动物学研究2023，Vol.44Issue(6) ：1003-1014.DOI:10.24272/j.issn.2095-8137.2023.108

Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model

Zhongyun Zhang Ning Zhang Xuancheng Lu Min Zhou Xiaoxiang Yan Weiqiong Gu Jingru Yang Qin Zhang Cheng Zhang Yuhuan Gong Mingjun Jia Xiaoyu Zhang Peng Ning Mei Liu Xiaoyan Li Xiaomeng Shi Wenjun Liu George F.Gao Guang Ning Jiqiu Wang Yuhai Bi
动物学研究2023，Vol.44Issue(6) ：1003-1014.DOI:10.24272/j.issn.2095-8137.2023.108
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Anti-infection effects of heparin on SARS-CoV-2 in a diabetic mouse model

Zhongyun Zhang 1Ning Zhang 2Xuancheng Lu 3Min Zhou 4Xiaoxiang Yan 5Weiqiong Gu 1Jingru Yang 6Qin Zhang 3Cheng Zhang 2Yuhuan Gong 2Mingjun Jia 2Xiaoyu Zhang 2Peng Ning 2Mei Liu 3Xiaoyan Li 3Xiaomeng Shi 3Wenjun Liu 7George F.Gao 8Guang Ning 1Jiqiu Wang 1Yuhai Bi9
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作者信息

  • 1. Department of Endocrinology and Metabolism,Shanghai Institute of Endocrine and Metabolic Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Shanghai National Clinical Research Center for Metabolic Diseases,Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China,Shanghai National Center for Translational Medicine,Shanghai 200025,China
  • 2. CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Center for Influenza Research and Early-warning(CASCIRE),CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID),Chinese Academy of Sciences,Beijing 100101,China
  • 3. Laboratory Animal Center,Chinese Center for Disease Control and Prevention(China CDC),Beijing 102206,China
  • 4. Department of Respiratory and Critical Care Medicine,Institute of Respiratory Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China
  • 5. Department of Cardiology,Institute of Cardiovascular Diseases,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China
  • 6. School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou,Zhejiang 325000,China
  • 7. CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Center for Influenza Research and Early-warning(CASCIRE),CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID),Chinese Academy of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China
  • 8. CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Center for Influenza Research and Early-warning(CASCIRE),CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID),Chinese Academy of Sciences,Beijing 100101,China;Laboratory Animal Center,Chinese Center for Disease Control and Prevention(China CDC),Beijing 102206,China;University of Chinese Academy of Sciences,Beijing 100049,China
  • 9. CAS Key Laboratory of Pathogen Microbiology and Immunology,Institute of Microbiology,Center for Influenza Research and Early-warning(CASCIRE),CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID),Chinese Academy of Sciences,Beijing 100101,China;School of Laboratory Medicine and Life Sciences,Wenzhou Medical University,Wenzhou,Zhejiang 325000,China;University of Chinese Academy of Sciences,Beijing 100049,China
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Abstract

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the combined impact of coronavirus disease 2019(COVID-19)and diabetes have not yet been elucidated,and effective treatment options for SARS-CoV-2-infected diabetic patients remain limited.To investigate the disease pathogenesis,K18-hACE2 transgenic(hACE2Tg)mice with a leptin receptor deficiency(hACE2-Lepr-/-)and high-fat diet(hACE2-HFD)background were generated.The two mouse models were intranasally infected with a 5x105 median tissue culture infectious dose(TCID50)of SARS-CoV-2,with serum and lung tissue samples collected at 3 days post-infection.The hACE2-Lepr-/-mice were then administered a combination of low-molecular-weight heparin(LMWH)(1 mg/kg or 5 mg/kg)and insulin via subcutaneous injection prior to intranasal infection with 1×104 TCID50 of SARS-CoV-2.Daily drug administration continued until the euthanasia of the mice.Analyses of viral RNA loads,histopathological changes in lung tissue,and inflammation factors were conducted.Results demonstrated similar SARS-CoV-2 susceptibility in hACE2Tg mice under both lean(chow diet)and obese(HFD)conditions.However,compared to the hACE2-Lepr+/+mice,hACE2-Lepr-/-mice exhibited more severe lung injury,enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1a(HIF-1a),and increased apoptosis.Moreover,combined LMWH and insulin treatment effectively reduced disease progression and severity,attenuated lung pathological changes,and mitigated inflammatory responses.In conclusion,pre-existing diabetes can lead to more severe lung damage upon SARS-CoV-2 infection,and LMWH may be a valuable therapeutic approach for managing COVID-19 patients with diabetes.

Key words

SARS-CoV-2/Diabetes/Mouse model/Heparin/Antiviral therapy

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基金项目

Strategic Priority Research Program of the Chinese Academy of Sciences(CAS)(XDB29010102)

National Natural Science Foundation of China(NSFC)(91957124)

National Natural Science Foundation of China(NSFC)(82161148010)

National Natural Science Foundation of China(NSFC)(32041010)

Selfsupporting Program of Guangzhou Laboratory(SRPG22-001)

National Science and Technology Infrastructure of China(National Pathogen Resource Center)(NPRC-32)

China Health Promotion Foundation()

Youth Innovation Promotion Association of CAS(Y2021034)

Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202208)

出版年

2023
动物学研究
中国科学院昆明动物研究所 中国动物学会

动物学研究

CSTPCDCSCD
影响因子：0.582
ISSN：0254-5853
参考文献量66
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