Preactivated Antivirus Download
Leanne Wittlin
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To understand the higher capacity of children for controlling SARS-CoV-2 infection at an early stage, we systematically characterized the transcriptional landscape of upper airways, an airway region with high susceptibility for SARS-CoV-2 infection7, in SARS-CoV-2-negative and SARS-CoV-2-positive children and adults.
Interestingly, many of the epithelial cell populations showed a clear age dependency with, for example, goblet cells decreasing and ciliated cells increasing with age (Fig. 1d,e). A recent complementary study analyzed the cell composition of the nasal mucosa in healthy and SARS-CoV-2-infected children based on bulk RNA-seq and cell deconvolution methods. The authors were unable to identify children-specific goblet cells, but rather described that samples from healthy children were dominated by a ciliated cell signature, highlighting the limitations of bulk RNA approaches10.
To demonstrate a direct association between MDA5 expression levels and activation of ISGs upon SARS-CoV-2 infection, we established an in vitro model using the human lung epithelial cell line A549, which exhibits very low basal expression levels of MDA5 similar to expression levels found in nasal epithelial cells of healthy adults. As expected, based on inefficient MDA5 sensing in concert with rapid replication and expression of virus-encoded antagonists20, only minute amounts of IFNB1 and ISG transcripts were induced upon SARS-CoV-2 infection in these cells. However, in cells with moderately increased basal expression of MDA5 by lentiviral transduction, permitting efficient virus sensing before the expression of antagonists, we observed a significant induction of the expression of IFNB1 and key ISGs including MX1, BST2 (tetherin), RSAD2 (viperin) and IFIT1 (Fig. 2e). These findings corroborate the central role of MDA5 expression before infection for sensing SARS-CoV-2 and inducing a swift and robust ISG response.
Apart from the upregulated cell-intrinsic antiviral capacity of airway epithelial cells, macrophages and dendritic cells, we found specific patterns of immune cell subpopulations in children versus adults. We identified, among others, a subpopulation of KLRC1 (NKG2A)+ cytotoxic T cells (CTL2) occurring predominantly in children (Fig. 3c). NKG2A is a lectin-like inhibitory receptor on cytotoxic T cells playing a role in limiting excessive activation, preventing apoptosis and sustaining the virus-specific CD8+ T cell response21. Already without viral infection, this CD8 cytotoxic T cell subset was characterized by a strong expression level of cytotoxic mediators (Fig. 3d, Extended Data Fig. 4 and Supplementary Table 5). Furthermore, IFNG was highly expressed in these cells when comparing SARS-CoV-2-negative children to adults. Upon infection, children were characterized by a significantly higher expression level of IFNG compared to adults both in the early phase and in the later phase of infection. Similarly, the potent chemoattractant gene CCL5 was increased in children compared to adults with or without infection (Fig. 3d). The cytotoxic potential and the predominance of this cytotoxic T cell subset necessary for efficient killing of virus-infected cells provides further evidence for a better antivirus response in children compared to adults. In addition, SARS-CoV-2-infected children showed a distinct CD8+ T cell population (CD8_Tm) with a memory phenotype that was almost absent in adults (Fig. 3c, EDF4). It remains unclear whether these cells are beneficial for protection of the children against future reinfection.
RNA was extracted by using the MagNA Pure 96 DNA and Viral NA Small Volume Kit (Roche) on a MagNA Pure 96 System as recommended by the manufacturer. Real-time PCR with reverse transcription was performed targeting the envelope (E) gene and nucleocapsid (N) gene on the Roche Light Cycler 480 system (Tib-Molbiol).
Single-cell datasets were aligned and preprocessed using Cellranger 3.0.1. A custom human hg19 reference genome (10x Genomics, version 3.1.0) with the SARS-CoV-2 genome (Refseq-ID: NC_045512) added as additional chromosome was used. For downstream analysis Seurat 3.2.2 was used. Cells with fewer than 3 genes and cells with more than or equal to 15% mitochondrial reads or fewer than 200 genes expressed were discarded. To remove doublets, a cutoff for the number of unique molecular identifiers and genes was determined manually per sample.
To test whether elevated MDA5 and RIG-I levels in A549 cells significantly increased by IFNB1 and ISG induction upon infection, an unpaired one-tailed Student t-test of three biologically independent repetitions was performed (GraphPad Prism v9.1).
Processed data in the form of a Seurat object are available without access restrictions on FigShare ( ). This dataset can be used to replicate and extend the analyses presented in this paper. Due to potential risk of de-identification of pseudonymized RNA-seq data, the raw sequencing data can be obtained through EGA (EGAS00001005461) for non-commercial research purposes alone, subject to controlled access as mandated by EU data protection laws. For access, contact the corresponding author, R.E. In addition, these data can be further visualized and analyzed in the Magellan COVID-19 data explorer at
S.T., S. Lukassen, I.L., M.A.M. and R.E. conceived, designed and supervised the project. B.S., M.R., J.R., L.S., V.M.C. and M.A.M. designed the RECAST cohort. J.R., S.S., L.S. and S. Laudi recruited the patients and provided the human specimens, clinical data and annotation of the patients. J. Loske, A.S., J. Liebig, M.M. and R.L.C. performed scRNA experiments. V.G.M. and M.B. performed and analyzed the in vitro experiments. J. Loske, L.T., S. Lukassen and R.L.C. analyzed data. B.S., L.S., S. Laudi, V.M.C., M.R., C.C., M.B. and M.A.M. contributed with discussion of the results. B.T. and S.K. provided technical and experimental support. J. Loske, S. Lukassen, S.T., M.B., R.E. and I.L. wrote the manuscript; all authors read, revised and approved the manuscript.
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