Interference between rhinovirus and influenza A virus: a clinical data analysis and experimental infection study

Abstract

Summary Background During 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. Methods We 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. Findings Between 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. Interpretation These 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. ...

Magnitude and timing of the antiviral response determine SARS-CoV-2 replication early in infection

“…Based on previous studies, we expected that rhinovirus might curtail infection by inducing an epithelial antiviral response, but also could potentially promote infection by increasing expression of SARS-CoV-2 entry receptors (Wu et al, 2020;Ziegler et al, 2020). Similar to previous observations, rhinovirus infection (HRV-01A, MOI ~0.05) led to robust induction of interferon stimulated genes by day 3 post-infection ( Fig 5B).…”

“…One factor that can potentially modulate ISG-mediated defenses in the airway epithelium is recent infection by other viruses, as demonstrated in recent work from our group and others (Essaidi-Laziosi et al, 2020;Wu et al, 2020). Rhinovirus, the most frequent cause of the common cold, is frequently detected in the human upper respiratory tract in the presence and absence of symptoms, and both symptomatic and asymptomatic infections can induce ISG expression in the upper respiratory tract mucosa (Landry and Foxman, 2018;Wolsk et al, 2016;Yu et al, 2019).…”

Where has all the influenza gone? The impact of COVID-19 on the circulation of influenza and other respiratory viruses, Australia, March to September 2020

“…It is possible that these infections were detected in people who may not have met clinical criteria for testing in prior years. Alternatively, absent competition from influenza and RSV [ 8 ], rhinoviruses may be taking advantage of this niche. The drop in rhinovirus percentage-positivity around weeks 15–21 coincided with school holidays, 4-week school closures in NSW and voluntary withdrawal of children from school by many parents, underscoring the role of children in rhinovirus circulation [ 9 ].…”

RSV and HMPV Infections in 3D Tissue Cultures: Mechanisms Involved in Virus-Host and Virus-Virus Interactions

“…The mechanism of RSV–HMPV interaction is still poorly studied. Previous works recently showed that respiratory virus–virus negative interaction could be mediated by the interplay between viruses and immune response and particularly IFN induction [ 15 , 18 , 30 ]. In the present work, we also provided new evidence probing the role of the epithelial anti-viral immune response in the differential pathogenesis of HMPV and RSV.…”