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RNA helicases required for viral propagation in humans.

ABSTRACT: RNA viruses cause many routine illnesses, such as the common cold and the flu. Recently, more deadly diseases have emerged from this family of viruses. The hepatitis C virus has had a devastating impact worldwide. Despite the cures developed in the U.S. and Europe, economically disadvantaged countries remain afflicted by HCV infection due to the high cost of these medications. More recently, COVID-19 has swept across the world, killing millions and disrupting economies and lifestyles; the virus responsible for this pandemic is a coronavirus. Our understanding of HCV and SARS CoV-2 replication is still in its infancy. Helicases play a critical role in the replication, transcription and translation of viruses. These key enzymes need extensive study not only as an essential player in the viral lifecycle, but also as targets for antiviral therapeutics. In this review, we highlight the current knowledge for RNA helicases of high importance to human health.

SUBMITTER: Marecki JC

PROVIDER: S-EPMC8562938 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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RNA helicases required for viral propagation in humans.

Marecki John C JC Belachew Binyam B Gao Jun J Raney Kevin D KD

The Enzymes 20211102

RNA viruses cause many routine illnesses, such as the common cold and the flu. Recently, more deadly diseases have emerged from this family of viruses. The hepatitis C virus has had a devastating impact worldwide. Despite the cures developed in the U.S. and Europe, economically disadvantaged countries remain afflicted by HCV infection due to the high cost of these medications. More recently, COVID-19 has swept across the world, killing millions and disrupting economies and lifestyles; the virus ...[more]

PMID: 34861942

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Project description:Human parainfluenza viruses cause a large burden of human respiratory illness. While much research relies upon viruses grown in cultured immortalized cells, human parainfluenza virus 3 (HPIV-3) evolves in culture. Cultured viruses differ in their properties compared to clinical strains. We present a genome-wide survey of HPIV-3 adaptations to culture using metagenomic next-generation sequencing of matched pairs of clinical samples and primary culture isolates (zero passage virus). Nonsynonymous changes arose during primary viral isolation, almost entirely in the genes encoding the two surface glycoproteins-the receptor binding protein hemagglutinin-neuraminidase (HN) or the fusion protein (F). We recovered genomes from 95 HPIV-3 primary culture isolates and 23 HPIV-3 strains directly from clinical samples. HN mutations arising during primary viral isolation resulted in substitutions at HN's dimerization/F-interaction site, a site critical for activation of viral fusion. Alterations in HN dimer interface residues known to favor infection in culture occurred within 4 days (H552 and N556). A novel cluster of residues at a different face of the HN dimer interface emerged (P241 and R242) and imply a role in HPIV-3-mediated fusion. Functional characterization of these culture-associated HN mutations in a clinical isolate background revealed acquisition of the fusogenic phenotype associated with cultured HPIV-3; the HN-F complex showed enhanced fusion and decreased receptor-cleaving activity. These results utilize a method for identifying genome-wide changes associated with brief adaptation to culture to highlight the notion that even brief exposure to immortalized cells may affect key viral properties and underscore the balance of features of the HN-F complex required for fitness by circulating viruses.IMPORTANCE Human parainfluenza virus 3 is an important cause of morbidity and mortality among infants, the immunocompromised, and the elderly. Using deep genomic sequencing of HPIV-3-positive clinical material and its subsequent viral isolate, we discover a number of known and novel coding mutations in the main HPIV-3 attachment protein HN during brief exposure to immortalized cells. These mutations significantly alter function of the fusion complex, increasing fusion promotion by HN as well as generally decreasing neuraminidase activity and increasing HN-receptor engagement. These results show that viruses may evolve rapidly in culture even during primary isolation of the virus and before the first passage and reveal features of fitness for humans that are obscured by rapid adaptation to laboratory conditions.

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RNA helicases required for viral propagation in humans.

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RNA helicases required for viral propagation in humans.

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