Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses.
Srirupa ChatterjeePriya LuthraEkaterina EsaulovaEugene AgapovBenjamin C YenDominika M BorekMegan R EdwardsAnuradha MittalDavid S JordanParameshwar RamananMartin L MooreRohit V PappuMichael J HoltzmanMaxim N ArtyomovChristopher F BaslerGaya K AmarasingheDaisy W LeungPublished in: Nature microbiology (2017)
Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the paediatric, elderly and immune-compromised populations1,2. A gap in our understanding of hRSV disease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists3-6; however, the role of these proteins in viral pathogenesis is incompletely understood. Here, we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralogue of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 wild type or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I interferon responses, suppression of dendritic cell maturation and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV-associated morbidity and mortality.
Keyphrases
- dengue virus
- respiratory syncytial virus
- dendritic cells
- endothelial cells
- wild type
- intensive care unit
- structural basis
- emergency department
- induced apoptosis
- transcription factor
- aedes aegypti
- immune response
- cell proliferation
- amino acid
- signaling pathway
- protein protein
- endoplasmic reticulum stress
- pluripotent stem cells
- single cell
- heat stress