Identification of Novel Gene Signatures using Next-Generation Sequencing Data from COVID-19 Infection Models: Focus on Neuro-COVID and Potential Therapeutics

Abstract

SARS-CoV-2 is the causative agent for coronavirus disease-19 (COVID-19) and belongs to the family Coronaviridae that causes sickness varying from the common cold to more severe illnesses such as severe acute respiratory syndrome, sudden stroke, neurological complications (Neuro-COVID), multiple organ failure, and mortality in some patients. The gene expression profiles of COVID-19 infection models can be used to decipher potential therapeutics for COVID-19 and related pathologies, such as Neuro-COVID. Here, we used the raw RNA-seq reads (Single-End) in quadruplicates derived using Illumina Next Seq 500 from SARS-CoV-infected primary human bronchial epithelium (NHBE) and mock-treated NHBE cells obtained from the Gene Expression Omnibus (GEO) (GSE147507), and the quality control (QC) was evaluated using the CLC Genomics Workbench 20.0 (Qiagen, United States) before the RNA-seq analysis using BioJupies web tool and iPathwayGuide for gene ontologies (GO), pathways, upstream regulator genes, small molecules, and natural products. Additionally, single-cell transcriptomics data (GSE163005) of meta clusters of immune cells from the cerebrospinal fluid (CSF), such as T-cells/natural killer cells (NK) (TcMeta), dendritic cells (DCMeta), and monocytes/granulocyte (monoMeta) cell types for comparison, namely, Neuro-COVID versus idiopathic intracranial hypertension (IIH), were analyzed using iPathwayGuide. L1000 fireworks display (L1000FWD) and L1000 characteristic direction signature search engine (L1000 CDS2) web tools were used to uncover the small molecules that could potentially reverse the COVID-19 and Neuro-COVID-associated gene signatures. We uncovered small molecules such as camptothecin, importazole, and withaferin A, which can potentially reverse COVID-19 associated gene signatures. In addition, withaferin A, trichostatin A, narciclasine, camptothecin, and JQ1 have the potential to reverse Neuro-COVID gene signatures. Furthermore, the gene set enrichment analysis (GSEA) preranked method and Metascape web tool were used to decipher and annotate the gene signatures that were potentially reversed by these small molecules. In conclusion, our study unravels a rapid approach for applying next-generation knowledge discovery (NGKD) platforms to discover small molecules with therapeutic potential against COVID-19 and its related disease pathologies.

A path-based analysis of infected cell line and COVID-19 patient transcriptome reveals novel potential targets and drugs against SARS-CoV-2

“…Lastly, for NHBE cell line, we saw molecular functions such as small molecule binding, carbohydrate derivative binding, etc. as shown in previous works ( 34 , 35 ). In stark contrast, for top 100 DEGs, only one statistically significant molecular function was enriched across all cell lines, namely, “sequence specific DNA binding function” in the Vero cell line.…”

“…Lastly, for NHBE cell line, we saw molecular functions such as small molecule binding, carbohydrate derivative binding, etc. as shown in previous works (34,35).…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Additionally, some of the purple module hub-high traffic genes, such as MAPK1 ( 189 , 374 ), CUL2 ( 210 ), CMTM6 ( 162 ), TXNRD1 ( 375 ), RAB1A ( 376 ), DICER1 ( 377 ), RAB5A ( 209 ), HSP90B1 ( 343 ), MAGT1 ( 378 ), ADAM10 ( 379 , 380 ), SNX2 ( 89 ), OLA1 ( 381 ), SPTLC1 ( 382 ), SH3GLB1 ( 383 ), TIMM10B ( 384 ), and CREB1 ( 385 ) hub-high traffic TF, which are central for information exchange in this module, are potential targets for development of COVID-19 therapeutic strategies. Among these, the mitogen-activated protein kinase 1 ( MAPK1 ) hub-high traffic gene is a potential core target for many anti-COVID-19 therapeutic strategies ( 189 , 374 , 386 – 390 ).…”

Decoding the Role of Astrocytes in the Entorhinal Cortex in Alzheimer’s Disease Using High-Dimensional Single-Nucleus RNA Sequencing Data and Next-Generation Knowledge Discovery Methodologies: Focus on Drugs and Natural Product Remedies for Dementia

“…We have previously shown that natural products such as albiziasaponin-A, iso-orientin, and salvadorin can ameliorate the pathologies associated with AD in vivo ( Rasool et al, 2018 ) and that the natural products could be useful for the treatment of age-related degenerative diseases ( Kalamegam et al, 2020 ). In addition, we have recently shown that NGKD platforms can be successfully used to find drugs and natural products that may reverse disease-specific gene signatures ( Pushparaj et al, 2021 ). Therefore, NGKD platforms can be used to find drugs and natural products that can potentially reverse AD-associated gene signatures in astrocytes.…”

“…Trichostatin A increased the antioxidant capacity and cell viability of SH -SY5Y cells by enhancing Keap1-mediated inhibition of the Nrf2 pathway, thereby reducing amyloid-β peptide-mediated cell damage ( Li et al, 2020 ). Importantly, we recently predicted the potential of withaferin A, narciclasine, and trichostatin A to reverse gene signatures in neuro- COVID ( Pushparaj et al, 2021 ). However, the effects of natural products such as emetine, cephaeline, narciclasine, withaferin A, trichostatin A and drugs such as DMARDs and dasatinib which may be able to reverse AD gene signatures in astrocytes should be validated with appropriate experimental models from AD before being used for further clinical testing.…”