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

Author:

Budhraja Anshul1,Basu Anubhav1,Gheware Atish2,Abhilash Dasari1,Rajagopala Seesandra3,Pakala Suman3,Sumit Madhuresh1,Ray Animesh4ORCID,Subramaniam Arulselvi5,Mathur Purva5,Nambirajan Aruna2,Kumar Sachin6,Gupta Ritu78,Wig Naveet4,Trikha Anjan9,Guleria Randeep10,Sarkar Chitra2,Gupta Ishaan1ORCID,Jain Deepali2ORCID

Affiliation:

1. Indian Institute of Technology 1 Department of Biochemical Engineering and Biotechnology , , New Delhi 110016 , India

2. All India Institute of Medical Sciences 2 Department of Pathology , , New Delhi 110029 , India

3. Vanderbilt University Medical Center 3 Department of Medicine, Division of Infectious Diseases , , Nashville, TN 37232 , USA

4. All India Institute of Medical Sciences 4 Department of Medicine , , New Delhi, 110029 , India

5. JPNATC, All India Institute of Medical Sciences 5 Department of Laboratory Medicine , , New Delhi 110029 , India

6. All India Institute of Medical Sciences 6 Department of Medical Oncology , , New Delhi 110029 , India

7. Dr. B. R. Ambedkar Institute Rotary Cancer Hospital (IRCH) 7 Laboratory Oncology , , , New Delhi 110029 , India

8. All India Institute of Medical Sciences 7 Laboratory Oncology , , , New Delhi 110029 , India

9. All India Institute of Medical Sciences 8 Department of Anaesthesiology, Critical Care and Pain Medicine , , New Delhi 110029 , India

10. All India Institute of Medical Sciences 9 Department of Pulmonary Medicine and Sleep Disorders , , New Delhi 110029 , India

Abstract

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.

Funder

All-India Institute of Medical Sciences

Indian Institute of Technology Delhi

Publisher

The Company of Biologists

Subject

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

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