Type-I interferon signatures in SARS-CoV-2 infected Huh7 cells

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes Coronavirus disease 2019 (COVID-19) has caused a global health emergency. A key feature of COVID-19 is dysregulated interferon-response. Type-I interferon (IFN-I) is one of the earliest antiviral innate immune responses following viral infection and plays a significant role in the pathogenesis of SARS-CoV-2. In this study, using a proteomics-based approach, we identified that SARS-CoV-2 infection induces delayed and dysregulated IFN-I signaling in Huh7 cells. We demonstrate that SARS-CoV-2 is able to inhibit RIG-I mediated IFN-b production. Our results also confirm the recent findings that IFN-I pretreatment is able to reduce susceptibility of Huh7 cells to SARS-CoV-2, but not post-treatment. Moreover, senescent Huh7 cells, in spite of showing accentuated IFN-I response were more susceptible to SARS-CoV-2 infection, and the virus effectively inhibited IFIT1 in these cells. Finally, proteomic comparison between SARS-CoV-2, SARS-CoV and MERS-CoV revealed a distinct differential regulatory signature of interferon-related proteins emphasizing that therapeutic strategies based on observations in SARS-CoV and MERS-CoV should be used with caution. Our findings provide a better understanding of SARS-CoV-2 regulation of cellular interferon response and a perspective on its use as a treatment. Investigation of different interferon stimulated genes and their role in inhibition of SARS-CoV-2 pathogenesis may direct novel antiviral strategies.

Cell-type-resolved quantitative proteomics map of interferon response against SARS-CoV-2

“…In another study by us, we have observed that in Huh7 cells SARS-CoV-2 can inhibit type-I IFN signaling early, and the dysregulation in this pathway is only observed at 48hpi (Chen et al, 2021), which correlates with moderate production of the virus. In spite of differences in the dynamics of the cellular response, type-I IFN pre-sensitization of the Caco2, Calu-3 (Shuai et al, 2020), and Huh7 (Chen et al, 2021) has been shown to effectively inhibit SARS-CoV-2 infection. In addition, many of the ISGs such as IFIT1, ISG15, and DDX58 were upregulated in all three cell lines (Figure 6).…”

“…Previous proteomics-based studies have observed that SARS-CoV-2 causes global proteomic changes after 48hpi specifically in pathways related to ErbB, HIF-1, mTOR, and TNF signaling ; complement system and coagulation cascades (Tiwari et al, 2020); and interferon signaling (Chen et al, 2021). In order to understand the delayed changes in Huh7 cells (Huh7 48h ) compared with Calu-3 and Caco2 cells, we extracted the proteomics dataset from our earlier study .…”

Kite-shaped molecules block SARS-CoV-2 cell entry at a post-attachment step

“…SARS-CoV-S and SARS-CoV-2-S pseudoviruses did not infect the hepatocyte cell line, Huh-7. The heterogeneity in ACE2 expression in Huh-7 cell populations together with the widely varied characteristics of different laboratory-passaged Huh-7 lines may explain the discrepancy in the susceptibility of Huh-7 cells to native SARS-CoV-2 infection (13,30–32). In contrast, MERS-CoV-S pseudovirus, which preferentially binds DPP4 as a receptor rather than ACE2 (16), showed a high level of infectivity in Huh-7 cells.…”

The RNA sensor MDA5 detects SARS-CoV-2 infection

“…Huh7 cells have been reported to be permissive to viral replication 4,23,[26][27][28][29][30] . Recently, a proteomics-based approach found activation of the type I IFN system in Huh7 cells at 48 hours but not 24 hours postinfection 31 . This indicates a delayed IFN induction in Huh7 cells, potentially explaining our results obtained at the 24-hour timepoint.…”