SARS-COV-2-mediated liver injury

• Applicant: Dr. Pietro Scaturro
• Subject Area: Virology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458684684

COVID-19 patients primarily feature infections of the respiratory tract. However, next to pneumonia and acute respiratory distress syndrome, hospitalized patients often develop multi-system pathologies including kidney, liver, cardiac injury and eventually multi-organ failure. Mounting evidence from multiple clinical studies suggests that SARS-CoV-2 displays a multi-organ tropism, with a high affinity for kidney, liver, and heart. Importantly, the liver emerged as one of the most important targets for SARS-CoV-2 outside of the respiratory tract, featuring often the highest viral RNA load after the lungs. Indeed, upon admission to the hospital, the majority of patients display markers of liver injury, which is associated with adverse clinical outcomes, including transfer to intensive care units, need for mechanical ventilation, and increased mortality. Recently, we identified SARS-CoV-2 subgenomic viral RNA, as well as hallmarks of innate immune responses, in the liver of autopsy cases from severe COVID19 patients. Furthermore, ACE2 - the main SARS-CoV-2 cellular receptor - is highly expressed in multiple hepatic cell lineages, especially in cholangiocytes. Altogether, these data support active SARS-CoV-2 hepatic replication, and suggest that liver infections contribute significantly to severe disease progression. In the past few months, multiple omics approaches, including bottom-up mass-spectrometry-based methods, have extended our knowledge of COVID-19 pathophysiology, however, analogous systems-wide investigation of well-characterized patients cohorts in a discovery and validation settings are completely missing. Here, we propose to use a unique human autopsy tissue repository in combination with state-of-the-art tissue proteomics and tissue multiplex imaging to profile the signaling pathways and key host proteins associated with SARS-CoV-2 liver infections. Functionally, our integrative approach aims to provide a comprehensive and cross-validated framework for a system-level understanding of COVID19-induced perturbations, providing important clinical cues with therapeutic potential for the treatment of severe SARS-CoV-2 infections.

• DFG Programme: Research Grants
• Co-Investigator: Professor Victor G. Puelles, Ph.D.