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

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-β or IFN-λ, 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-β1 or IFN-λ2 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 IFNβ1 or IFNλ2, 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-β1 or IFN-λ2, markedly reduces SARS-CoV-2 replication.

How did respiratory syncytial virus and other pediatric respiratory viruses change during the COVID‐19 pandemic?

“…First, viral factors (co‐suppression) and virus‐specific response differences in host immunity may play a role. Type I IFNs are elevated in most viral respiratory infections, but this response is diminished in COVID‐19 infections in vivo and in vitro 4,5 . RSV and RV infections have been shown to enhance TH2 immune responses, which may reduce SARS‐CoV2 infectivity 6 .…”

“…RSV and RV infections have been shown to enhance TH2 immune responses, which may reduce SARS‐CoV2 infectivity 6 . In fact, pre‐infection of airway epithelial cell cultures with RV markedly reduces SARS‐CoV‐2 replication 4 . Second, the host risk factors linked to severe SARS‐CoV2 are very different from those seen with other respiratory viruses.…”

“…Additional studies are needed to understand how RSV and other pediatric respiratory viruses interact with each other and may change in the presence of an emergent pathogen like SARS‐CoV‐2. The molecular mechanisms governing the coregulation of mixed viral respiratory infections, including beneficial or deleterious effects in infectivity, host immunity and clinical outcomes should be further explored in human‐based studies, as recently reported 4 . Through further investigations and pediatric data analysis of the COVID‐19 pandemic, we may be able to determine whether co‐infections with SARS‐CoV‐2 result in worse acute and/or long‐term outcomes; we can also discern if the incidence of certain respiratory viral subtypes are decreased either directly by SARS‐CoV‐2 or only indirectly by ever‐changing community viral mitigation measures including social distancing, masking, and vaccinations.…”

Regulation of mRNA transcripts, protein isoforms, glycosylation and spatial localization of ACE2 and other SARS-CoV-2-associated molecules in human airway epithelium upon viral infection and type 2 inflammation

“…SARS-CoV-2 RNA is recognized by MDA5 47 . Infection with RV initiates type I/III IFN response, therefore pre-infection with rhinovirus reduces SARS-CoV-2 replication 48 , but RV and SARS-CoV-2 co-infection leads to the greater damage of airway epithelium, especially in patients with asthma 21 . An observed ACE2 increase was caused presumably by an increase in short ACE2 mRNA, as we demonstrated above.…”

“…However, IL-13 has been also shown to be a major driver of COVID-19 severity and anti-IL-4/13 treatment is showing positive effects in COVID-19 clinical trials 16,17 . Moreover, infection with rhinovirus (RV), the most common exacerbation-inducing factor in asthma, has been shown to inhibit SARS-CoV-2 infection via type I/III IFN-dependent mechanism [18][19][20] , which might suggest that this mechanism could constitute some form of protection. However, we recently reported that co-infection of rhinovirus (RV) and SARS-CoV-2 leads to a greater retinoic acid-inducible gene I (RIG-I) inflammasome-dependent damage of airway epithelium in patients with asthma 21 , which is strongly supported by the clinical findings that patients with RV and SARS-CoV-2 coinfection are more prone to severe COVID-19 22 .…”