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

Anshul Budhraja, Anubhav Basu, Atish Gheware, Dasari Abhilash, Seesandra Rajagopala, Suman Pakala, Madhuresh Sumit, Animesh Ray, Arulselvi Subramaniam, Purva Mathur, Aruna Nambirajan, Sachin Kumar, Ritu Gupta, Naveet Wig, Anjan Trikha, Randeep Guleria, Chitra Sarkar, Ishaan Gupta, Deepali Jain

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number049572
JournalDMM Disease Models and Mechanisms
Volume15
Issue number5
DOIs
StatePublished - May 2022

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology

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