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Complement-Mediated Pneumonic Insults in Severe COVID-19

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Complement-Mediated Pneumonic Insults in Severe COVID-19 Enhanced eosinophilic inammation associated with antibody and complement-mediated pneumonic insults in severe COVID-19 Dong-Min Kim Chosun University College of Medicine Jun-Won Seo Chosun University College of Medicine Yuri Kim Seoul National University College of Medicine Jooyeon Lee Chungnam National University School of Medicine Uni Park Seoul National University College of Medicine Na-Young Ha Seoul National University College of Medicine Jaemoon Koh Seoul National University College of Medicine Hyoree Park Seoul National University College of Medicine Jae-Won Lee Seoul National University College of Medicine Hyo-Jin Ro Seoul National University College of Medicine Na Ra Yun Chosun University College of Medicine Da Young Kim Chosun University College of Medicine Sung Ho Yoon Chosun University College of Medicine Yong Sub Na Chosun University College of Medicine Do Sik Moon Chosun University College of Medicine Sung-Chul Lim Chosun University College of Medicine Choon-Mee Kim Chosun University College of Medicine Kyeongseok Jeon Seoul National University College of Medicine Jun-Gu Kang Jeonbuk National University Hyeongseok Jeong Chungnam National University School of Medicine Jungok Kim Chungnam National University School of Medicine Shinhyea Cheon Chungnam National University School of Medicine Kyung Mok Sohn Chungnam National University School of Medicine Jae Young Moon Chungnam National University School of Medicine Sungmin Kym Chungnam National University Sejong Hospital Myung-Shin Lee Eulji University School of Medicine Hyun-Je Kim Samsung Advanced Institute for Health Sciences & Technology Woong-Yang Park Samsung Advanced Institute for Health Sciences & Technology Hyun-Woo Shin Seoul National University College of Medicine Hye-Young Kim Seoul National University College of Medicine Chung-Hyun Cho Seoul National University College of Medicine Yoon Kyung Jeon Seoul National University College of Medicine Yeon-Sook Kim Chungnam National University School of Medicine Nam-Hyuk Cho ( [email protected] ) Seoul National University College of Medicine Research Article Keywords: COVID-19, SARS-CoV-2, eosinophilic inammation, pneumonia Posted Date: November 3rd, 2020 DOI: https://doi.org/10.21203/rs.3.rs-101027/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License 1 Enhanced eosinophilic inflammation associated with antibody and 2 complement-mediated pneumonic insults in severe COVID-19 3 4 Dong-Min Kim1,13,*, Jun-Won Seo1,13, Yuri Kim2,3,4,13, Jooyeon Lee5, 13, Uni Park2,3,13, 5 Na-Young Ha2,3,4,13, Jaemoon Koh6,13, Hyoree Park2,3, Jae-Won Lee2,3, Hyo-Jin Ro2,3, Na Ra Yun1, 6 Da Young Kim1, Sung Ho Yoon1, Yong Sub Na1, Do Sik Moon1, Sung-Chul Lim7, 7 Choon-Mee Kim8, Kyeongseok Jeon2,3, Jun-Gu Kang9, Hyeongseok Jeong5, Jungok Kim10, 8 Shinhyea Cheon5, Kyung Mok Sohn5, Jae Youg Moon10, Sungmin Kym10, Myung-Shin Lee11, 9 Hyun-Je Kim12, Woong-Yang Park12, Hyun-Woo Shin3, Hye-Young Kim3, Chung-Hyun Cho3, 10 Yoon Kyung Jeon6, Yeon-Sook Kim5,*, and Nam-Hyuk Cho2,3,4,* 11 12 1Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Republic 13 of Korea. 14 2Department of Microbiology and Immunology, 3Department of Biomedical Sciences, Seoul 15 National University College of Medicine, Seoul, Republic of Korea. 16 4Institute of Endemic Disease, Seoul National University Medical Research Center and Bundang 17 Hospital, Seoul, Republic of Korea. 18 5Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 19 Republic of Korea. 20 6Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of 21 Korea 22 7Department of Pathology, 8Premedical Science, Chosun University College of Medicine, 1 23 Gwangju, Republic of Korea. 24 9Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, Republic of Korea. 25 10Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, 26 Republic of Korea. 27 11Department of Microbiology and Immunology, Eulji University School of Medicine, Daejeon, 28 Republic of Korea. 29 12Department of Health Sciences and Technology, Samsung Advanced Institute for Health 30 Sciences & Technology, Sungkyunkwan University, Seoul, South Korea. 31 13These authors contributed equally. 32 *Correspondence: Dong-Min Kim ([email protected]), Yeon-Sook Kim 33 ([email protected]), and Nam-Hyuk Cho ([email protected]) 34 35 36 37 38 39 40 41 42 43 2 44 Abstract 45 Despite the worldwide effect of the Coronavirus disease 2019 (COVID-19) pandemic, the 46 underlying mechanisms of fatal viral pneumonia remain elusive. Here, we conducted kinetic 47 profiling of respiratory leukocytes and associated inflammatory mediators to show that severe 48 COVID-19 is associated with delayed but enhanced eosinophilic inflammation when compared 49 to mild cases. In addition, we confirmed increased Th2-biased adaptive immune responses, 50 accompanying overt complement activation, in the severe group. Moreover, enhanced antibody 51 responses and complement activation was associated with disease pathogenesis as evidenced by 52 formation of immune complexes and membrane attack complexes in airways and vasculature of 53 lung biopsies from a fatal case, as well as by enhanced hallmark gene set signatures of FcγR 54 signaling and complement activation in myeloid cells of respiratory specimens from severe 55 COVID-19 patients. We also observed expression of viral antigen in lung epithelial and 56 endothelial cells without producing viruses during late stage of COVID-19, indicating abortive 57 viral infection which may further fuel antibody responses and aggravate immune-complex- 58 mediated inflammation. These results suggest that SARS-CoV-2 infection may drive scripted 59 specific innate immune responses, including eosinophilic inflammation, and subsequent 60 pulmonary pathogenesis via enhanced Th2-biased immune responses, which might be crucial 61 drivers of severe pneumonia in COVID-19 patients. 62 63 Keywords: COVID-19, SARS-CoV-2, eosinophilic inflammation, pneumonia 64 65 3 66 Introduction 67 Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)1 has been rapidly spreading 68 worldwide since Dec. 2019 with an average mortality rate of approximately 3.2% 69 (https://covid19.who.int). The primary cause of disease fatality is severe pneumonia, resulting in 70 acute respiratory syndrome (ARDS).2 Around 80% of confirmed cases are asymptomatic or have 71 mild symptoms, including fever, cough, sore throat, and myalgia, whereas the rest often develop 72 severe pneumonia requiring supplemental oxygen therapy.3,4 The most common finding of 73 radiological imaging is bilateral, ground-glass opacity in the periphery of the lungs.4 The 74 mechanisms underlying this varying degree of pneumonia severity observed in COVID-19 75 patients remain elusive.5 In particular, the dynamics of pathologic inflammation and the central 76 culprits of pneumonic progression leading to severe ARDS and death still remain unclear, 77 despite numerous studies profiling systemic immune signatures.6,7 78 In order to characterize the pathogenic hallmarks of severe pneumonia in COVID-19 patients, we 79 performed kinetic analysis of inflammatory features of specimens collected from confirmed 80 patients with various degrees of clinical symptoms. We systematically analyzed inflammatory 81 components and leukocytes in bronchoalveolar lavage fluids (BALFs), sputa, lung tissue 82 biopsies, and bloods to characterize kinetic responses of pulmonary inflammation upon viral 83 infection. This extensive analysis revealed that severe COVID-19 is associated with enhanced 84 eosinophilic pulmonary inflammation, as identified by cytological analysis and detection of 85 granular contents derived from the inflammatory cells. In addition, kinetic profiling of 86 inflammatory mediators, including various cytokines and chemokines, and titration of antibodies 87 against a viral antigen revealed emerging Th2-biased adaptive immune responses, coupled to 4 88 overt complement activation, especially in the severe group. In addition, we observed extensive 89 immune complexes and membrane attack complexes in pulmonary airways and vasculatures of 90 lung biopsies from a fatal case. Moreover, persistent expression of viral antigens, potentially via 91 abortive infection, in inflamed lungs at late stage may irreversibly aggravate antibody and 92 complement-mediated pulmonary damage in fatal COVID-19. These results suggest that SARS- 93 CoV-2 infection may drive scripted specific innate immune responses, including eosinophilic 94 inflammation, and subsequent Th2-biased antigen-specific immune responses, which may 95 contribute to COVID-19 associated severe pneumonia. 96 97 Results and Discussion 98 Baseline characteristics of the confirmed patients included in this study are summarized in 99 Supplementary Table S1 and Fig. S1. The mild group includes 36 patients who were 100 asymptomatic, with mild respiratory symptoms but no detectable pneumonia, or with mild to 101 moderate pneumonia determined by chest imaging and clinical symptoms. The severe group 102 includes 16 patients who suffered from severe pneumonia requiring high flow oxygen supply 103 and/or mechanical ventilation. All the patients in the severe group survived and were discharged, 104 except one patient (P15) who succumbed to death due to fatal ARDS. The patients were also 105 divided into two sets: Group 1 includes 15 patients (10 mild and 5 severe group patients)
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