Establishment and characterization of an hACE2/hTMPRSS2 knock-in mouse model to study SARS-CoV-2

被引:0
|
作者
Liu, Hongwei [1 ]
Brostoff, Terza [1 ]
Ramirez, Ana [1 ]
Wong, Talia [1 ]
Rowland, Douglas J. [2 ]
Heffner, Mollie [3 ]
Flores, Arturo [1 ]
Willis, Brandon [3 ]
Evans, Jeffrey J. [3 ]
Lanoue, Louise [3 ]
Lloyd, K. C. Kent [3 ,4 ]
Coffey, Lark L. [1 ]
机构
[1] Univ Calif Davis, Sch Vet Med, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA
[2] Univ Calif Davis, Coll Engn, Ctr Mol & Genom Imaging, Davis, CA USA
[3] Univ Calif Davis, Mouse Biol Program, Davis, CA USA
[4] Univ Calif Davis, Sch Med, Dept Surg, Davis, CA USA
来源
FRONTIERS IN IMMUNOLOGY | 2024年 / 15卷
基金
美国国家卫生研究院;
关键词
SARS-CoV-2; mouse ACE2; mouse TMPRSS2; knock-in mouse; COVID-19; virus; pathogenesis; pulmonary function; EXPRESSION; COVID-19;
D O I
10.3389/fimmu.2024.1428711
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Despite a substantial body of research, we lack fundamental understanding of the pathophysiology of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) including pulmonary and cardiovascular outcomes, in part due to limitations of murine models. Most models use transgenic mice (K18) that express the human (h) angiotensin converting enzyme 2 (ACE2), ACE2 knock-in (KI) mice, or mouse-adapted strains of SARS-CoV-2. Further, many SARS-CoV-2 variants produce fatal neurologic disease in K18 mice and most murine studies focus only on acute disease in the first 14 days post inoculation (dpi). To better enable understanding of both acute (<14 dpi) and post-acute (>14 dpi) infection phases, we describe the development and characterization of a novel non-lethal KI mouse that expresses both the ACE2 and transmembrane serine protease 2 (TMPRSS2) genes (hACE2/hTMPRSS2). The human genes were engineered to replace the orthologous mouse gene loci but remain under control of their respective murine promoters, resulting in expression of ACE2 and TMPRSS2 instead of their murine counterparts. After intranasal inoculation with an omicron strain of SARS-CoV-2, hACE2/hTMPRSS2 KI mice transiently lost weight but recovered by 7 dpi. Infectious SARS-CoV-2 was detected in nasopharyngeal swabs 1-2 dpi and in lung tissues 2-6 dpi, peaking 4 dpi. These outcomes were similar to those in K18 mice that were inoculated in parallel. To determine the extent to which hACE2/hTMPRSS2 KI mice are suitable to model pulmonary and cardiovascular outcomes, physiological assessments measuring locomotion, behavior and reflexes, biomonitoring to measure cardiac activity and respiration, and micro computed tomography to assess lung function were conducted frequently to 6 months post inoculation. Male but not female SARS-CoV-2 inoculated hACE2/hTMPRSS2 KI mice showed a transient reduction in locomotion compared to control saline treated mice. No significant changes in respiration, oxygen saturation, heart rate variability, or conductivity were detected in SARS-CoV-2 inoculated mice of either sex. When re-inoculated 6 months after the first inoculation, hACE2/hTMPRSS2 KI became re-infected with disease signs similar to after the first inoculation. Together these data show that a newly generated hACE2/hTMPRSS2 KI mouse can be used to study mild COVID-19.
引用
收藏
页数:15
相关论文
共 50 条
  • [21] SARS-CoV-2 infection induces thymic atrophy mediated by IFN-γ in hACE2 transgenic mice
    Rizvi, Zaigham Abbas
    Sadhu, Srikanth
    Dandotiya, Jyotsna
    Sharma, Puja
    Binayke, Akshay
    Singh, Virendra
    Das, Vinayaka
    Khatri, Ritika
    Kumar, Rajesh
    Samal, Sweety
    Kalia, Manjula
    Awasthi, Amit
    EUROPEAN JOURNAL OF IMMUNOLOGY, 2024, 54 (07)
  • [22] Development of a novel human CD147 knock-in NSG mouse model to test SARS-CoV-2 viral infection
    Badeti, Saiaditya
    Jiang, Qingkui
    Naghizadeh, Alireza
    Tseng, Hsiang-chi
    Bushkin, Yuri
    Marras, Salvatore A. E.
    Nisa, Annuurun
    Tyagi, Sanjay
    Chen, Fei
    Romanienko, Peter
    Yehia, Ghassan
    Evans, Deborah
    Lopez-Gonzalez, Moises
    Alland, David
    Russo, Riccardo
    Gause, William
    Shi, Lanbo
    Liu, Dongfang
    CELL AND BIOSCIENCE, 2022, 12 (01):
  • [23] hACE2 upregulation and participation of macrophages and clear cells in the immune response of epididymis to SARS-CoV-2 in K18-hACE2 mice
    da Silva, Andre Acacio Souza
    de Oliveira, Salmo Azambuja
    Battistone, Maria Agustina
    Hinton, Barry Thomas
    Cerri, Paulo Sergio
    Sasso-Cerri, Estela
    ANDROLOGY, 2024,
  • [24] COVID-19 pandemic: Insights into structure, function, and hACE2 receptor recognition by SARS-CoV-2
    Mittal, Anshumali
    Manjunath, Kavyashree
    Ranjan, Rajesh Kumar
    Kaushik, Sandeep
    Kumar, Sujeet
    Verma, Vikash
    PLOS PATHOGENS, 2020, 16 (08)
  • [25] Lethal synergy between SARS-CoV-2 and Streptococcus pneumoniae in hACE2 mice and protective efficacy of vaccination
    Barman, Tarani Kanta
    Singh, Amit K.
    Bonin, Jesse L.
    Nafiz, Tanvir Noor
    Salmon, Sharon L.
    Metzger, Dennis W.
    JCI INSIGHT, 2022, 7 (11)
  • [26] A Comparative Analysis of SARS-CoV-2 Variants of Concern (VOC) Spike Proteins Interacting with hACE2 Enzyme
    Chen, Jiawei
    Chen, Lingtao
    Quan, Heng
    Lee, Soongoo
    Khan, Kaniz Fatama
    Xie, Ying
    Li, Qiaomu
    Valero, Maria
    Dai, Zhiyu
    Xie, Yixin
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2024, 25 (15)
  • [27] Isoelectric point determination by imaged CIEF of commercially available SARS-CoV-2 proteins and the hACE2 receptor
    Krebs, Finja
    Scheller, Christin
    Grove-Heike, Kristina
    Pohl, Lena
    Watzig, Hermann
    ELECTROPHORESIS, 2021, 42 (06) : 687 - 692
  • [28] Engineering a NanoBiT biosensor for detecting angiotensin-converting enzyme-2 (hACE2) interaction with SARS-CoV-2 spike protein and screening the inhibitors to block hACE2 and spike interaction
    Lin, Cheng-Han
    Yang, Xin-Rui
    Lin, Meng-Wei
    Chang, Ho-Ju
    Lee, Che-Hsiung
    Lin, Chih-Sheng
    BIOSENSORS & BIOELECTRONICS, 2024, 263
  • [29] Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor
    Al-Karmalawy, Ahmed A.
    Dahab, Mohammed A.
    Metwaly, Ahmed M.
    Elhady, Sameh S.
    Elkaeed, Eslam B.
    Eissa, Ibrahim H.
    Darwish, Khaled M.
    FRONTIERS IN CHEMISTRY, 2021, 9
  • [30] Role of neutrophil chemoattractant CXCL5 in SARS-CoV-2 infection-induced lung inflammatory innate immune response in an in vivo hACE2 transfection mouse model
    Liang, Yan
    Li, Heng
    Li, Jing
    Yang, Ze-Ning
    Li, Jia-Li
    Zheng, Hui-Wen
    Chen, Yan-Li
    Shi, Hai-Jing
    Guo, Lei
    Liu, Long-Ding
    ZOOLOGICAL RESEARCH, 2020, 41 (06) : 621 - +