A recent study conducted at the University of Washington and the Seattle Children’s Research Institute, USA, has shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a significantly lower interferon response than rhinovirus infection.
Study: Respiratory epithelial interferon response to SARS-CoV-2 is inferior to rhinovirus, and heterologous rhinovirus infection suppresses SARS-CoV-2 replication. Image credit: Corona Borealis Studio / Shutterstock
In addition, rhinovirus pre-infection significantly reduces the replication of SARS-CoV-2 in respiratory epithelial cells.
A pre-printed version of the survey is available at bioRxiv* server while the article is undergoing peer review.
SARS-CoV-2, the causative pathogen of coronavirus disease 2019 (COVID-19), is an encapsulated RNA virus from the human beta-coronavirus family that primarily affects respiratory epithelial cells.
Unlike other common cold viruses, such as alpha-coronavirus and rhinovirus, SARS-CoV-2 suppresses both systemic and mucosal type I and type III interferon responses, which are vital host innate immune responses required to suppress viral replication.
According to the available literature, infection of respiratory epithelium with human rhinoviruses causes a significant increase in anti-viral interferon response, increasing the expression of SARS-CoV-2 host cell receptor, namely angiotensin-converting enzyme 2 (ACE2). This indicates that co-infection of epithelial cells with SARS-CoV-2 and rhinovirus may have synergistic consequences.
In the current study, researchers evaluated the dynamics of type I and type III interferon responses in human respiratory epithelial cells following SARS-CoV-2 or rhinovirus infection.
In addition, they have investigated whether pre-infection with rhinovirus can modulate the prevalence of subsequent SARS-CoV-2 infection.
The researchers collected airway epithelial cells from children (age: 6 – 18 years) and older adults (age: 60 – 75 years) and differentiated them to generate organotypic primary airway epithelial cell cultures.
The cultures were mono-infected with SARS-CoV-2 or rhinovirus to determine the virus-specific interferon response.
In addition, the effect of rhinovirus pre-infection on SARS-CoV-2 replication was determined by infecting the cultures first with rhinovirus and subsequently with SARS-CoV-2.
To directly assess the effect of interferon signaling on SARS-CoV-2 replication, a separate set of experiments was performed by pretreating the cultures with recombinant interferon β1 and interferon λ2, followed by infection with SARS-CoV-2.
In primary cultures generated from pediatric and adult cells, a significant difference in the rate of SARS-CoV-2 replication between donors was observed. Despite this difference, SARS-CoV-2 showed a 100-fold higher replication efficiency than rhinovirus in primary respiratory epithelial cell cultures. However, no significant difference in SARS-CoV-2 replication was observed between pediatric and adult cultures. Similarly, no difference in viral replication was observed between cultures generated from children with asthma and healthy children.
In mono-infected cultures, significantly higher expressions of interferon β1, interferon λ2 and CXCL10 genes were observed after rhinovirus infection compared to that after SARS-CoV-2 infection. A similar trend was observed in protein expression.
In pediatric and adult cultures successively infected with rhinovirus and SARS-CoV-2, a significant reduction in SARS-CoV-2 replication was observed after 96 hours of infection. A similar reduction in viral replication was observed in cultures pretreated with interferon β1 or interferon λ2.
Mechanism for escaping the host’s innate immune response
In the innate immune system, pattern recognition receptors play a vital role in sensing viral RNA and subsequently induce a cascade of signaling events, ultimately leading to the induction of type I and type III interferon responses. An optimal interferon response is the key to eliminating invasive viruses in the early stages of infection.
In this study, the expression of IFIH1 / MDA5, a pattern recognition receptor, was assessed in SARS-CoV-2 or rhinovirus-infected cultures to understand the mechanism of immune evasion of SARS-CoV-2.
The results revealed that rhinovirus infection causes a significantly higher expression of IFIH1 / MDA5 (more than 2-fold) compared to SARS-CoV-2 infection. This observation indicates that SARS-CoV-2 evades the host’s innate immune response by suppressing viral sensing of pattern recognition receptors.
The significance of the study
The study reveals that the interferon response induced by SARS-CoV-2 in respiratory epithelial cells is significantly lower than that induced by rhinovirus. In addition, prior exposure to rhinovirus or recombinant interferons may significantly reduce SARS-CoV-2 replication in airway epithelial cells.
As observed in the study, SARS-CoV-2 achieves replication suitability in epithelial cells by suppressing the viral sensory mechanism of the innate immune system.
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