SARS-CoV-2 receptor ACE2 is co-expressed with genes related to transmembrane serine proteases, viral entry, immunity and cellular stress

  1. Wasco Wruck
  2. James Adjaye

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Abstract

The COVID-19 pandemic resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December 2019 in Wuhan in China has placed immense burden on national economies and global health. At present neither vaccination nor therapies are available. Here, we performed a meta-analysis of RNA-sequencing data from three studies employing human lung epithelial cells. Of these one focused on lung epithelial cells infected with SARS-CoV-2. We aimed at identifying genes co-expressed with angiotensin I converting enzyme 2 (ACE2) the human cell entry receptor of SARS-CoV-2, and unveiled several genes correlated or inversely correlated with high significance, among the most significant of these was the transmembrane serine protease 4 (TMPRSS4). Serine proteases are known to be involved in the infection process by priming the virus spike protein. Pathway analysis revealed virus infection amongst the most significantly correlated pathways. Gene Ontologies revealed regulation of viral life cycle, immune responses, pro-inflammatory responses- several interleukins such as IL6, IL1, IL20 and IL33, IFI16 regulating the interferon response to a virus, chemo-attraction of macrophages, and cellular stress resulting from activated Reactive Oxygen Species. We believe that this dataset will aid in a better understanding of the molecular mechanism(s) underlying COVID-19.

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  1. Version published to 10.1038/s41598-020-78402-2
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    However, we have to state the limitation that this study is a meta-analysis based solely on transcriptome and not proteome data. Besides the identification of TMPRSS4, we found several significantly over-represented GOs and pathways such as Endocytosis, Papilloma virus infection and Bacterial invasion of epithelial cells for which we provide full gene lists to foster further elucidation of disease mechanisms. Genes from the constructed protein interaction network provide a first snapshot of a comprehensive image: IFI16 controls the interferon response to the virus20, LIMA1 mediating the interaction between Cadherins (CDH1, CDH13) and Actin in the context of adherens junctions potentially playing a role in virus infection, CALM1 inhibits shedding of the ectodomain of the virus receptor ACE2 25. Furthermore, GO analyses revealed several biological processes related to viral cell entry, host reaction, immune response, ROS, inflammation and apoptosis. This led us to propose a cascade of events taking place post SARS-CoV-2 entry into host cells-illustrated in Figure 7 together with possible drug targets. The coronavirus SARS-CoV-2 docks at the receptor ACE2 on the membrane of the human epithelial cell, the early stage of infection. According to reports by Monteil et al. these processes can be blocked with recombinant hrsACE210. Transmembrane serine proteases TMPRSS2 mediate SARS-CoV-2 cell entry via ACE211,34. TMPRSS2 has been described as a mediator of ACE2-coupled endocytosis in...

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    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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  3. Version published to 10.1101/2020.05.12.091314v1 on bioRxiv