Interferon-Dependent and Respiratory Virus-Specific Interference in Dual Infections of Airway Epithelia

Manel Essaidi-Laziosi,Caroline Tapparel,Johan Geiser,Song Huang,Samuel Constant,Laurent Kaiser

doi:10.1038/s41598-020-66748-6

Manel Essaidi-Laziosi, Caroline Tapparel + Show 4 more

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https://doi.org/10.1038/s41598-020-66748-6

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Abstract

Many respiratory viruses cocirculate in the population and multiple infections are commonly reported. The clinical impact of coinfection is unclear and may vary depending on the viral couples involved. Using three-dimensional reconstituted human airway epithelia and clinical viral strains, we investigated the interaction between influenza virus (Flu), respiratory syncytial virus (RSV) and rhinovirus (RV). We showed that Flu and RSV interfere with RV replication, whereas RV does not interfere with either of these viruses. We then experimentally demonstrated that, when present, the interference is not related to a block of viral entry but rather to type I and type III interferon (IFN), the front-line antiviral defense of the respiratory mucosa. Consistent with this observation, we highlighted the differential sensitivity of each virus to IFNs, with RV being the only virus significantly inhibited by IFN-λ and the most sensitive to IFN-α. Finally, as type III IFN is of therapeutic interest due to its low proinflammatory profile, we also assessed and confirmed an inhibitory effect of IFN-λ in the context of persistent RV infections. The present work provides mechanistic clues concerning innate immunity involvement during respiratory virus interactions and confirms that IFN-λ is a promising candidate in the treatment of RV infections.

Highlights

Adaptive immunity is not expected to impact coinfections by distantly related viruses while competition for cellular processes, and/or innate immunity may play a role
H1N1 and respiratory syncytial virus (RSV)-A interfere with RV-A16 replication, while RV-A16 does not interfere with either of these viruses
To assess the type of interaction between RV and other respiratory viruses, we tested the replication of RV-A16 in the context of co- or sequential infections with RSV-A and Flu H1N1

Summary

Introduction

Adaptive immunity is not expected to impact coinfections by distantly related viruses while competition for cellular processes (such as nucleotide and lipid biosynthesis, carbon metabolism, protein synthesis...), and/or innate immunity may play a role. Numerous epidemiological studies have described either positive or negative associations between given respiratory viruses based on statistical analyses, with some pairs of viruses being frequently co-detected in patients and others very rarely[1,2,3,4,5,6,7,8] In line with these observations, experimental coinfections have put forth different types of viral interactions, from unidirectional of mutualistic inhibition of growth due to competition for cellular resources[9] to synergism[10]. We showed that, in contrast to RSV and Flu, RV is highly sensitive to IFNs and to type III IFN As this latter is known to induce less inflammation and side effects than type I IFN in the infected host and could be of therapeutic interest[21], we tested its effect against RV and showed that this cytokine can significantly impair RV replication during viral persistence in respiratory tissues

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