Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

Vanderwall, E. R.; Barrow, K. A.; Rich, L. M.; Read, D. F.; Trapnell, C.; Oghenemega, O.; Ziegler, S. F.; Hallstrand, T. S.; White, M. P.; Debley, J. S.

doi:10.1101/2021.11.20.469409

bioRxiv · 10.1101/2021.11.20.469409

Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication

Vanderwall, E. R.·Barrow, K. A.·Rich, L. M.·Read, D. F.·Trapnell, C.·Oghenemega, O.·Ziegler, S. F.·Hallstrand, T. S.·White, M. P.·Debley, J. S.

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Abstract

IntroductionCommon alphacoronaviruses and human rhinoviruses (HRV) induce type I and III interferon (IFN) responses important to limiting viral replication in the airway epithelium. In contrast, highly pathogenic betacoronaviruses including SARS-CoV-2 may evade or antagonize RNA-induced IFN I/III responses. MethodsIn airway epithelial cells (AECs) from children and older adults we compared IFN I/III responses to SARS-CoV-2 and HRV-16, and assessed whether pre-infection with HRV-16, or pretreatment with recombinant IFN-{beta} or IFN-{lambda}, modified SARS-CoV-2 replication. Bronchial AECs from children (ages 6-18 yrs.) and older adults (ages 60-75 yrs.) were differentiated ex vivo to generate organotypic cultures. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 or HRV-16, and RNA and protein was harvested from cell lysates 96 hrs. following infection and supernatant was collected 48 and 96 hrs. following infection. In additional experiments cultures were pre-infected with HRV-16, or pre-treated with recombinant IFN-{beta}1 or IFN-{lambda}2 before SARS-CoV-2 infection. ResultsDespite significant between-donor heterogeneity SARS-CoV-2 replicated 100 times more efficiently than HRV-16. IFNB1, INFL2, and CXCL10 gene expression and protein production following HRV-16 infection was significantly greater than following SARS-CoV-2. IFN gene expression and protein production were inversely correlated with SARS-CoV-2 replication. Treatment of cultures with recombinant IFN{beta}1 or IFN{lambda}2, or pre-infection of cultures with HRV-16, markedly reduced SARS-CoV-2 replication. DiscussionIn addition to marked between-donor heterogeneity in IFN responses and viral replication, SARS-CoV-2 elicits a less robust IFN response in primary AEC cultures than does rhinovirus, and heterologous rhinovirus infection, or treatment with recombinant IFN-{beta}1 or IFN-{lambda}2, markedly reduces SARS-CoV-2 replication.

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Vanderwall, E. R., Barrow, K. A., Rich, L. M., Read, D. F., Trapnell, C., Oghenemega, O., Ziegler, S. F., Hallstrand, T. S., White, M. P., Debley, J. S.. 2021-11-23. Airway epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus and heterologous rhinovirus infection suppresses SARS-CoV-2 replication. https://doi.org/10.1101/2021.11.20.469409

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