Antibodies targeting the middle capsid protein VP6 are particularly abundant, and as VP6 is only exposed inside cells, neutralisation must be post-entry. However, while a system of poly immune globulin receptor (pIgR) transcytosis has been proposed for anti-VP6 IgAs, the mechanism by which VP6-specific IgG mediates protection remains less clear. We have developed an intracellular neutralisation assay to examine how antibodies neutralise rotavirus inside cells, enabling comparison between IgG and IgA isotypes. Unexpectedly we found that neutralisation by VP6-specific IgG was much more efficient than by VP6-specific IgA. This observation was highly dependent on the activity of the cytosolic antibody receptor TRIM21 and was confirmed using an in vivo model of murine rotavirus infection. Furthermore, mice deficient in only IgG and not other antibody isotypes had a serious deficit in intracellular antibody-mediated protection. The finding that VP6-specific IgG protect mice against rotavirus infection has important implications for rotavirus vaccination. Current assays determine protection in humans predominantly by measuring rotavirus-specific IgA titres. Measurements of VP6-specific IgG may add to existing mechanistic correlates of protection.
Highlights
Species A rotaviruses are a major cause of acute gastroenteritis in infants and young children under 5 years of age worldwide [1]
Effective rotavirus vaccines have been available for over a decade, but detailed understanding of the immune response to rotavirus infection is essential for further improvement of vaccines
High levels of antibodies are made in response to infection, especially antibodies targeting the inner capsid protein VP6, but while both IgA and IgG isotypes are produced, previous work has focused predominantly on VP6-specific IgA
Summary
Species A rotaviruses are a major cause of acute gastroenteritis in infants and young children under 5 years of age worldwide [1]. Antibodies are rapidly generated in response to both natural infection and vaccination, and have been shown to be essential for protection against future rotavirus-associated disease. The precise nature of this protection is poorly understood, since rotavirus-specific antibodies of different isotypes (IgG or IgA) target a diverse range of viral proteins [3]. Rotavirus is a triple-layered particle, and a large body of evidence indicates that antibodies targeting the VP6 protein of the middle capsid layer play a key role in protection against rotavirus infection. VP6-specific antibodies are produced to high titres in response to rotavirus infection or vaccination [4,5], and mice experimentally infected with rotavirus are protected by passive transfer of anti-VP6 antibodies [6,7] or anti-VP6 nanobodies [8]. A number of VP6-based vaccine approaches show induction or enhancement of protective immunity [9,10,11,12,13]
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