Modelling SARS-CoV-2 Infection in Mice Using Lentiviral hACE2 Vectors Suggests Two Modes of Immune Responses to SARS-CoV-2 Infection
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ABSTRACT:
PROVIDER: PRJNA772769 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16490865.fastq.gz | Fastqsanger.gz | |||
| SRR16490866.fastq.gz | Fastqsanger.gz | |||
| SRR16490867.fastq.gz | Fastqsanger.gz | |||
| SRR16490868.fastq.gz | Fastqsanger.gz | |||
| SRR16490869.fastq.gz | Fastqsanger.gz |
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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of individuals worldwide, causing a severe global pandemic. Mice models are wildly used to investigate viral infection pathology, antiviral drugs, and vaccine development. However, since wild-type mice do not express human angiotensin-converting enzyme 2 (hACE2), which mediates SARS-CoV-2 entry into human cells, they are not susceptible to infection with SARS-CoV-2 and are not suitable to simulate symptomatic COVID-19 disease. HACE2 transgenic mice could provide an efficient model, but they are expensive, not always readily available and practically restricted to specific strain(s). Since additional models are needed to study the disease at varying genetic and immune backgrounds, there is a dearth of mouse models for SARS-CoV-2 infection. Here we report the application of lentiviral vectors to generate hACE2 expression in mouse lung epithelial cells (LET1) as well as in interferon receptor knock-out (IFNAR1-/-) mice. Lenti-hACE2 transduction supported SARS-CoV-2 replication both in vitro and in vivo, simulating mild acute lung disease1. Gene expression analysis revealed two modes of immune responses to SARS-CoV-2 infection: one in response to the exposure of mouse lungs to SARS-CoV-2 particles in the absence of productive viral replication, and the second in response to a productive infection. This approach expands our knowledge on the role of type-1 interferon signaling in COVID-19 disease, and can be further implemented for a range of COVID-19 studies and drug development.
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Project description:Purpose: The goals of this study are to compare the difference between WT and hCD147 mice, hACE2 and hCD147 mice lung tissues Transcriptomes after infection with SARS-CoV-2 Methods: After receiving anesthesia with pentobarbital sodium, each mouse of the WT group, hCD147 group, and hACE2 group was infected with SARS-CoV-2 by nasal drip at a dose of 3 x 10^5 TCID50. The lung tissues were take for RNA-seq at 2 dpi. each mouse of the hCD147 group, and hACE2 group was infected with SARS-CoV-2 by nasal drip at a dose of 3 x 10^5 TCID50. The lung tissues were take for RNA-seq at 2 dpi. Results: RNA-seq of lung homogenates from C57BL/6 and hCD147 mice at 2 d.p.i. showed 354 upregulated and 175 downregulated genes). hCD147 mice mediated strong inflammatory responses, including Th17 cell responses, the NF-kappaB pathway and MAPK pathway, etc. The levels of cytokines and chemokines were increased in the lung of hCD147 mice, such as IL6, IL10, ILbeta, CXCL1, CXCL2, CCL2, etc. Analysis of RNA-Seq data of hACE2 mice versus hCD147 mice showed that hACE2 mice had stronger antiviral responses, including type I IFN and IFNalpha/IFNbeta responses, while hCD147 mice showed activation of multiple proinflammatory pathways, which is consistent with clinical features of COVID-19 patients. The significantly upregulated genes during SARS-CoV-2 infection of hACE2 mice enriched in cellular response to IFN-?. The upregulated genes in SARS-CoV-2-infected hCD147 mice were enriched secretory proteins, including ILbeta, IL6 and CXCL1. Conclusions: CD147 mediates potent inflammatory responses in SARS-CoV-2 infection. RNA-seq of lung homogenates from hACE2 and hCD147 mice at 2 d.p.i. showed 354 upregulated and 175 downregulated genes). hCD147 mice mediated strong inflammatory responses, including Th17 cell responses, the NF-kappaB pathway and MAPK pathway, etc. The levels of cytokines and chemokines were increased in the lung of hCD147 mice, such as IL6, IL10, ILbeta, CXCL1, CXCL2, CCL2, etc.
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Project description:The COVID-19 pandemic is an infectious disease caused by SARS-CoV-2. The first step of SARS-CoV-2 infection is the recognition of angiotensin-converting enzyme 2 (hACE2) receptors by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Although the molecular and structural bases of the SARS-CoV-2-RBD/hACE2 interaction have been thoroughly investigated in vitro, the relationship between hACE2 expression and in vivo infection is less understood. Here, we developed an efficient SARS-CoV-2-RBD binding assay suitable for super resolution microscopy and simultaneous hACE2 immunodetection and mapped the correlation between hACE2 receptor abundance and SARS-CoV-2-RBD binding, both in vitro and in human lung biopsies. Next, we explored the specific proteome of SARS-CoV-2-RBD/hACE2 through a comparative mass spectrometry approach. We found that only a minority of hACE2 positive spots are actually SARS-CoV-2-RBD binding sites, and that the relationship between SARS-CoV-2-RBD binding and hACE2 presence is variable, suggesting the existence of additional factors. Indeed, we found several interactors that are involved in receptor localization and viral entry and characterized one of them: SLC1A5, an amino acid transporter. High-resolution receptor-binding studies showed that co-expression of membrane-bound SLC1A5 with hACE2 predicted SARS-CoV-2 binding and entry better than hACE2 expression alone. Accordingly, SLC1A5 depletion reduces SARS-CoV-2 binding and entry. Notably, the Omicron variant is more efficient in binding hACE2 sites, but equally sensitive to SLC1A5 downregulation. We propose a method for mapping functional SARS-CoV-2 receptors in vivo. We confirm the existence of hACE2 co-factors that may contribute to differential sensitivity of cells to infection.
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