BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Infected individuals display a wide spectrum of disease severity, as defined by the World Health Organization (WHO). One of the main factors underlying this heterogeneity is the host immune response, with severe COVID-19 often associated with a hyperinflammatory state. AIM: Our current study aimed to pinpoint the specific genes and pathways underlying differences in the disease spectrum and outcomes observed, through in-depth analyses of whole blood transcriptomics in a large cohort of COVID-19 participants. RESULTS: All WHO severity levels were well represented and mild and severe disease displaying distinct gene expression profiles. WHO severity levels 1-4 were grouped as mild disease, and signatures from these participants were different from those with WHO severity levels 6-9 classified as severe disease. Severity level 5 (moderate cases) presented a unique transitional gene signature between severity levels 2-4 (mild/moderate) and 6-9 (severe) and hence might represent the turning point for better or worse disease outcome. Gene expression changes are very distinct when comparing mild/moderate or severe cases to healthy controls. In particular, we demonstrated the hallmark down-regulation of adaptive immune response pathways and activation of neutrophil pathways in severe compared to mild/moderate cases, as well as activation of blood coagulation pathways. CONCLUSIONS: Our data revealed discrete gene signatures associated with mild, moderate, and severe COVID-19 identifying valuable candidates for future biomarker discovery.

Centre for Clinical Research in Emergency Medicine Harry Perkins Institute of Medical Research Royal Perth Hospital Perth WA Australia

Centre for Clinical Research in Emergency Medicine Royal Perth Bentley Group Perth WA Australia

Centre for Immunology and Allergy Research The Westmead Institute for Medical Research Westmead NSW Australia

Centre for Infectious Diseases and Microbiology The Westmead Institute for Medical Research Westmead NSW Australia

Department of Infectious Diseases The University of Melbourne at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia

Department of Intensive Care Medicine Nepean Hospital Penrith NSW Australia

Department of Microbiology Immunology and Biochemistry University of Tennessee Health Science Center Memphis TN United States

Department of Microbiology St George Hospital Kogarah NSW Australia

Emergency Department Royal Perth Hospital Perth WA Australia

Faculty of Medicine and Health School of Medical Sciences The University of Sydney Sydney NSW Australia

Faculty of Medicine and Health Sydney Medical School Nepean Nepean Hospital University of Sydney Penrith NSW Australia

Faculty of Medicine and Health Sydney Medical School Westmead Westmead Hospital University of Sydney NSW Westmead Australia

Institute of Molecular Virology University of Münster Münster Germany

Medical ICU 1st Department of Internal Medicine Charles University and Teaching Hospital Pilsen Czechia

Medical School University of Western Australia Perth WA Australia

Research and Education Network Western Sydney Local Health District Westmead Hospital NSW Westmead Australia

School of Chemistry and Molecular Biosciences The University of Queensland Brisbane QLD Australia

Sydney Informatics Hub Core Research Facilities The University of Sydney Sydney NSW Australia

Sydney Institute for Infectious Disease The University of Sydney Sydney NSW Australia

Victorian Infectious Disease Service The Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity Melbourne VIC Australia

Westmead Hospital Western Sydney Local Health District Westmead NSW Australia

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