Fibrin drives thromboinflammation and neuropathology in COVID-19

Jae Kyu Ryu, Zhaoqi Yan, Mauricio Montano, Elif G. Sozmen, Karuna Dixit, Rahul K. Suryawanshi, Yusuke Matsui, Ekram Helmy, Prashant Kaushal, Sara K. Makanani, Thomas J. Deerinck, Anke Meyer-Franke, Pamela E. Rios Coronado, Troy N. Trevino, Min-Gyoung Shin, Reshmi Tognatta, Yixin Liu, Renaud Schuck, Lucas Le, Hisao Miyajima, Andrew S. Mendiola, Nikhita Arun, Brandon Guo, Taha Y. Taha, Ayushi Agrawal, Eilidh MacDonald, Oliver Aries, Aaron Yan, Olivia Weaver, Mark A. Petersen, Rosa Meza Acevedo, Maria del Pilar S. Alzamora, Reuben Thomas, Michela Traglia, Valentina L. Kouznetsova, Igor F. Tsigelny, Alexander R. Pico, Kristy Red-Horse, Mark H. Ellisman, Nevan J. Krogan, Mehdi Bouhaddou, Melanie Ott, Warner C. Greene () and Katerina Akassoglou ()
Additional contact information
Jae Kyu Ryu: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Zhaoqi Yan: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Mauricio Montano: Gladstone Institute of Virology
Elif G. Sozmen: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Karuna Dixit: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Rahul K. Suryawanshi: Gladstone Institute of Virology
Yusuke Matsui: Gladstone Institute of Virology
Ekram Helmy: Gladstone Institute of Virology
Prashant Kaushal: University of California Los Angeles
Sara K. Makanani: University of California Los Angeles
Thomas J. Deerinck: University of California San Diego
Anke Meyer-Franke: Gladstone Institute of Neurological Disease
Pamela E. Rios Coronado: Stanford University
Troy N. Trevino: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Min-Gyoung Shin: Gladstone Institute of Data Science and Biotechnology
Reshmi Tognatta: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Yixin Liu: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Renaud Schuck: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Lucas Le: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Hisao Miyajima: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Andrew S. Mendiola: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Nikhita Arun: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Brandon Guo: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Taha Y. Taha: Gladstone Institute of Virology
Ayushi Agrawal: Gladstone Institute of Data Science and Biotechnology
Eilidh MacDonald: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Oliver Aries: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Aaron Yan: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Olivia Weaver: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Mark A. Petersen: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Rosa Meza Acevedo: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Maria del Pilar S. Alzamora: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Reuben Thomas: Gladstone Institute of Data Science and Biotechnology
Michela Traglia: Gladstone Institute of Data Science and Biotechnology
Valentina L. Kouznetsova: University of California San Diego
Igor F. Tsigelny: Center for Neurovascular Brain Immunology at Gladstone and UCSF
Alexander R. Pico: Gladstone Institute of Data Science and Biotechnology
Kristy Red-Horse: Stanford University
Mark H. Ellisman: University of California San Diego
Nevan J. Krogan: Gladstone Institute of Data Science and Biotechnology
Mehdi Bouhaddou: University of California Los Angeles
Melanie Ott: Gladstone Institute of Virology
Warner C. Greene: Gladstone Institute of Virology
Katerina Akassoglou: Center for Neurovascular Brain Immunology at Gladstone and UCSF

Nature, 2024, vol. 633, issue 8031, 905-913

Abstract: Abstract Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1–4. Despite the clinical evidence1,5–7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8–10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.

Date: 2024
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DOI: 10.1038/s41586-024-07873-4

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