PMID- 36933413 OWN - NLM STAT- MEDLINE DCOM- 20230418 LR - 20230418 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 90 DP - 2023 Apr TI - Proteomic and phosphoproteomic characteristics of the cortex, hippocampus, thalamus, lung, and kidney in COVID-19-infected female K18-hACE2 mice. PG - 104518 LID - S2352-3964(23)00083-X [pii] LID - 10.1016/j.ebiom.2023.104518 [doi] LID - 104518 AB - BACKGROUND: Neurological damage caused by coronavirus disease 2019 (COVID-19) has attracted increasing attention. Recently, through autopsies of patients with COVID-19, the direct identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in their central nervous system (CNS) has been reported, indicating that SARS-CoV-2 might directly attack the CNS. The need to prevent COVID-19-induced severe injuries and potential sequelae is urgent, requiring the elucidation of large-scale molecular mechanisms in vivo. METHODS: In this study, we performed liquid chromatography-mass spectrometry-based proteomic and phosphoproteomic analyses of the cortex, hippocampus, thalamus, lungs, and kidneys of SARS-CoV-2-infected K18-hACE2 female mice. We then performed comprehensive bioinformatic analyses, including differential analyses, functional enrichment, and kinase prediction, to identify key molecules involved in COVID-19. FINDINGS: We found that the cortex had higher viral loads than did the lungs, and the kidneys did not have SARS-COV-2. After SARS-CoV-2 infection, RIG-I-associated virus recognition, antigen processing and presentation, and complement and coagulation cascades were activated to different degrees in all five organs, especially the lungs. The infected cortex exhibited disorders of multiple organelles and biological processes, including dysregulated spliceosome, ribosome, peroxisome, proteasome, endosome, and mitochondrial oxidative respiratory chain. The hippocampus and thalamus had fewer disorders than did the cortex; however, hyperphosphorylation of Mapt/Tau, which may contribute to neurodegenerative diseases, such as Alzheimer's disease, was found in all three brain regions. Moreover, SARS-CoV-2-induced elevation of human angiotensin-converting enzyme 2 (hACE2) was observed in the lungs and kidneys, but not in the three brain regions. Although the virus was not detected, the kidneys expressed high levels of hACE2 and exhibited obvious functional dysregulation after infection. This indicates that SARS-CoV-2 can cause tissue infections or damage via complicated routes. Thus, the treatment of COVID-19 requires a multipronged approach. INTERPRETATION: This study provides observations and in vivo datasets for COVID-19-associated proteomic and phosphoproteomic alterations in multiple organs, especially cerebral tissues, of K18-hACE2 mice. In mature drug databases, the differentially expressed proteins and predicted kinases in this study can be used as baits to identify candidate therapeutic drugs for COVID-19. This study can serve as a solid resource for the scientific community. The data in this manuscript will serve as a starting point for future research on COVID-19-associated encephalopathy. FUNDING: This study was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the National Natural Science Foundation of China, and the Natural Science Foundation of Beijing. CI - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Liu, Jiang-Feng AU - Liu JF AD - State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. FAU - Peng, Wan-Jun AU - Peng WJ AD - NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, CAMS and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China. FAU - Wu, Yue AU - Wu Y AD - School of Statistics and Data Science, Nankai University, Tianjin 300071, China. FAU - Yang, Ye-Hong AU - Yang YH AD - State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. FAU - Wu, Song-Feng AU - Wu SF AD - State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Research Unit of Proteomics & Research and Development of New Drug of Chinese Academy of Medical Sciences, Institute of Lifeomics, Beijing 102206, China. FAU - Liu, De-Pei AU - Liu DP AD - State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: liudp@pumc.edu.cn. FAU - Liu, Jiang-Ning AU - Liu JN AD - NHC Key Laboratory of Human Disease Comparative Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, CAMS and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China. Electronic address: liujn@cnilas.org. FAU - Yang, Jun-Tao AU - Yang JT AD - State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China. Electronic address: yangjt@pumc.edu.cn. LA - eng PT - Journal Article DEP - 20230316 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) RN - 0 (K-18 conjugate) SB - IM MH - Mice MH - Humans MH - Female MH - Animals MH - *COVID-19 MH - SARS-CoV-2 MH - Angiotensin-Converting Enzyme 2 MH - Proteomics MH - Mice, Transgenic MH - Lung MH - Hippocampus MH - Kidney MH - Thalamus MH - Disease Models, Animal PMC - PMC10017276 OTO - NOTNLM OT - Brain OT - K18-hACE2 mouse OT - Label-free proteomics and phosphoproteomics OT - Multiple organs OT - SARS-CoV-2 COIS- Declaration of interests The authors declare no conflict of interest. EDAT- 2023/03/19 06:00 MHDA- 2023/04/18 10:16 PMCR- 2023/03/16 CRDT- 2023/03/18 19:06 PHST- 2022/10/24 00:00 [received] PHST- 2023/02/22 00:00 [revised] PHST- 2023/02/23 00:00 [accepted] PHST- 2023/04/18 10:16 [medline] PHST- 2023/03/19 06:00 [pubmed] PHST- 2023/03/18 19:06 [entrez] PHST- 2023/03/16 00:00 [pmc-release] AID - S2352-3964(23)00083-X [pii] AID - 104518 [pii] AID - 10.1016/j.ebiom.2023.104518 [doi] PST - ppublish SO - EBioMedicine. 2023 Apr;90:104518. doi: 10.1016/j.ebiom.2023.104518. Epub 2023 Mar 16.