Researchers at RI-MUHC and the McGill Genome Center examine the differences in ICU patients who recovered or died from COVID-19 and identify candidate drugs to treat serious illnesses.
Montreal, June 1, 2022 – Despite the availability of highly effective vaccines, SARS-CoV-2 still causes serious medical complications. The lack of effective drug treatment for hospitalized patients with severe COVID-19 has contributed to more than six million deaths worldwide since the start of the pandemic, including more than 50,000 deaths in May 2022 alone. To address this therapeutic gap, a team of researchers from the McGill University Health Center Research Institute (RI-MUHC), the Canadian Center for Computational Genomics (C3G), and the McGill Genome Center studied the biological responses of the host of hospitalized patients with serious illnesses. COVID-19, looking for differences between patients who recovered and those who succumbed to the disease. They found that certain cell pathways were overactivated at the time of admission to the intensive care unit (ICU) in dead patients. Researchers then identified three existing drugs targeting these pathways. His study, published in Science Advances, provides the preclinical data needed to support the testing of these drugs (tacrolimus, zotatifin, and nintedanib) in controlled clinical trials.
Vinicius Fava and Mathieu Bourgey, first co-authors of the study
“We have identified overactivation of messenger RNA metabolism, RNA splicing, and interferon signaling pathways in patients who would not survive,” said Vinicius Fava, PhD, an associate researcher at RI-MUHC. author of the study. “Identification by different assays of these pathways activated differently in the cells of COVID-19 survivors and dead patients suggests that they are determinants of the prognosis and makes them promising targets for pharmacological intervention at the point earliest hospitalization of critically ill patients “.
Understand the physiology of immune cells in severe COVID-19
The researchers performed a series of cell and genomic tests on seven patients hospitalized in the ICU at McGill University Health Center in Montreal, Canada, at the start of the pandemic, between March and April 2020. These patients, three of whom died and four recovered, had the same level of severity of the disease on the WHO ordinal scale at the time of admission to the ICU.
The research team characterized the transcriptome (expression of the messenger RNA molecule) and the epigenetic landscape (alterations in the structure of DNA that affect the ability of cells to regulate gene expression). of patients’ immune cells at different times: on admission, on the 5th and on the 15th after admission, to monitor the course of the disease. They compared data between dead patients, survivors, and six healthy individuals.
Specifically, the team used unicellular RNA sequencing to understand the cell composition and physiological status of peripheral blood mononuclear cells (PBMCs) after hospitalization. PBMCs are critical components of the immune system that mediate the response to pathogens that enter the human body. Analyzes focused on three main populations of PBMC cells: B cells, myeloid cells, and T cells. The team found significant differences in the proportions of T cells and myeloid cells. among patients with critical versus moderate symptoms. Critical patients on day 5 and day 15 showed a significant reduction in T cells (P = 0.006) and a significant increase in myeloid cells (P = 0.04), suggesting that the severity of COVID-19 has an impact on the proportions of PBMC.
David Langlais and Erwin Schurr, co-authors of the study
“Our results show a strong correlation of PBMC composition with disease progression. Critically ill patients with a poor prognosis showed a significant reduction in T cells and a significant increase in monocytes, according to the findings. previously in patients with severe COVID-19, ”write the study authors.
In contrast, at the time of hospital admission, the researchers detected significant changes in the expression of genes in key molecular pathways that are associated with epigenetic changes in monocytes, a type of white blood cell that transforms into macrophages. that is, cells capable of traveling. in an area where there is an infection to kill the pathogen and control proliferation.
“This study confirms the key role of monocytes in the severity of COVID-19 and the prognosis of the disease, as well as the involvement of interferon pathways in the development of COVID-19,” says David Langlais, PhD. , adjunct professor at McGill School of Biomedical Sciences. at the McGill Genome Center and lead co-author of the study. “It also suggests that variations in transcriptional activity, and the accompanying epigenomic changes, occurred primarily in an early stage of COVID-19 disease, dictating how the disease will evolve in terms of severity and end result.”
Reuse the right drug for the right purpose
The researchers used several approaches to identify drugs that could suppress overactivated cell pathways in monocytes of patients who succumbed to COVID-19.
The initial approach resulted in more than 1,500 candidate drugs, which were reduced to 53 candidate drugs / compounds previously used to treat cancers and / or inflammatory conditions. Using drug-protein and protein-protein interaction databases, the team was finally able to identify three promising candidate drugs (tacrolimus, zotatifin, and nintedanib) that act in targeted pathways.
“Our work demonstrates the power of combining transcriptomic and epigenomic analyzes to identify biological factors that influence the evolution of COVID-19 hospitalization and the survival of patients with severe disease,” says Erwin Schurr, PhD, Disease Scientist Infectious Diseases and Immunity in the RI-MUHC Global Health Program and Professor of the McGill Department of Medicine and co-author. “We look forward to clinical trials that we hope will confirm the effectiveness of all three drugs in reducing the mortality of critically ill COVID-19 patients.”
About the study
Vinicius M. Fava, Mathieu Bourgey, Pubudu M. Nawarathna, Marianna Orlova, Pauline Cassart, Donald C. Vinh, and Matthew Pellan Cheng conducted the study A systems biology approach that identifies candidate drugs to reduce mortality in critically ill patients with COVID-19. , Guillaume Bourque, Erwin Schurr and David Langlais.
DOI: 10.1126 / sciadv.abm2510
Funding for this study was provided by the Canadian Institutes of Health Research (CIHR) and McGill University’s Interdisciplinary Infection and Immunity Initiative (MI4), thanks to the generosity of multiple donors to the COVID Emergency Fund. -19 from the MUHC Foundation.
Researchers are grateful to the patients who participated in this study.
Media contacts
Fabienne LandryCoordinator of Communications, Research, MUHC[email protected]
Cynthia Lee
Media Relations, McGill University / McGill University
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