Researchers model how novel coronavirus causes severe symptoms of COVID-19

Teresa Herbert therbert@bidmc.harvard.edu

NOVEMBER 10, 2020

Analysis IDs specific genes and proteins that could serve as potential therapeutic targets

BOSTON – Since the COVID-19 pandemic began early in 2020, more than 10 million Americans have tested positive for the virus, and more than 230,000 have died — most often from severe respiratory distress linked to the infection. In less than a year, researchers and physicians around the world have made enormous strides in treating and preventing the disease, but much remains unknown about the mechanisms by which the SARS-CoV-2 virus causes the potentially deadly clinical symptoms of COVID-19.

A new study led by scientists at Beth Israel Deaconess Medical Center (BIDMC) sheds more light on how molecules of the immune and vascular systems interact to produce extensive damage to the lung and vascular tissues seen in patients with severe COVID-19. Researchers conducted comprehensive analyses of tissue and blood samples from humans and from non-human primates infected with the novel coronavirus. The team’s findings, published in the journal Cell, help define the pathways by which the illness induces vascular disease and also point to potential therapeutic targets in the complement, coagulation and inflammatory pathways.

"Our data reveal the key biological processes involved in triggering the clotting and vascular damage observed with SARS-CoV-19 infection," said corresponding author Dan H. Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research (CVVR) at BIDMC. "Our results suggest how critical interactions between inflammatory and clotting pathways lead to severe vascular injury seen in critically ill patients with COVID-19.

Barouch and colleagues compared pulmonary pathology in specimens taken from humans and from rhesus macaques infected with COVID-19 and found analogous prominent vascular changes. The researchers — including first author Malika Aid-Boudries, PhD, an instructor in the Barouch laboratory — observed thickening of the blood vessel lining and an accumulation of immune cells such as macrophages and inflammatory molecules including fibrin, a key clotting protein.

Further analyses of the genetic activity and proteins present in the macaque specimens demonstrated that SARS-CoV-2 infection triggered the production of a variety of molecules associated with coagulation and clot-ting cascade, which is part of the body's inflammatory response.

"Our integrated analyses suggest a model in which critical interactions between inflammatory and clotting pathways lead to SARS-CoV-2 vascular disease — a feature not seen in other respiratory infections," said Aid-Boudries. “These data also suggest novel therapeutic targets in the inflammatory, coagulation and other pathways."

Barouch is also Professor of Medicine at Harvard Medical School, and a member of the Ragon Institute of MGH, MIT, and Harvard. Additional authors included Samuel J. Vidal, Abishek Chandrasheker, Shivani Patel, Kathryn Stephenson, and Amanda J. Martinot of BIDMC’s CVVR; Olga Brook and Jonathan L. Hecht of BIDMC; Kathleen Busman-Sahay, Stephen Bondoc, Carly Strake, Margaret Terry, and Jacob D. Estes of Oregon Health & Sciences University; Zoltan Maliga, Connor A. Jacobson, Peter K. Sorger of Harvard Medical School; Linda Wrijil and Sarah Ducat of Tufts University Cummings School of Veterinary Medicine; Andrew Miller of Cornell University College of Veterinary Medicine; Maciel Porto, Hanne Anderson, and Mark G. Lewis of Bioqual; and Kathryn L. Pellegrini, Maria Pino, Timothy N. Hoang, and Steven E. Bosinger of Yerkes National Primate Research Center.

This work was supported by the Ragon Institute of MGH, MIT and Harvard; Mark and Lisa Schwartz Foundation; BIDMC; Massachusetts Consortium on Pathogen Readiness; Bill & Melinda Gates Foundation (INV-006131), and the National Institutes of Health (OD024917, CA260476, AI124377, AI126603, AI128751, AI129797, AI149670). The Yerkes Genomics Core is supported in part by the National Institutes of Health (P51 OD0111320) and sequencing data was acquired with NIH funding (NIH S10 OD026799).

The authors declare no competing financial interests.

About Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center is a part of Beth Israel Lahey Health, a new health care system that brings together academic medical centers and teaching hospitals, community and specialty hospitals, more than 4,000 physicians and 35,000 employees in a shared mission to expand access to great care and advance the science and practice of medicine through groundbreaking research and education.