한빛사논문
- 조회366
Jae Kyu Ryu 1,2,3,23, Zhaoqi Yan 1,2,23, Mauricio Montano 4,5,23, Elif G. Sozmen 1,2,3,23, Karuna Dixit 1,2,23, Rahul K. Suryawanshi 4,23, Yusuke Matsui 4,5, Ekram Helmy 4,5, Prashant Kaushal 6,7, Sara K. Makanani 6,7, Thomas J. Deerinck 8, Anke Meyer-Franke 2, Pamela E. Rios Coronado 9, Troy N. Trevino 1,2, Min-Gyoung Shin 10, 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 Agrawal 10, 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 Thomas 10, Michela Traglia 10, Valentina L. Kouznetsova 12,13, Igor F. Tsigelny 1,12,13,14, Alexander R. Pico 10, 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 4,5,20,22 ,* & Katerina Akassoglou 1,2,3,*
1Center for Neurovascular Brain Immunology at Gladstone and UCSF, San Francisco, CA, USA.
2Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
3Department ofNeurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
4Gladstone Institute of Virology, San Francisco, CA, USA.
5Michael Hulton Center for HIV Cure Research at Gladstone, San Francisco, CA, USA.
6Department of Microbiology, Immunology and Molecular Genetics (MIMG), University of California Los Angeles, Los Angeles, CA, USA.
7Institute for Quantitative and Computational Biosciences (QCBio), University of California Los Angeles, Los Angeles, CA, USA.
8National Center for Microscopy and Imaging Research, Center for Research on Biological Systems, University of California San Diego, La Jolla, CA, USA.
9Department of Biology, Stanford University, Stanford, CA, USA.
10Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA.
11Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
12San Diego Supercomputer Center, University of California San Diego, La Jolla, CA, USA.
13CureScience Institute, San Diego, CA, USA.
14Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.
15Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
16Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
17Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
18Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
19COVID-19 Research Group (QCRG), University of California San Francisco, San Francisco, CA, USA.
20Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
21Chan Zuckerberg Biohub, San Francisco, CA, USA.
22Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
23These authors contributed equally: Jae Kyu Ryu, Zhaoqi Yan, Mauricio Montano, Elif G. Sozmen, Karuna Dixit, Rahul K. Suryawanshi.
*Corresponding authors: correspondence to Warner C. Greene or Katerina Akassoglou
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. Despite the clinical evidence, 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. 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.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-09-05)
- 국외 연구진
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