Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2

Abstract

The nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we applied single-cell RNA sequencing and proteomics to a primary cell model of human primary nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrated widespread tropism for nasal epithelial cell types. The host response was dominated by type I and III IFNs and interferon-stimulated gene products. Nevertheless, this response was notably delayed in onset compared to viral gene expression, and thus failed to impact substantially on SARS-CoV-2 replication. However, when provided prior to infection, recombinant IFNβ or IFNλ1 induced an efficient antiviral state that potently restricted SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.

Human genetic and immunological determinants of critical COVID-19 pneumonia

“…The discovery that insufficient type I IFN can underlie critical COVID-19 pneumonia in vivo is remarkably convergent with various elegant virological studies conducted in human cells in vitro. Indeed, SARS-CoV-2 induces type I IFN production less strongly than seasonal influenza A viruses (IAV) 155 or Sendai virus (SeV) 156 . The ability of SARS-CoV-2 to evade type I IFN induction results not only from the non-specific inhibition of host cellular functions, such as transcription and translation [157][158][159] , but also from the specific suppression of type I IFN induction pathways.…”

Metabolic dyshomeostasis induced by SARS-CoV-2 structural proteins reveals immunological insights into viral olfactory interactions

“…Due to our experimental design, the overexpression of exogenous proteins may generate drawbacks concerning protein misfolding, localization and regulation as well as intrinsic limitations associated to GFP expression systems (Jensen, 2012). Based on the olfactory cellular system used, additional experiments are needed to verify the specific role of the SARS-CoV-2 structural proteome in different human olfactory cellular contexts (Lachen-Montes et al, 2020;Hatton et al, 2021). As shown in previous reports performed at cellular and tissular levels (Nie et al, 2021;Stukalov et al, 2021), the application of proteomics in different olfactory cell layers as well as in olfactory areas directly derived from COVID-19 individuals, would increase our understanding of not only the early smell impairment associated to SARS-CoV-2 infection but also the olfactory recovery potential in COVID-19 patients.…”

Development of a physiological model of human middle ear epithelium

“…The initial viral stock was propagated in Vero E6 cells as previously described. 5 Infections were performed in a containment level 3 facility. 2 × 10 5 pfu of SARS‐CoV‐2 was added to the apical side of two wells of middle ear epithelial cells differentiated at an ALI and one well of confluent Vero E6 cells (passage 10).…”