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Journal Article Ppublish 56 citations

PubMed: 37924708 DOI: 10.1016/j.ebiom.2023.104851

Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors.

EBioMedicine 98:104851

Authors: Xiaoying Gu, Siyuan Wang, Wanying Zhang, Caihong Li, Li Guo, Zai Wang, Haibo Li, Hui Zhang, Yuhan Zhou, Weijian Liang, Hui Li, Yan Liu, Yeming Wang, Lixue Huang, Tao Dong, Dingyu Zhang, Catherine C L Wong, Bin Cao

Affiliations

  • National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Clinical Research and Data Management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, PR China; Changping Laboratory, Beijing, PR China.
  • State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, PR China.
  • National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, PR China.
  • Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, PR China.
  • Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; NHC Key Laboratory of Systems Biology of Pathogens and Christophe Merieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences, Beijing, PR China.
  • Changping Laboratory, Beijing, PR China; Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, PR China.
  • Changping Laboratory, Beijing, PR China; National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, PR China.
  • State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, PR China; Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, PR China.
  • Foreseen Biotechnology, Beijing, PR China.
  • Changping Laboratory, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, PR China.
  • State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, PR China; Department of Infectious Disease, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, PR China.
  • Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, PR China.
  • Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province, PR China; Wuhan Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences, Wuhan, Hubei Province, PR China; Hubei Clinical Research Center for Infectious Diseases, Wuhan, Hubei Province, PR China.
  • State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, PR China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, PR China.
  • Changping Laboratory, Beijing, PR China; National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, PR China; Department of Pulmonary and Critical Care Medicine, Capital Medical University, Beijing, PR China; Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, PR China.

Abstract

BACKGROUND

As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified.

METHODS

Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID.

FINDINGS

The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder.

INTERPRETATION

The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID.

FUNDING

National Natural Science Foundation of China; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; Clinical Research Operating Fund of Central High Level Hospitals; the Talent Program of the Chinese Academy of Medical Science; Training Program of the Big Science Strategy Plan; Ministry of Science and Technology of the People's Republic of China; New Cornerstone Science Foundation; Peking Union Medical College Education Foundation; Research Funds from Health@InnoHK Program.

MeSH

Cardiomyopathy, Dilated, Neurons, Biomedical Research, Cohort Studies, Recycling, Biomarkers, Cholesterol, Complement System Proteins, Infections, Cardiomyopathies, Plasma, Post-Acute Covid-19 Syndrome

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