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 (IFN) 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 apply single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrates widespread tropism for nasal epithelial cell types. The host response is dominated by type I and III IFNs and interferon-stimulated gene products. This response is notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response begins to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induces an efficient antiviral state that potently restricts SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data imply that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.

Deep Time Course Proteomics of SARS-CoV- and SARS-CoV-2-Infected Human Lung Epithelial Cells (Calu-3) Reveals Strong Induction of Interferon-Stimulated Gene Expression by SARS-CoV-2 in Contrast to SARS-CoV

“…To shed light on this discrepancy, we performed a comparative analysis of type I IFN-related proteins by comparing data from this study to four other proteomic studies of SARS-CoV-2-infected human cells. 22 − 25 Interestingly, most of the strongly affected ISGs, including MX1, MX2, IFIT1, IFIT2, IFIT3, OASL, and OASL2, were not identified in these studies except by Puray-Chavez et al This study supports our findings for SARS-COV-2 induction of expression of the aforementioned ISGs in another human lung cell line quite well. The low coverage of this pathway in the other studies could explain at least partially the discrepancy.…”

Innate and Adaptive Immune Responses in the Upper Respiratory Tract and the Infectivity of SARS-CoV-2

“…Knowledge of the early innate and adaptive immune responses in the URT during SARS-CoV-2 infections has progressed rapidly since a recent review [ 15 ]. New studies with primary human nasal epithelial cell cultures have been particularly illuminating in this regard [ 28 ]. Single-cell RNA-seq and proteomics analyses showed the rapid production of type 1 and 3 IFNs in response to Sendai virus infection of the cultures, while the IFN responses were delayed during SARS-CoV-2 infection, so that SARS-CoV-2 gene expression reached maximum levels before the upregulation of type 1 IFN gene expression in the cultures [ 28 ].…”

“…New studies with primary human nasal epithelial cell cultures have been particularly illuminating in this regard [ 28 ]. Single-cell RNA-seq and proteomics analyses showed the rapid production of type 1 and 3 IFNs in response to Sendai virus infection of the cultures, while the IFN responses were delayed during SARS-CoV-2 infection, so that SARS-CoV-2 gene expression reached maximum levels before the upregulation of type 1 IFN gene expression in the cultures [ 28 ]. Infection of the cultures with SARS-CoV-2, however, produced a progressive upregulation of genes for the proinflammatory cytokines IL6, TNFα and IL1β, demonstrating that the virus was being recognized within the cells [ 28 ].…”

Myeloid-derived suppressor cells in COVID-19: A review

“…On the other hand, the virus itself has evolved mechanisms to suppress antiviral immune responses. The type I and type III IFN systems are critical for early antiviral innate immune responses [ [38] , [39] , [40] ]. SARS-CoV-2 is able to successfully impede IFN responses by several mechanisms [ [40] , [41] , [42] , [43] ].…”