Single-nucleus lung transcriptomics and inflammatory responses in lethal COVID-19 reveal potential drugs in advanced-stage clinical trials

Abstract:

There is pressing urgency to identify drugs that allow treating COVID-19 patients effectively. Respiratory failure is the leading cause of death in patients with severe COVID-19, and the host in ammatory response at the lungs remains poorly understood. Therefore, we retrieved data from postmortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, in ammatory protein interactome network, functional enrichment, and shortest pathways to cancer hallmark phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials. Herein, we analyzed transcriptomics data of 719 in ammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 signi cantly expressed genes showed that the most relevant biological annotations were: in ammatory response, innate immune response, cytokine production, interferon production, macrophage activation, thymic stromal lymphopoietin, blood coagulation, IL-1 and megakaryocytes in obesity, NLRP3 in ammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M, AGE-RAGE signaling pathways. Subsequently, we identi ed 34 essential in ammatory proteins with both high-con dence protein interactions and shortest pathways to in ammation, cell death, glycolysis, and angiogenesis. Lastly, we propose ve small molecules involved in advanced-stage COVID-19 clinical trials: baricitinib, pacritinib, and ruxolitinib are tyrosine-protein kinase JAK2 inhibitors, losmapimod is a MAP kinase p38 alpha inhibitor, and eritoran is a TLR4/MD-2 …

Año de publicación:

2021

Keywords:

Fuente:

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