Researchers from the RI-MUHC and the McGill Genome Center investigated differences in intensive care patients who recovered or died from COVID-19 and identified candidate drugs for the treatment of severe disease.
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 pandemic, including more than 50,000 deaths in May 2022 alone. To bridge this therapeutic gap, Researchers at McGill University Health Research Institute (RI-MUHC), the Canadian Center for Computational Genomics (C3G) and the McGill Genome Center studied the biological responses of the recipient in patients hospitalized with severe COVID-19 differences between patients. who have recovered and those who have succumbed to the disease. They found that certain cell pathways were overactivated during intensive care (ICU) in deceased patients. The researchers then identified three existing drugs targeting these pathways. Their study, published in Science Advances, provides the necessary preclinical data to support the testing of these drugs – tacrolimus, zotatifin and nintedanib – in controlled clinical trials.
Vinicius Fava and Mathieu Bourgey, co-authors of the study
“We have identified overactivation of RNA metabolism, RNA splicing and interferon signaling pathways in patients who would not survive,” said Dr. Vinicius Fava, a research fellow at RI-MUHC, co-author of the study. “The identification of these differentially activated pathways in the cells of COVID-19 survivors and deceased patients through various analyzes suggests that they are determinants of prognosis and make them promising targets for pharmacological intervention at the earliest point of hospitalization of critically ill patients.
Understanding the physiology of immune cells in severe COVID-19
The researchers performed a series of cellular and genomic analyzes of seven patients hospitalized in the intensive care unit of McGill University Health Center in Montreal, Canada, at the beginning of the pandemic between March and April 2020. These patients, three of whom died and four recovered , had the same level of disease severity on the WHO regular scale at the time of admission to the intensive care unit.
The research team characterized the transcriptome (RNA molecule expression) and epigenetic landscape (changes in DNA structure that affect the ability of cells to regulate gene expression) of patients’ immune cells at different time points: on admission, on day 5 and on day 15 after admission, to monitor the evolution of the disease. They compared data between deceased patients, survivors and six healthy individuals.
In particular, the team used single-cell RNA sequencing to understand the cell composition and physiological state of peripheral blood mononuclear cells (PBMCs) after hospitalization. PBMCs are critical components of the immune system that mediate the response of pathogens entering the human body. The 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 between patients who showed critical to moderate symptoms. Critically ill patients on day 5 and day 15 showed a significant decrease in T cells (P = 0.006) and a significant increase in myeloid cells (P = 0.04), suggesting that the severity of COVID-19 affects the proportions of PBMC.
David Langley and Erwin Schur, co-senior authors of the study
“Our results show a strong correlation between the composition of PBMC and disease progression. Critically ill patients with a poor prognosis show a significant decrease in T cells and a significant increase in monocytes, in line with previously reported findings in patients with severe COVID-19, the study authors wrote.
In contrast, during hospital admission, the researchers found significant changes in gene expression in key molecular pathways that are associated with epigenetic changes in monocytes, a type of white blood cell that transforms into macrophages, i. cells capable of traveling. to an area where there is an infection to kill the pathogen and control proliferation.
“This study confirms the key role of monocytes in COVID-19 severity and disease prognosis, as well as the involvement of interferon pathways in the development of COVID-19,” said David Langley, Ph.D., assistant professor at the McGill School of Biomedical Sciences. . at the McGill Genome Center and co-author of the study. “This also suggests that variations in transcriptional activity and concomitant changes in epigenomy occur mainly in the early stages of COVID-19 disease, dictating how the disease will develop in terms of severity and end result.
Redirecting the right medicine to the right goal
Researchers have used different approaches to identify drugs that can suppress cell pathways overactivated in the monocytes of patients who have succumbed to COVID-19.
The initial approach resulted in more than 1,500 candidate drugs, which were narrowed to 53 candidate drugs / compounds previously used to treat cancer and / or inflammatory conditions. Using drug-protein and protein-protein interaction databases, the team finally managed to identify three promising candidate drugs (tacrolimus, zotatifin and nintedanib) that act on the target pathways.
“Our work demonstrates the power of combining transcriptome and epigenomic assays to identify biological factors that influence the development of COVID-19 hospitalization and the survival of patients with severe disease,” said Erwin Schur, PhD, Infectious Diseases Scientist and immunity in the Global Health Program at RI-MUHC and Professor in the Department of Medicine at McGill and co-senior author. “We look forward to clinical trials that hope to confirm the effectiveness of the three drugs in reducing the mortality of critically ill patients with COVID-19.
About the study
The study A system biology approach identifies candidate drugs to reduce mortality in critically ill patients with COVID-19 was conducted by Vinicius M. Fava, Mathieu Bourgey, Pubudu M. Nawarathna, Marianna Orlova, Pauline Cassart, Donald C. Vinh, Matthew Pellan Cheng, Guillaume Burke, Erwin Schur and David Langle.
DOI: 10.1126 / sciadv.abm2510
Funding for this study was provided by the Canadian Institute for Health Research (CIHR) and McGill University’s Interdisciplinary Infection and Immunity Initiative (MI4), thanks to the generosity of many donors to the MUHC Foundation’s COVID-19 Emergency Fund.
The researchers are grateful to the patients who participated in this study.
Media contacts
Fabien Landry Communications, Research Coordinator, MUHC[email protected]
Cynthia Lee
Media Relations, Université McGill / McGill University
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