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Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality

To elucidate the molecular mechanisms that manifest lung abnormalities during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, we performed whole-transcriptome sequencing of lung autopsies from 31 patients with severe COVID-19 and ten uninfected controls. Using metatranscript...

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Autores principales: Budhraja, Anshul, Basu, Anubhav, Gheware, Atish, Abhilash, Dasari, Rajagopala, Seesandra, Pakala, Suman, Sumit, Madhuresh, Ray, Animesh, Subramaniam, Arulselvi, Mathur, Purva, Nambirajan, Aruna, Kumar, Sachin, Gupta, Ritu, Wig, Naveet, Trikha, Anjan, Guleria, Randeep, Sarkar, Chitra, Gupta, Ishaan, Jain, Deepali
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194484/
https://www.ncbi.nlm.nih.gov/pubmed/35438176
http://dx.doi.org/10.1242/dmm.049572
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author Budhraja, Anshul
Basu, Anubhav
Gheware, Atish
Abhilash, Dasari
Rajagopala, Seesandra
Pakala, Suman
Sumit, Madhuresh
Ray, Animesh
Subramaniam, Arulselvi
Mathur, Purva
Nambirajan, Aruna
Kumar, Sachin
Gupta, Ritu
Wig, Naveet
Trikha, Anjan
Guleria, Randeep
Sarkar, Chitra
Gupta, Ishaan
Jain, Deepali
author_facet Budhraja, Anshul
Basu, Anubhav
Gheware, Atish
Abhilash, Dasari
Rajagopala, Seesandra
Pakala, Suman
Sumit, Madhuresh
Ray, Animesh
Subramaniam, Arulselvi
Mathur, Purva
Nambirajan, Aruna
Kumar, Sachin
Gupta, Ritu
Wig, Naveet
Trikha, Anjan
Guleria, Randeep
Sarkar, Chitra
Gupta, Ishaan
Jain, Deepali
author_sort Budhraja, Anshul
collection PubMed
description To elucidate the molecular mechanisms that manifest lung abnormalities during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, we performed whole-transcriptome sequencing of lung autopsies from 31 patients with severe COVID-19 and ten uninfected controls. Using metatranscriptomics, we identified the existence of two distinct molecular signatures of lethal COVID-19. The dominant ‘classical’ signature (n=23) showed upregulation of the unfolded protein response, steroid biosynthesis and complement activation, supported by massive metabolic reprogramming leading to characteristic lung damage. The rarer signature (n=8) that potentially represents ‘cytokine release syndrome’ (CRS) showed upregulation of cytokines such as IL1 and CCL19, but absence of complement activation. We found that a majority of patients cleared SARS-CoV-2 infection, but they suffered from acute dysbiosis with characteristic enrichment of opportunistic pathogens such as Staphylococcus cohnii in ‘classical’ patients and Pasteurella multocida in CRS patients. Our results suggest two distinct models of lung pathology in severe COVID-19 patients, which can be identified through complement activation, presence of specific cytokines and characteristic microbiome. These findings can be used to design personalized therapy using in silico identified drug molecules or in mitigating specific secondary infections.
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spelling pubmed-91944842022-06-14 Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality Budhraja, Anshul Basu, Anubhav Gheware, Atish Abhilash, Dasari Rajagopala, Seesandra Pakala, Suman Sumit, Madhuresh Ray, Animesh Subramaniam, Arulselvi Mathur, Purva Nambirajan, Aruna Kumar, Sachin Gupta, Ritu Wig, Naveet Trikha, Anjan Guleria, Randeep Sarkar, Chitra Gupta, Ishaan Jain, Deepali Dis Model Mech Research Article To elucidate the molecular mechanisms that manifest lung abnormalities during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, we performed whole-transcriptome sequencing of lung autopsies from 31 patients with severe COVID-19 and ten uninfected controls. Using metatranscriptomics, we identified the existence of two distinct molecular signatures of lethal COVID-19. The dominant ‘classical’ signature (n=23) showed upregulation of the unfolded protein response, steroid biosynthesis and complement activation, supported by massive metabolic reprogramming leading to characteristic lung damage. The rarer signature (n=8) that potentially represents ‘cytokine release syndrome’ (CRS) showed upregulation of cytokines such as IL1 and CCL19, but absence of complement activation. We found that a majority of patients cleared SARS-CoV-2 infection, but they suffered from acute dysbiosis with characteristic enrichment of opportunistic pathogens such as Staphylococcus cohnii in ‘classical’ patients and Pasteurella multocida in CRS patients. Our results suggest two distinct models of lung pathology in severe COVID-19 patients, which can be identified through complement activation, presence of specific cytokines and characteristic microbiome. These findings can be used to design personalized therapy using in silico identified drug molecules or in mitigating specific secondary infections. The Company of Biologists Ltd 2022-06-06 /pmc/articles/PMC9194484/ /pubmed/35438176 http://dx.doi.org/10.1242/dmm.049572 Text en © 2022. Published by The Company of Biologists Ltd https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Budhraja, Anshul
Basu, Anubhav
Gheware, Atish
Abhilash, Dasari
Rajagopala, Seesandra
Pakala, Suman
Sumit, Madhuresh
Ray, Animesh
Subramaniam, Arulselvi
Mathur, Purva
Nambirajan, Aruna
Kumar, Sachin
Gupta, Ritu
Wig, Naveet
Trikha, Anjan
Guleria, Randeep
Sarkar, Chitra
Gupta, Ishaan
Jain, Deepali
Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality
title Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality
title_full Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality
title_fullStr Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality
title_full_unstemmed Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality
title_short Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality
title_sort molecular signature of postmortem lung tissue from covid-19 patients suggests distinct trajectories driving mortality
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194484/
https://www.ncbi.nlm.nih.gov/pubmed/35438176
http://dx.doi.org/10.1242/dmm.049572
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