TY - JOUR
T1 - Elevated Myl9 reflects the Myl9-containing microthrombi in SARS-CoV-2–induced lung exudative vasculitis and predicts COVID-19 severity
AU - Iwamura, Chiaki
AU - Hirahara, Kiyoshi
AU - Kiuchi, Masahiro
AU - Ikehara, Sanae
AU - Azuma, Kazuhiko
AU - Shimada, Tadanaga
AU - Kuriyama, Sachiko
AU - Ohki, Syota
AU - Yamamoto, Emiri
AU - Inaba, Yosuke
AU - Shiko, Yuki
AU - Aoki, Ami
AU - Kokubo, Kota
AU - Hirasawa, Rui
AU - Hishiya, Takahisa
AU - Tsuji, Kaori
AU - Nagaoka, Tetsutaro
AU - Ishikawa, Satoru
AU - Kojima, Akira
AU - Mito, Haruki
AU - Hase, Ryota
AU - Kasahara, Yasunori
AU - Kuriyama, Naohide
AU - Tsukamoto, Tetsuya
AU - Nakamura, Sukeyuki
AU - Urushibara, Takashi
AU - Kaneda, Satoru
AU - Sakao, Seiichiro
AU - Tobiume, Minoru
AU - Suzuki, Yoshio
AU - Tsujiwaki, Mitsuhiro
AU - Kubo, Terufumi
AU - Hasegawa, Tadashi
AU - Nakase, Hiroshi
AU - Nishida, Osamu
AU - Takahashi, Kazuhisa
AU - Baba, Komei
AU - Iizumi, Yoko
AU - Okazaki, Toshiya
AU - Kimura, Motoko Y.
AU - Yoshino, Ichiro
AU - Igari, Hidetoshi
AU - Nakajima, Hiroshi
AU - Suzuki, Takuji
AU - Hanaoka, Hideki
AU - Nakada, Taka Aki
AU - Ikehara, Yuzuru
AU - Yokote, Koutaro
AU - Nakayama, Toshinori
N1 - Funding Information:
We thank Takashi Yoshida (Juntendo University Faculty of Medicine and Graduate School of Medicine), Yoshifumi Suzuki (Juntendo University Faculty of Medicine and Graduate School of Medicine), Ryogo Ema (Eastern Chiba Medical Center), and Rintaro Nishimura (Eastern Chiba Medical Center) for their support in performing sample acquisition; Toshiro Masuda and Haruna Ebisu for managing this clinical study; Mr. Shintaro Hishiyama (BRUKER) for technical assistance on energy-dispersive X-ray spectroscopy analysis; Mrs. Mika Hashimoto (Advanced Institute of Science and Technology) for technical assistance on histological analysis using immunofluorescence detection; and Damon Tumes for his careful reading and valuable suggestions. This work was supported by grants from the following: the Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) Grants-in-Aid for Scientific Research (S) JP19H05650, (B) 20H03685, (C) 19K16683, 20K08769, 22K15485, and 22K15484, Transformative Research Areas (B) JP21H05120 and JP21H05121; the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from the Japan Agency for Medical Research and Development (AMED) (JP21ek0410060 and JP21ek0410082); the Program to Develop Countermeasure Technologies against Viral and Other Infectious Diseases, AMED (JP20he0622037); AMED-Programs for Medical Intervention (JP20gm6110005); AMED-Core Research for Evolutionary Science and Technology (JP21gm1210003); AMED-Advanced Measurement and Analysis Systems project (JP19hm0102069h001); the Japan Science and Technology Agency (JST) Fusion Oriented REsearch for disruptive Science and Technology (FOREST) Project (JPMJFR200R); JST-Moonshot R&D (JPMJMS2025), and by the Mochida Memorial Foundation for Medical and Pharmaceutical Research; the MSD Life Science Foundation; Kowa Life Science Foundation; and the Takeda Science Foundation.
Funding Information:
ACKNOWLEDGMENTS. We thank Takashi Yoshida (Juntendo University Faculty of Medicine and Graduate School of Medicine), Yoshifumi Suzuki (Juntendo University Faculty of Medicine and Graduate School of Medicine), Ryogo Ema (Eastern Chiba Medical Center), and Rintaro Nishimura (Eastern Chiba Medical Center) for their support in performing sample acquisition; Toshiro Masuda and Haruna Ebisu for managing this clinical study; Mr. Shintaro Hishiyama (BRUKER) for technical assistance on energy-dispersive X-ray spectroscopy analysis; Mrs. Mika Hashimoto (Advanced Institute of Science and Technology) for technical assistance on histological analysis using immunofluorescence detection; and Damon Tumes for his careful reading and valuable suggestions. This work was supported by grants from the following: the Ministry of Education, Culture, Sports, Science and Technology (MEXT Japan) Grants-in-Aid for Scientific Research (S) JP19H05650, (B) 20H03685, (C) 19K16683, 20K08769, 22K15485, and 22K15484, Transformative Research Areas (B) JP21H05120 and JP21H05121; the Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from the Japan Agency for Medical Research and Development (AMED) (JP21ek0410060 and JP21ek0410082); the Program to Develop Countermeasure Technologies against Viral and Other Infectious Diseases, AMED (JP20he0622037); AMED-Programs for Medical Intervention (JP20gm6110005); AMED-Core Research for Evolutionary Science and Technology (JP21gm1210003); AMED-Advanced Measurement and Analysis Systems project (JP19hm0102069h001); the Japan Science and Technology Agency (JST) Fusion Oriented REsearch for disruptive Science and Technology (FOREST) Project (JPMJFR200R); JST-Moonshot R&D (JPMJMS2025), and by the Mochida Memorial Foundation for Medical and Pharmaceutical Research; the MSD Life Science Foundation; Kowa Life Science Foundation; and the Takeda Science Foundation.
Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/8/16
Y1 - 2022/8/16
N2 - The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection–triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1–expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)–containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.
AB - The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection–triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1–expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)–containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.
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U2 - 10.1073/pnas.2203437119
DO - 10.1073/pnas.2203437119
M3 - Article
C2 - 35895716
AN - SCOPUS:85135378186
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 33
M1 - e2203437119
ER -