A respiratory syncytial virus attachment (G) gene variant associated with more severe disease in infants decreases fusion (F) protein expression which may facilitate immune evasion
AUTHORS
- PMID: 33115881 [PubMed].
ABSTRACT
This study identified a genotype of RSV associated with increased acute respiratory disease severity in a cohort of term, previously healthy infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4 position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wild type A2 strain G gene (one stop codon preceding a wild type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulence-associated combination were generated and characterized. Infection with the rA4G RSV mutant resulted in transcriptional read-through and lower G and fusion (F) protein levels relative to wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational read-through. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naïve BALB/c mice compared to wild type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of pre-existing immunity in comparison to rA4G RSV. Together these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains. Strain-specific differences in respiratory syncytial virus (RSV) isolates are associated with differential pathogenesis in mice. However, the role of RSV genotypes in human infection is incompletely understood. This work demonstrates that one such genotype, 2stop+A4G, present in the RSV attachment (G) gene terminus is associated with greater infant disease severity. The genotype consists of two tandem stop codons preceding an A-to-G point mutation in the 4 position of the G gene end transcription termination signal. Virologically, the 2stop+A4G RSV genotype results in reduced levels of the RSV fusion (F) glycoprotein. A recombinant 2stop+A4G RSV was better able to establish infection in the presence of existing RSV immunity compared to a virus harboring the common A4G mutation. These data suggest that regulation of G and F expression has implications for virulence and potentially immune evasion.
Tags: alumni publications 2020