Dataset Information

Suppression of influenza virus infection by rhinovirus interference – at the population, individual and cellular levels

ABSTRACT: Highlights • Negative correlation of RV prevalence in suppressing influenza viruses is independent of meteorological effects.• A low odds of RV/IV co-detection infers a unique interference effect.• Sequential RV infection model demonstrates the inhibitory effect of RV on the replication of influenza A and B viruses.

Background

Influenza virus (IV) and the rhinovirus (RV) are the two most common circulating respiratory viruses circulating. Natural viral interference has been suggested between them. The effect of such at the population level has been described in temperate region, while its effect at the individual and cellular levels warrants further validation. In this study, we described the respiratory virus epidemiology and the co-infection landscape in the hospitalized population and investigated the distinct molecular pathways involved in the inhibition of virus replication.

Methods

Nasopharyngeal aspirates (NPAs) collected from patients during 2015 to 2019 were examined for the presence of respiratory viruses. The correlation of the monthly prevalence between all the tested respiratory viruses, the co-infection rate and the temporal interference of RV and IV were tested. The viral interference was validated in vitro by conducting sequential RV and IV infections in the well-differentiated primary human airway epithelial cells. The contributing molecular pathways were determined by transcriptome analysis.

Findings

A total of 112,926 NPAs were evaluated, and the Enterovirus/RV was the most prevalent respiratory virus detected. The negative correlation between EV/RV and IVs prevalence was independent of age and meteorological factors. Compare with other viruses, EV/RV had a significantly lower incidence of co-infection with IVs. Prior exposure to RV inhibited the replication of IV species A, B and oseltamivir-resistance stain in vitro. RV uniquely downregulated genes related to processing of viral mRNA, ribosomal proteins, translation and influenza infection.

Interpretation

Epidemiological surveillance and the sequential infection in vitro suggested viral interference between EV/RV and IV operates at the population, individual and cellular levels.

Funding

This study was supported by the 10.13039/501100012479General Research Fund (Ref: 24107017 and 14103119 to RWYC) and the Chinese University Direct Grant for Research (Ref: 2019·073 to RWYC). Graphical abstract Image, graphical abstract

SUBMITTER: Tao K

PROVIDER: S-EPMC9325905 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundDuring the 2009 pandemic of an emerging influenza A virus (IAV; H1N1pdm09), data from several European countries indicated that the spread of the virus might have been interrupted by the annual autumn rhinovirus epidemic. We aimed to investigate viral interference between rhinovirus and IAV with use of clinical data and an experimental model.MethodsWe did a clinical data analysis and experimental infection study to investigate the co-occurrence of rhinovirus and IAV in respiratory specimens from adults (≥21 years) tested with a multiplex PCR panel at Yale-New Haven Hospital (CT, USA) over three consecutive winter seasons (Nov 1 to March 1, 2016-17, 2017-18, and 2018-19). We compared observed versus expected co-detections using data extracted from the Epic Systems electronic medical record system. To assess how rhinovirus infection affects subsequent IAV infection, we inoculated differentiated primary human airway epithelial cultures with rhinovirus (HRV-01A; multiplicity of infection [MOI] 0·1) or did mock infection. On day 3 post-infection, we inoculated the same cultures with IAV (H1N1 green fluorescent protein [GFP] reporter virus or H1N1pdm09; MOI 0·1). We used reverse transcription quantitative PCR or microscopy to quantify host cell mRNAs for interferon-stimulated genes (ISGs) on day 3 after rhinovirus or mock infection and IAV RNA on days 4, 5, or 6 after rhinovirus or mock infection. We also did sequential infection studies in the presence of BX795 (6 μM), to inhibit the interferon response. We compared ISG expression and IAV RNA and expression of GFP by IAV reporter virus.FindingsBetween July 1, 2016, and June 30, 2019, examination of 8284 respiratory samples positive for either rhinovirus (n=3821) or IAV (n=4463) by any test method was used to establish Nov 1 to March 1 as the period of peak virus co-circulation. After filtering for samples within this time frame meeting the inclusion criteria (n=13 707), there were 989 (7·2%) rhinovirus and 922 (6·7%) IAV detections, with a significantly lower than expected odds of co-detection (odds ratio 0·16, 95% CI 0·09-0·28). Rhinovirus infection of cell cultures induced ISG expression and protected against IAV infection 3 days later, resulting in an approximate 50 000-fold decrease in IAV H1N1pdm09 viral RNA on day 5 post-rhinovirus inoculation. Blocking the interferon response restored IAV replication following rhinovirus infection.InterpretationThese findings show that one respiratory virus can block infection with another through stimulation of antiviral defences in the airway mucosa, supporting the idea that interference from rhinovirus disrupted the 2009 IAV pandemic in Europe. These results indicate that viral interference can potentially affect the course of an epidemic, and this possibility should be considered when designing interventions for seasonal influenza epidemics and the ongoing COVID-19 pandemic.FundingNational Institutes of Health, National Institute of General Medical Sciences, and the Yale Department of Laboratory Medicine.