Frontiers in Pharmacology (Mar 2022)

Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials

  • Andrés López-Cortés,
  • Andrés López-Cortés,
  • Santiago Guerrero,
  • Esteban Ortiz-Prado,
  • Verónica Yumiceba,
  • Antonella Vera-Guapi,
  • Ángela León Cáceres,
  • Katherine Simbaña-Rivera,
  • Katherine Simbaña-Rivera,
  • Ana María Gómez-Jaramillo,
  • Gabriela Echeverría-Garcés,
  • Jennyfer M. García-Cárdenas,
  • Patricia Guevara-Ramírez,
  • Alejandro Cabrera-Andrade,
  • Lourdes Puig San Andrés,
  • Doménica Cevallos-Robalino,
  • Jhommara Bautista,
  • Isaac Armendáriz-Castillo,
  • Isaac Armendáriz-Castillo,
  • Andy Pérez-Villa,
  • Andrea Abad-Sojos,
  • María José Ramos-Medina,
  • Ariana León-Sosa,
  • Estefanía Abarca,
  • Álvaro A. Pérez-Meza,
  • Karol Nieto-Jaramillo,
  • Andrea V. Jácome,
  • Andrea Morillo,
  • Fernanda Arias-Erazo,
  • Luis Fuenmayor-González,
  • Luis Abel Quiñones,
  • Luis Abel Quiñones,
  • Nikolaos C. Kyriakidis

DOI
https://doi.org/10.3389/fphar.2022.833174
Journal volume & issue
Vol. 13

Abstract

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Background: It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood.Methods: Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials.Results: Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis.Conclusion: We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.

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