Researchers have identified a new potential trigger for cytokine storm, a severe inflammatory response that significantly raises the risk of fatality in COVID-19 patients.
As part of the COVID-19 International Research Team, scientists from the Johns Hopkins Kimmel Cancer Center, Children’s Hospital of Philadelphia, the University of Pittsburgh, and Weill Cornell Medicine uncovered a fresh cause of cytokine storm — the intense inflammatory reaction linked to a higher likelihood of death in individuals infected with COVID-19.
The results of their study were published online on November 27 in Proceedings of the National Academy of Sciences.
The research team conducted an extensive genomic investigation into the causes of cytokine storm by analyzing autopsy samples from 40 COVID-19 fatalities. They performed genome analysis on samples collected from various organs including the lungs, heart, liver, kidneys, lymph nodes in the chest that initially process the virus, and the nasal cavity where the virus enters the body.
Focusing on approximately 50 immune genes that were highly active in the nasal swab samples, they tracked their genomic profiles in the autopsy tissues.
Stephen Baylin, M.D., a distinguished cancer research professor and one of the study’s senior authors, along with lead author Michael Topper, Ph.D., a Glick Scholar and oncology instructor, were
acquainted with many of these genes, which are part of a protein signaling network known as the inflammasome — a system they helped characterize. The inflammasome is activated to eliminate cells infected by viruses or bacteria.
“Several of the genes involved in the excessive activation of the inflammasome seem to be crucial regulators of the immune response that contributes to this hyperinflammatory process. This provides a new perspective on how they trigger the ‘cytokine storm syndrome’ that inflicts serious harm on various tissues,” notes Topper.
These immune genes, Baylin explains, should normally switch on and off; however, if they remain continually active, this leads to cytokine storm — a dangerous level of inflammation that can be fatal for COVID-19 patients.
Essentially, immune genes in the nasal cavity, the entry point for the virus, transmit signals through a system known as the renin-angiotensin-aldosterone system (RAAS), which initiates cytokine storm.
RAAS, a hormone system that typically regulates blood pressure, body fluids, and electrolytes, can ignite an overwhelming immune response, compromising the ability of lymph nodes to fight infection and causing significant damage to the lungs, kidneys, heart, liver, and other organs, according to the researchers.
“Indicators of this inflammatory response in patients who succumb to COVID-19 can be traced in their blood, allowing us to identify those at risk for the most severe and fatal forms of the infection and suggesting potential treatment options,” states Baylin.
The researchers also believe their discoveries might shed light on long COVID, a persistent condition following COVID-19 that presents a variety of symptoms such as fever, fatigue, cough, chest pain, heart palpitations, headaches, joint and muscle pain, gastrointestinal issues, and more. Topper and Baylin indicated that this aspect is part of their ongoing research.
Alongside Baylin and Topper, the study included contributions from co-first author Joseph W. Guarnieri and co-corresponding authors with Baylin: Afshin Behesti (leader of COVIRT), Douglas C. Wallace, Simon Pollett, Deanne Taylor, Eve Syrkin Wurtele, Robert E. Schwartz, Christopher E. Mason, Jeffrey A. Haltom, Amy Chadburn, Henry Cope, Justin Frere, Julia An, Alain Borczuk, Saloni Sinha, JangKeun Kim, Jiwoon Park, Daniel Butler, Cem Meydan, Jonathan Foox, Yaron Bram, Stephanie A. Richard, Nusrat J. Epsi, Brian Agan, Josh G. Chenoweth, Mark P. Simons, David Tribble, Timothy Burgess, Clifton Dalgard, Mark T. Heise, Nathaniel J. Moorman, Victoria K. Baxter, Emily A. Madden, Sharon A. Taft-Benz, Elizabeth J. Anderson, Wes A. Sanders, Rebekah J. Dickmander, Katherine Beigel, Gabrielle A. Widjaja, Kevin A. Janssen, Timothy Lie, Deborah G. Murdock, Alessia Angelin, Yentli E. Soto Albrecht, Arnold Z. Olali, Zimu Cen, Joseph Dybas, Waldemar Priebe, Mark R. Emmett, Sonja M. Best, Maya Kelsey Johnson, Nidia S. Trovao, Kevin B. Clark, Victoria Zaksas, Robert Meller, Peter Grabham, Jonathan C. Schisler, and Pedro M. Moraes-Vieira.
This research received backing from the Division of Intramural Research, NIAID, NIH grant to Sonja Best, alongside grant W81XWH-21-1-0128 from DOD awarded to Douglas Wallace, the Bill & Melinda Gates Foundation Grant INV-046722 also awarded to Wallace, and other various foundations that supported Stephen Baylin through multiple initiatives.
Robert Schwartz serves on scientific advisory boards for Miromatrix, Inc. and Lime Therapeutics, and provides consultancy for Alnylam, Inc. Douglas Wallace is an advisory board member for Pano Therapeutics, Inc. and Medical Excellent Capital. Simon Pollett, Mark Simons, Timothy Burgess, and Deanne Taylor acknowledge that their work was funded by an unrelated phase III COVID-19 clinical trial in collaboration with AstraZeneca, backed by the Department of Defense via the USU Infectious Diseases Clinical Research Program and associated foundations. Neither funding nor affiliation pertained to the research discussed herein. All other authors claim no competing interests for this study.
