A new study from the Hebrew University of Jerusalem has uncovered a surprising mechanism by which the SARS-CoV-2 virus—the cause of COVID-19—may provoke immune-mediated tissue damage, even in cells it has never directly infected. The research, published in Cell Reports, reveals that the virus’s nucleocapsid protein (NP) can transfer from infected to uninfected cells, inadvertently marking healthy tissue for immune attack.
Unravelling a Hidden Pathway of Immune Damage
The collaborative study, led by PhD students Jamal Fahoum and Maria Billan under the supervision of Dr Alexander Rouvinski, Professor Ora Schueler-Furman, and Professor Reuven Wiener, involved close cooperation with clinicians from the Hebrew University-Hadassah Medical Centre. Essential infection experiments were conducted in the recently established Barry Skolnick Biosafety Level 3 (BSL3) National Unit.
The team demonstrated that the SARS-CoV-2 nucleocapsid protein, best known for packaging viral RNA inside infected cells, can also migrate to the surface of neighbouring, uninfected epithelial cells. Once present, it binds to heparan sulphate proteoglycans—sugar-like molecules found on many cell surfaces—resulting in the formation of protein clusters. The immune system then mistakes these healthy cells for infected ones, targeting them with anti-NP antibodies. This process activates the classical complement pathway, leading to inflammation and tissue damage, which may contribute to severe COVID-19 complications, including long COVID.
A Promising Avenue for Treatment
Importantly, the researchers discovered that enoxaparin—a widely used anticoagulant—can block the nucleocapsid protein from attaching to healthy cells. As a heparin analogue, enoxaparin occupies the binding sites on cell surfaces, preventing this harmful interaction. Both laboratory experiments and tests on patient-derived samples confirmed that enoxaparin effectively stopped the protein from attaching, thereby reducing immune-mediated damage.
“This research highlights a previously unrecognised way in which SARS-CoV-2 can misdirect the immune response, causing collateral damage to healthy tissue,” said the study’s authors. “Understanding this mechanism opens new possibilities for preventing immune-driven complications in COVID-19 and potentially other viral infections.”
A Collaborative Effort
The study combined laboratory-grown cells, advanced imaging techniques, and clinical samples from COVID-19 patients. The findings not only elucidate the role of the nucleocapsid protein in immune misdirection but also suggest a therapeutic strategy that could mitigate some of the most severe outcomes of COVID-19.
The authors dedicate this work to the memory of the late Professor Hervé (Hillel) Bercovier, a gifted microbiologist, inspiring scientist, and esteemed mentor.
The research was generously supported by the Edmond and Benjamin de Rothschild Foundation, the Israel Science Foundation, and other research funds.
The full paper, “Transfer of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition,” is available in Cell Reports: https://doi.org/10.1016/j.celrep.2025.115512.
Researchers:
Jamal Fahoum, Maria Billan, Julia K. Varga, Dan Padawer, Yelena Britan-Rosich, Maya Elgrably-Weiss, Pallabi Basu, Miri Stolovich-Rain, Leah Baraz, Einav Cohen-Kfir, Sujata Kumari, Esther Oiknine-Djian, Manoj Kumar, Orly Zelig, Guy Mayer, Michail N. Isupov, Dana G. Wolf, Shoshy Altuvia, Reuven Wiener, Ora Schueler-Furman, and Alexander Rouvinski
Institutions:
- Department of Biochemistry, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School
- Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School
- The Kuvin Centre for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical School
- Institute of Pulmonary Medicine, Hebrew University-Hadassah Medical Centre
- Barry Skolnick Biosafety Level 3 (BSL3) Unit, Core Research Facility, Faculty of Medicine, Hebrew University of Jerusalem
- Dove Laboratory, Boston Children’s Hospital
- Department of Medical Laboratory Sciences, Jerusalem Multidisciplinary College
- Clinical Virology Unit, Hadassah Hebrew University Medical Centre
- Blood Bank, Hebrew University-Hadassah Medical Centre
- The Institute of Chemistry, The Hebrew University of Jerusalem
- The Henry Wellcome Building for Biocatalysis, Biosciences, University of Exeter
- Lautenberg Centre for Immunology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Hebrew University of Jerusalem