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; Katerina Akassoglou

doi:10.1038/s41586-024-07873-4

Fibrin drives thromboinflammation and neuropathology in COVID-19

Nature. 2024 Sep;633(8031):905-913. doi: 10.1038/s41586-024-07873-4. Epub 2024 Aug 28.

Authors

Jae Kyu Ryu^#^{1

2

3}, Zhaoqi Yan^#^{1

2}, Mauricio Montano^#^{4

5}, Elif G Sozmen^#^{1

2

3}, Karuna Dixit^#^{1

2}, Rahul K Suryawanshi^#⁴, Yusuke Matsui^{4

5}, Ekram Helmy^{4

5}, Prashant Kaushal^{6

7}, Sara K Makanani^{6

7}, Thomas J Deerinck⁸, Anke Meyer-Franke², Pamela E Rios Coronado⁹, Troy N Trevino^{1

2}, Min-Gyoung Shin¹⁰, Reshmi Tognatta^{1

2}, Yixin Liu^{1

2}, Renaud Schuck^{1

2}, Lucas Le^{1

2}, Hisao Miyajima^{1

2}, Andrew S Mendiola^{1

2}, Nikhita Arun^{1

2}, Brandon Guo^{1

2}, Taha Y Taha^{4

5}, Ayushi Agrawal¹⁰, Eilidh MacDonald^{1

2}, Oliver Aries^{1

2}, Aaron Yan^{1

2}, Olivia Weaver^{1

2

11}, Mark A Petersen^{1

2

11}, Rosa Meza Acevedo^{1

2}, Maria Del Pilar S Alzamora^{1

2}, Reuben Thomas¹⁰, Michela Traglia¹⁰, Valentina L Kouznetsova^{12

13}, Igor F Tsigelny^{1

12

13

14}, Alexander R Pico¹⁰, Kristy Red-Horse^{9

15

16}, Mark H Ellisman^{8

14}, Nevan J Krogan^{10

17

18

19}, Mehdi Bouhaddou^{6

7}, Melanie Ott^{4

5

19

20

21}, Warner C Greene^{22

23

24

25}, Katerina Akassoglou^{26

27

28}

Affiliations

¹ Center for Neurovascular Brain Immunology at Gladstone and UCSF, San Francisco, CA, USA.
² Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
³ Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
⁴ Gladstone Institute of Virology, San Francisco, CA, USA.
⁵ Michael Hulton Center for HIV Cure Research at Gladstone, San Francisco, CA, USA.
⁶ Department of Microbiology, Immunology and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA, USA.
⁷ Institute for Quantitative and Computational Biosciences (QCBio), University of California Los Angeles, Los Angeles, CA, USA.
⁸ National Center for Microscopy and Imaging Research, Center for Research on Biological Systems, University of California San Diego, La Jolla, CA, USA.
⁹ Department of Biology, Stanford University, Stanford, CA, USA.
¹⁰ Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
¹¹ Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
¹² San Diego Supercomputer Center, University of California San Diego, La Jolla, CA, USA.
¹³ CureScience Institute, San Diego, CA, USA.
¹⁴ Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
¹⁵ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
¹⁷ Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
¹⁹ COVID-19 Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
²⁰ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
²¹ Chan Zuckerberg Biohub, San Francisco, CA, USA.
²² Gladstone Institute of Virology, San Francisco, CA, USA. warner.greene@gladstone.ucsf.edu.
²³ Michael Hulton Center for HIV Cure Research at Gladstone, San Francisco, CA, USA. warner.greene@gladstone.ucsf.edu.
²⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. warner.greene@gladstone.ucsf.edu.
²⁵ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. warner.greene@gladstone.ucsf.edu.
²⁶ Center for Neurovascular Brain Immunology at Gladstone and UCSF, San Francisco, CA, USA. katerina.akassoglou@gladstone.ucsf.edu.
²⁷ Gladstone Institute of Neurological Disease, San Francisco, CA, USA. katerina.akassoglou@gladstone.ucsf.edu.
²⁸ Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. katerina.akassoglou@gladstone.ucsf.edu.

^# Contributed equally.

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 infection^1-4. Despite the clinical evidence^1,5-7, 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 deficits^1,5,8-10. 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.

MeSH terms

Animals
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology
Brain* / drug effects
Brain* / immunology
Brain* / pathology
Brain* / virology
COVID-19* / complications
COVID-19* / immunology
COVID-19* / pathology
COVID-19* / virology
Female
Fibrin* / antagonists & inhibitors
Fibrin* / metabolism
Fibrinogen / metabolism
Humans
Immunity, Innate
Inflammation* / complications
Inflammation* / immunology
Inflammation* / pathology
Inflammation* / virology
Killer Cells, Natural / immunology
Lung / drug effects
Lung / immunology
Lung / pathology
Lung / virology
Macrophage Activation / drug effects
Male
Mice
Microglia / immunology
Microglia / pathology
Neuroinflammatory Diseases / complications
Neuroinflammatory Diseases / immunology
Neuroinflammatory Diseases / pathology
Neuroinflammatory Diseases / virology
Neurons / pathology
Neurons / virology
Oxidative Stress
Post-Acute COVID-19 Syndrome / immunology
Post-Acute COVID-19 Syndrome / virology
SARS-CoV-2 / immunology
SARS-CoV-2 / pathogenicity
Spike Glycoprotein, Coronavirus / metabolism
Thrombosis* / complications
Thrombosis* / immunology
Thrombosis* / pathology
Thrombosis* / virology

Substances

Fibrin
Fibrinogen
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2
Antibodies, Monoclonal

Supplementary concepts

long COVID brain fog

Abstract

MeSH terms

Substances

Supplementary concepts

Grants and funding