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
Nature, doi:10.1038/s41586-024-07873-4
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] [2] [3] [4] . Despite the clinical evidence 1, [5] [6] [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] [9] [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 a s 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. Long COVID has emerged as a central public health issue that remains an unmet clinical need 4 . Coagulation and neurological complications in COVID-19 can occur during acute infection and persist in long COVID causing morbidity and mortality [1] [2] [3] [4] 11 . Notably, coagulopathy also occurs in young patients with COVID-19 with mild infections, breakthrough infections and long COVID, and is associated with neurological complications [3] [4] [5] [6] [7] 12 . Blood clots in patients with COVID-19 remain resistant to degradation despite adequate anticoagulation 1, 13, 14 . The prevalence and severity of coagulopathy and its correlations with the immune response and neurological complications in long COVID suggest as yet unknown mechanisms of COVID-19 pathogenesis. Hypercoagulability in COVID-19 is associated with extensive fibrin deposition in inflamed lung and brain [8] [9] [10] . Fibrin is derived from the soluble blood protein fibrinogen after activation of coagulation and forms the central structural component of blood clots 15, 16 . Fibrin is deposited at sites of vascular damage or blood-brain barrier (BBB) disruption, and is a key proinflammatory and prooxidant activator of the innate immune response in autoimmune, inflammatory and neurodegenerative diseases 15, [17] [18] [19] [20] [21] . Neurovascular injury and reactive microglia are..
RNA in situ hybridization with immunohistochemistry RNA in situ hybridization with immunohistochemistry was performed on brain sections from mice infected with Delta using RNAscope Multiplex Fluorescent Assay (ACD Bio) according to the manufacturer's protocol for FFPE tissue. In brief, tissue was deparaffinized and incubated in 3% hydrogen peroxide for 10 min, then subjected to antigen retrieval by boiling in RNAScope Target Retrieval Solution (ACD Bio) for 1 h. The samples were permeabilized with RNAScope Protease Plus reagent (ACD Bio) for 30 min at 40 °C. RNA probes were hybridized to tissue for 2 h at 40 °C. Oligonucleotide probes for mouse Trem2, Cst7 and Spp1 were designed by ACD Bio (498711-C3, and 435191-C3, respectively). Probe signals were amplified using the RNAScope Multiplex Fluorescent Reagent Kit v2 (ACD Bio) and detected with TSA Vivid Fluorophore 570 (Tocris, 7526). Tissue sections were stained for one RNA probe and counterstained for IBA1 (234 308, Synaptic Systems, 1:500) using the RNA-Protein Co-Detection Ancillary Kit (ACD Bio). The slides were imaged using the Zeiss Axioplan 2 epifluorescent microscope at ×20 and images were analysed using ImageJ (NIH). IBA1-postive microglia in each image were manually counted. Dense clusters of Trem2, Cst7 or Spp1 mRNA overlapping with IBA1 signal indicate microglia expressing disease-associated genes.
Statistical analysis All values are reported as mean ± s.e.m. The Shapiro-Wilk normality test 79 was used to..
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'abstract': '<jats:title>Abstract</jats:title><jats:p>Life-threatening thrombotic events and neurological '
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{ 'value': 'K.A. is listed as an inventor on US patents 7,807,645, 8,569,242, 8,877,195 and '
'8,980,836, covering fibrin antibodies, submitted by the University of '
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