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Mol. Cells

Published online November 2, 2022

© The Korean Society for Molecular and Cellular Biology

Temporal Transcriptome Analysis of SARS-CoV-2-Infected Lung and Spleen in Human ACE2-Transgenic Mice

Jung Ah Kim1,21 , Sung-Hee Kim2,21 , Jung Seon Seo2,21 , Hyuna Noh3,21 , Haengdueng Jeong2 , Jiseon Kim2 , Donghun Jeon2 , Jeong Jin Kim2 , Dain On3,4 , Suhyeon Yoon3 , Sang Gyu Lee5 , Youn Woo Lee6 , Hui Jeong Jang6 , In Ho Park2,7 , Jooyeon Oh8 , Sang-Hyuk Seok9 , Yu Jin Lee9 , Seung-Min Hong10 , Se-Hee An10 , Joon-Yong Bae11 , Jung-ah Choi12 , Seo Yeon Kim13 , Young Been Kim13 , Ji-Yeon Hwang13 , Hyo-Jung Lee14 , Hong Bin Kim15 , Dae Gwin Jeong16 , Daesub Song17 , Manki Song12 , Man-Seong Park11 , Kang-Seuk Choi10 , Jun Won Park9 , Jun-Won Yun18 , Jeon-Soo Shin2,7,8 , Ho-Young Lee6,19 , Jun-Young Seo2,* , Ki Taek Nam2,* , Heon Yung Gee1,* , and Je Kyung Seong3,4,5,20,*

1Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea, 2Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea, 3Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Korea, 4Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea, 5Interdisciplinary Program for Bioinformatics, Seoul National University, Seoul 08826, Korea, 6Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea, 7Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea, 8Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Korea, 9Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea, 10Laboratory of Avian Diseases, BK21 PLUS Program for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea, 11Department of Microbiology, Institute for Viral Diseases, Biosafety Center, Korea University College of Medicine, Seoul 02841, Korea, 12Science Unit, International Vaccine Institute, Seoul 08826, Korea, 13Preclinical Research Center, Seoul National University Bundang Hospital, Seongnam 13620, Korea, 14Department of Periodontology, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam 13620, Korea, 15Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea, 16Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea, 17Department of Veterinary Medicine Virology Laboratory, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea, 18Laboratory of Veterinary Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea, 19Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea, 20BIO-MAX Institute, Seoul National University, Seoul 08826, Korea, 21These authors contributed equally to this work.

Correspondence to : snumouse@snu.ac.kr (JKS); hygee@yuhs.ac (HYG); kitaek@yuhs.ac (KTN); jyseo0724@yuhs.ac (JYS)

Received: June 2, 2022; Revised: July 19, 2022; Accepted: August 5, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and potentially fatal virus. So far, most comprehensive analyses encompassing clinical and transcriptional manifestation have concentrated on the lungs. Here, we confirmed evident signs of viral infection in the lungs and spleen of SARS-CoV-2-infected K18-hACE2 mice, which replicate the phenotype and infection symptoms in hospitalized humans. Seven days post viral detection in organs, infected mice showed decreased vital signs, leading to death. Bronchopneumonia due to infiltration of leukocytes in the lungs and reduction in the spleen lymphocyte region were observed. Transcriptome profiling implicated the meticulous regulation of distress and recovery from cytokine-mediated immunity by distinct immune cell types in a time-dependent manner. In lungs, the chemokine-driven response to viral invasion was highly elevated at 2 days post infection (dpi). In late infection, diseased lungs, post the innate immune process, showed recovery signs. The spleen established an even more immediate line of defense than the lungs, and the cytokine expression profile dropped at 7 dpi. At 5 dpi, spleen samples diverged into two distinct groups with different transcriptome profile and pathophysiology. Inhibition of consecutive host cell viral entry and massive immunoglobulin production and proteolysis inhibition seemed that one group endeavored to survive, while the other group struggled with developmental regeneration against consistent viral intrusion through the replication cycle. Our results may contribute to improved understanding of the longitudinal response to viral infection and development of potential therapeutics for hospitalized patients affected by SARS-CoV-2.

Keywords immune-mediated response, SARS-CoV-2, transcriptome profiling

Article

On-line First

Mol. Cells

Published online November 2, 2022

Copyright © The Korean Society for Molecular and Cellular Biology.

Temporal Transcriptome Analysis of SARS-CoV-2-Infected Lung and Spleen in Human ACE2-Transgenic Mice

Jung Ah Kim1,21 , Sung-Hee Kim2,21 , Jung Seon Seo2,21 , Hyuna Noh3,21 , Haengdueng Jeong2 , Jiseon Kim2 , Donghun Jeon2 , Jeong Jin Kim2 , Dain On3,4 , Suhyeon Yoon3 , Sang Gyu Lee5 , Youn Woo Lee6 , Hui Jeong Jang6 , In Ho Park2,7 , Jooyeon Oh8 , Sang-Hyuk Seok9 , Yu Jin Lee9 , Seung-Min Hong10 , Se-Hee An10 , Joon-Yong Bae11 , Jung-ah Choi12 , Seo Yeon Kim13 , Young Been Kim13 , Ji-Yeon Hwang13 , Hyo-Jung Lee14 , Hong Bin Kim15 , Dae Gwin Jeong16 , Daesub Song17 , Manki Song12 , Man-Seong Park11 , Kang-Seuk Choi10 , Jun Won Park9 , Jun-Won Yun18 , Jeon-Soo Shin2,7,8 , Ho-Young Lee6,19 , Jun-Young Seo2,* , Ki Taek Nam2,* , Heon Yung Gee1,* , and Je Kyung Seong3,4,5,20,*

1Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea, 2Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea, 3Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Korea, 4Laboratory of Developmental Biology and Genomics, Research Institute for Veterinary Science, and BK21 PLUS Program for Creative Veterinary Science Research, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea, 5Interdisciplinary Program for Bioinformatics, Seoul National University, Seoul 08826, Korea, 6Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Korea, 7Institute of Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 03722, Korea, 8Department of Microbiology, Yonsei University College of Medicine, Seoul 03722, Korea, 9Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Korea, 10Laboratory of Avian Diseases, BK21 PLUS Program for Veterinary Science and Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea, 11Department of Microbiology, Institute for Viral Diseases, Biosafety Center, Korea University College of Medicine, Seoul 02841, Korea, 12Science Unit, International Vaccine Institute, Seoul 08826, Korea, 13Preclinical Research Center, Seoul National University Bundang Hospital, Seongnam 13620, Korea, 14Department of Periodontology, Section of Dentistry, Seoul National University Bundang Hospital, Seongnam 13620, Korea, 15Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea, 16Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea, 17Department of Veterinary Medicine Virology Laboratory, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea, 18Laboratory of Veterinary Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea, 19Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea, 20BIO-MAX Institute, Seoul National University, Seoul 08826, Korea, 21These authors contributed equally to this work.

Correspondence to:snumouse@snu.ac.kr (JKS); hygee@yuhs.ac (HYG); kitaek@yuhs.ac (KTN); jyseo0724@yuhs.ac (JYS)

Received: June 2, 2022; Revised: July 19, 2022; Accepted: August 5, 2022

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and potentially fatal virus. So far, most comprehensive analyses encompassing clinical and transcriptional manifestation have concentrated on the lungs. Here, we confirmed evident signs of viral infection in the lungs and spleen of SARS-CoV-2-infected K18-hACE2 mice, which replicate the phenotype and infection symptoms in hospitalized humans. Seven days post viral detection in organs, infected mice showed decreased vital signs, leading to death. Bronchopneumonia due to infiltration of leukocytes in the lungs and reduction in the spleen lymphocyte region were observed. Transcriptome profiling implicated the meticulous regulation of distress and recovery from cytokine-mediated immunity by distinct immune cell types in a time-dependent manner. In lungs, the chemokine-driven response to viral invasion was highly elevated at 2 days post infection (dpi). In late infection, diseased lungs, post the innate immune process, showed recovery signs. The spleen established an even more immediate line of defense than the lungs, and the cytokine expression profile dropped at 7 dpi. At 5 dpi, spleen samples diverged into two distinct groups with different transcriptome profile and pathophysiology. Inhibition of consecutive host cell viral entry and massive immunoglobulin production and proteolysis inhibition seemed that one group endeavored to survive, while the other group struggled with developmental regeneration against consistent viral intrusion through the replication cycle. Our results may contribute to improved understanding of the longitudinal response to viral infection and development of potential therapeutics for hospitalized patients affected by SARS-CoV-2.

Keywords: immune-mediated response, SARS-CoV-2, transcriptome profiling

Mol. Cells
Nov 30, 2022 Vol.45 No.11, pp. 763~867
COVER PICTURE
Naive (cyan) and axotomized (magenta) retinal ganglion cell axons in Xenopus tropicalis (Choi et al., pp. 846-854).

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