Abstract
Human respiratory syncytial virus (RSV) is an important cause of severe lower respiratory tract infections in infants and the elderly. In the vast majority of cases, however, RSV infections run mild and symptoms resemble those of a common cold. The immunological, clinical, and epidemiological profile of severe RSV infections suggests a disease caused by a virus with typical seasonal transmission behavior, lacking clear-cut virulence factors, but instead causing disease by modifying the host’s immune response in a way that stimulates pathogenesis. Yet, the interplay between RSV-evoked immune responses and epidemic behavior, and how this affects the genomic evolutionary dynamics of the virus, remains poorly understood. Here, we present a comprehensive collection of 33 novel RSV subgroup A genomes from strains sampled over the last decade, and provide the first measurement of RSV-A genomic diversity through time in a phylodynamic framework. In addition, we map amino acid substitutions per protein to determine mutational hotspots in specific domains. Using Bayesian genealogical inference, we estimated the genomic evolutionary rate to be 6.47×10−4 (credible interval: 5.56×10−4, 7.38×10−4) substitutions/site/year, considerably slower than previous estimates based on G gene sequences only. The G gene is however marked by elevated substitution rates compared to other RSV genes, which can be attributed to relaxed selective constraints. In line with this, site-specific selection analyses identify the G gene as the major target of diversifying selection. Importantly, statistical analysis demonstrates that the immune driven positive selection does not leave a measurable imprint on the genome phylogeny, implying that RSV lineage replacement mainly follows nonselective epidemiological processes. The roughly 50 years of RSV-A genomic evolution are characterized by a constant population size through time and general co-circulation of lineages over many epidemic seasons – a conclusion that might be taken into account when developing future therapeutic and preventive strategies.
Highlights
Human respiratory syncytial virus (RSV) is the single most important cause of severe lower respiratory tract infections (LRTI) in infants and young children
The institutional review board (IRB) confirmed that viral strains are not regarded as patient-owned material and the use of these strains is not restricted in the applicable Dutch law (‘‘Law Medical Scientific Research with People’’, WMO; art. 1b)
Changes in amino acid residues from all strains were mapped for each RSV protein to determine the protein substitution density for all proteins (Fig. 1)
Summary
Human respiratory syncytial virus (RSV) is the single most important cause of severe lower respiratory tract infections (LRTI) in infants and young children. RSV infections are the most frequent cause of hospitalization of infants and young children in industrialized countries. RSV is responsible for at least 100,000 infant hospitalizations for pneumonia or bronchiolitis every year in the USA alone [1]. The RSV disease spectrum ranges from mild symptoms such as rhinitis and otitis media, to severe illness such as bronchiolitis or pneumonia, which require supportive care such as mechanical ventilation [2]. Among elderly persons followed for 3 consecutive winters, RSV infection accounted for 10.6% of hospitalizations for pneumonia, 11.4% of hospitalizations for obstructive pulmonary disease, 5.4% for congestive heart failure, and 7.2% for asthma [7]
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