Abstract
The novel coronavirus SARS-CoV-2 is the causative agent of Coronavirus Disease 2019 (COVID-19), a global healthcare and economic catastrophe. Understanding of the host immune response to SARS-CoV-2 is still in its infancy. A 382-nt deletion strain lacking ORF8 (Δ382 herein) was isolated in Singapore in March 2020. Infection with Δ382 was associated with less severe disease in patients, compared to infection with wild-type SARS-CoV-2. Here, we established Nasal Epithelial cells (NECs) differentiated from healthy nasal-tissue derived stem cells as a suitable model for the ex-vivo study of SARS-CoV-2 mediated pathogenesis. Infection of NECs with either SARS-CoV-2 or Δ382 resulted in virus particles released exclusively from the apical side, with similar replication kinetics. Screening of a panel of 49 cytokines for basolateral secretion from infected NECs identified CXCL10 as the only cytokine significantly induced upon infection, at comparable levels in both wild-type and Δ382 infected cells. Transcriptome analysis revealed the temporal up-regulation of distinct gene subsets during infection, with anti-viral signaling pathways only detected at late time-points (72 hours post-infection, hpi). This immune response to SARS-CoV-2 was significantly attenuated when compared to infection with an influenza strain, H3N2, which elicited an inflammatory response within 8 hpi, and a greater magnitude of anti-viral gene up-regulation at late time-points. Remarkably, Δ382 induced a host transcriptional response nearly identical to that of wild-type SARS-CoV-2 at every post-infection time-point examined. In accordance with previous results, Δ382 infected cells showed an absence of transcripts mapping to ORF8, and conserved expression of other SARS-CoV-2 genes. Our findings shed light on the airway epithelial response to SARS-CoV-2 infection, and demonstrate a non-essential role for ORF8 in modulating host gene expression and cytokine production from infected cells.
Highlights
The novel coronavirus SARS-CoV-2 was first detected in China in late 2019, and has since spread rapidly across the globe [1,2]
We show that differentiated Nasal Epithelial cells (NECs) are a suitable model for studying the dynamics of SARSCoV-2 infection in vitro, and that the immune response from infected NECs is surprisingly limited
This limited early response to SARS-CoV-2 infection could impair viral clearance, and prolong the duration of infection. This further implies that infiltrating immune cells are the likely source of pro-inflammatory cytokines such as IL-6 and TNFα reported to be elevated in patient sera later during infection
Summary
The novel coronavirus SARS-CoV-2 was first detected in China in late 2019, and has since spread rapidly across the globe [1,2]. In particular those of the nasal epithelium, are postulated to be the first site for viral contact during the establishment of SARS-CoV-2 infection in a new host [5,6]. Besides providing a physical barrier to host infection, epithelial cells are proficient in mounting an immune response to infection. This includes the expression of antiviral factors upon pathogen detection by cellular pattern-recognition receptors, as well as the secretion of cytokines and chemokines which can recruit and activate both the innate and adaptive arms of the immune system [7]. As the early response from this initial site of infection can play a major role in determining the subsequent trajectory of disease development, there is an important need to establish model systems for studying the epithelial immune response to SARSCoV-2
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