Meta-analysis of transcriptomes of SARS-Cov2 infected human lung epithelial cells identifies transmembrane serine proteases co-expressed with ACE2 and biological processes related to viral entry, immunity, inflammation and cellular stress

Abstract

The COVID-19 pandemic resulting from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which emerged in December 2019 in the Chinese city of Wuhan in the province Hubei has placed immense burden on national economies and global health. At present neither vaccination nor therapies are available although several antiviral agents such as remdesivir, originally an Ebola drug, nelfinavir, an HIV-1 protease inhibitor and other drugs such as lopinavir have been evaluated. 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 Pathway analysis revealed papilloma virus infection amongst the most significantly was not certified by peer review) : bioRxiv preprint correlated pathways. Gene Ontologies revealed regulation of viral life cycle, immune responses, proinflammatory responses-several interleukins such as IL6, IL1, IL20 and IL33, IFI16 regulating the interferon response to a virus, chemo-attraction of macrophages, last and not least 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. previous publication 50 . However, here only direct interactors and no further interactors of interactors were extracted from the Biogrid database version 3.4.161 51 using the restrictively filtered (Bonferoniadjusted-p < 1E-11) genes significantly correlated or anti-correlated with ACE2 gene expression. The network was reduced to the n=30 nodes with most interactions and was plotted via the R package network 52 showing original genes in green and BioGrid-derived interactors in red. Author contributionsWW analysed the data and wrote the manuscript. JA supervised the work, co-wrote the manuscript and gave the final approval.

Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

“…1). Likewise, RNA-sequencing data from hiPSC-derived neural progenitor cells (NPCs) (Hoffman et al, 2017), NGN2-induced glutamatergic neurons (Ho et al, 2016;Zhang et al, 2013), ASCL1/DLX2-induced GABAergic neurons (Barretto et al, 2020;Yang et al, 2017), ASCL1/NURR1/LMX1A-induced dopaminergic neurons (Rehbach et al, 2020), as well as differentiated forebrain neurons (FB, comprised of a mixture of neurons and astrocytes), confirmed expression of many candidate host genes (Gordon et al, 2020;Ou et al, 2020;Wruck and Adjaye, 2020) (Fig. 1A).…”

“…Infection of neurons by SARS-CoV-2 in vitro.A. Expression of host genes associated with SARS-CoV-2 infection(Gordon et al, 2020;Ou et al, 2020;Wruck and Adjaye, 2020) examined by RNA-sequencing (Log 2 RNA-seq, CPM medians) of post-mortem human prefrontal cortex (PFC), human induced pluripotent stem cells (hiPSCs), neural progenitor cells (NPCs) and four hiPSC-derived neuronal cell types: induced glutamatergic (GLUT), differentiated forebrain (FB) populations (comprised of glutamatergic neurons, GABAergic neurons and astrocytes), induced GABAergic (GABA) and induced dopaminergic (DOPA). B. Immunoblot showing ACE2, FURIN and CD147 protein in post-mortem human adult substantia nigra (SN) and PFC.…”