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Cellular & Molecular Immunology 2012年第5期9卷 410-416页

作者： jian-Ping Ma Hou-Jun Xia Gao-Hong Zhang jian-bao han Li-Guo Zhang Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences&Yunnan Province Kunming Institute of ZoologyChinese Academy of SciencesKunmingChina Graduate University of the Chinese Academy of Sciences BeijingChina CAS Key Laboratory of Infection and Immunity Institute of BiophysicsChinese Academy of SciencesBeijingChina

It is currently widely accepted that immune activation in HIV-infected individuals leads to a severe loss of CD4＋ T cells and the progression to AIDS. However, the underlying mechanism of this immune activation remains unclear. Experimental data suggest that the activation of plasmacytoid dendritic cells （pDCs） by plasma viremia may play a critical role in HIV-induced immune activation. In this study, we found that the level of immune activation was higher in the late phase of SIVmac239 infection compared with chronic infection, which suggests that immune activation might be related to disease progression in SIVmac239-infected non-human primate models. Our work also showed that chloroquine could effectively inhibit the activation of pDCs in vitro and in vivo. However, chloroquine treatment of SIVmac239-infected macaques had no significant influence on the Cellular composition of peripheral blood in these animals.

关键词： Chinese rhesus macaque chloroquine immune activation pDC SIV

Tissue distribution of SARS-CoV-2 in non-human primates after combined intratracheal and intranasal inoculation

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Science China(Life Sciences) 2021年第10期64卷 1792-1794页

作者： Tian-Zhang Song jian-bao han Xiang Yang Ming-Hua Li Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Kunming National High-level Biosafety Research Center for Non-human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academic of SciencesKunming 650107China

Dear Editor,As of 5 July,2020,approximately 20,162,000 confirmed cases of coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),have been reported globally,including an estimated 740,000 *** the clinical manifestations of COVID-19 are heterogeneous,viral infection and pathological changes in the respiratory system,especially the lungs,still represent common characteristics of *** nose,served as the entrance to the respiratory system,seems to produce absent or minimal symptoms of nasal congestion or rhinorrhea during SRAS-CoV-2 infection,while other viral rhinitis(i.e.,adenovirus,rhinovirus,influenza virus,etc.)are characterized by typical nasal symptoms,including nasal congestion,rhinorrhea,and *** studies suggest that,despite a lack of other nasal symptoms,anosmia is an important sign of early-stage COVID-19(Lechien et al.,2020).

关键词： nasal respiratory acute

Emerging SARS-CoV-2 B.1.621/Mu variant is prominently resistant to inactivated vaccine-elicited antibodies

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Zoological Research 2021年第6期42卷 789-791页

作者： Xiaochun Xie jian-bao han Guanqin Ma Xiao-Li Feng Xiaohong Li Qing-Cui Zou Zhong-Hua Deng jianxiong Zeng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650201China Kunming National High-level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China National Resource Center for Non-Human Primates National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China

Although it first appeared almost two years ago,the COVID-19 pandemic continues to have an impact on a global scale,in part due to newly emerging SARS-CoV-2 variants such as Delta and *** B.1.621 variant,first identified in Colombia in January 2021,was classified as a variant of interest(VOI)and designated as Mu by the World Health Organization(WHO)in August ***,its infectivity and resistance to neutralizing antibodies remain largely ***,in comparison to Delta,the Mu variant showed an unexpectedly enhanced immune resistance to inactivated vaccine-elicited ***,Mu demonstrated less infectivity than Delta,implying a biological trade-off between viral transmission and immune *** study strongly calls for urgent evaluation of the protective efficacy of current COVID-19 vaccines against the Mu *** of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)are of concern regarding control of the global COVID-19 pandemic(Wang et al.,2021).The SARS-CoV-2 B.1.621 variant was first identified in Colombia in January *** its epidemiological prevalence,the WHO defined B.1.621(named Mu)as a VOI on 30 August *** of September 2021,the WHO has classified four variants of concern(VOC),i.e.,Alpha(B.1.1.7),Beta(B.1.351),Gamma(P.1),and Delta(B.1.617.2),and two VOI,i.e.,Lambda(C.37)and Mu(B.1.621)(Supplementary Figure S1A).

关键词： Figure protective continue

Single-nucleus transcriptomic profiling of multiple organs in a rhesus macaque model of SARS-CoV-2 infection

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Zoological Research 2022年第6期43卷 1041-1062页

作者： Qiang Ma Wenji Ma Tian-Zhang Song Zhaobo Wu Zeyuan Liu Zhenxiang Hu jian-bao han Ling Xu Bo Zeng Bosong Wang Yinuo Sun Dan-Dan Yu Qian Wu Yong-Gang Yao Yong-Tang Zheng Xiaoqun Wang State Key Laboratory of Brain and Cognitive Science Institute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China Kunming National High-Level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China National Resource Center for Non-Human Primates National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China LivzonBio Inc.ZhuhaiGuangdong 519045China State Key Laboratory of Cognitive Neuroscience and Learning Beijing Normal UniversityBeijing 100875China IDG/McGovern Institute for Brain Research Beijing Normal UniversityBeijing 100875China Advanced Innovation Center for Human Brain Protection Beijing Institute for Brain DisordersCapital Medical UniversityBeijing 100069China

Infection with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple ***, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000single-nucleus transcriptomes of the lung, liver,kidney, and cerebral cortex in rhesus macaques(Macaca mulatta) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multiorgan dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019(COVID-19).Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway,which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy(an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection,which may facilitate the development of therapeutic interventions for COVID-19.

关键词： SARS-CoV-2 Rhesus macaque Animal model Single-nucleus RNA sequencing Antiviral immune defects Multiple organs

Delayed severe cytokine storm and immune cell infiltration in SARS-CoV-2-infected aged Chinese rhesus macaques

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Zoological Research 2020年第5期41卷 503-516页

作者： Tian-Zhang Song Hong-Yi Zheng jian-bao han Lin Jin Xiang Yang Feng-Liang Liu Rong-Hua Luo Ren-Rong Tian Hou-Rong Cai Xiao-Li Feng Chao Liu Ming-Hua Li Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China Kunming National High-Level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China Department of Respiratory and Critical Care Medicine Affiliated Drum Tower Hospital of Nanjing UniversityNanjingJiangsu 210008China National Resource Center for Non-Human Primates National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China

As of June 2020, Coronavirus Disease 2019(COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years,making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection. To examine the effect of age on death, we established a SARSCoV-2 infection model in Chinese rhesus macaques(Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b^+ and CD8^+ cells in lungs at one-week post infection(wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b^+ cells, and persistent infiltration of CD8^+ cells in the lungs at 2 wpi. In addition,peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.

关键词： COVID-19 Non-human primate animal model Elderly Immune response

Pro-inflammatory microenvironment and systemic accumulation of CXCR3+cell exacerbate lung pathology of old rhesus macaques infected with SARS-CoV-2

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Signal Transduction and Targeted Therapy 2021年第10期6卷 3033-3044页

作者： Hong-Yi Zheng Xiao-Yan He Wei Li Tian-Zhang Song jian-bao han Xiang Yang Feng-Liang Liu Rong-Hua Luo Ren-Rong Tian Xiao-Li Feng Yu-Hua Ma Chao Liu Ming-Hua Li Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina Kunming College of Life Science University of Chinese Academy of SciencesKunmingYunnanChina Kunming National High-Level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina National Resource Center for Non-Human Primates National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnanChina Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory) GuangzhouChina

Understanding the pathological features of severe acute respiratory syn drome coronavirus 2(SARS-CoV-2)infect io n in an animal model is crucial for the treatment of coronavirus disease 2019(COVID-19).Here,we compared imnnunopathological changes in young and old rhesus macaques(RMs)before and after SARS-CoV-2 infection at the tissue *** analysis of multiplex immunofluoresce nee staining images of formali n-fixed paraffi n-embedded(FFPE)sections showed that SARS-CoV-2 infectio n specifically induced elevated levels of apoptosis,autophagy,and nuclear factor kappa-B(NF-kB)activation of angiotensirv convert!ng enzyme 2(ACE2)+cells,and increased interferon a(IFN-a)-and interleukin 6(IL-6)-secreting cells and C-X-C motif chemokine receptor 3(CXCR3)+cells in lung tissue of old *** pathological pattern,which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens,was significantly correlated with the systemic accumulation of CXCR3+cells in lungs,spleens,and peripheral ***,the ratio of CXCR3+to T-box protein expression in T cell(T-bet)+(CXCR3+/T-bet+ratio)in CD8+cells may be used as a predictor of severe *** findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+cells in predicting severe COVID-19.

关键词： CXCR3 spleen lung

COVID-19-like symptoms observed in Chinese tree shrews infected with SARS-CoV-2

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Zoological Research 2020年第5期41卷 517-526页

作者： Ling Xu Dan-Dan Yu Yu-Hua Ma Yu-Lin Yao Rong-Hua Luo Xiao-Li Feng Hou-Rong Cai jian-bao han Xue-Hui Wang Ming-Hua Li Chang-Wen Ke Yong-Tang Zheng Yong-Gang Yao Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China Kunming National High-level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academic of SciencesKunmingYunnan 650107China National Resource Center for Non-Human Primates National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China Kunming College of Life Science University of Chinese Academy of SciencesKunmingYunnan 650204China Department of Respiratory and Critical Care Medicine the Affiliated Drum Tower Hospital of Nanjing UniversityNanjingJiangsu 210008China Medical Key Laboratory for Repository and Application of Pathogenic Microbiology Guangdong Provincial Center for Disease Control and PreventionGuangzhouGuangdong 510440China CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghai 2Q0Q3AChina

Thecoronavirusdisease2019(COVID-19)pandemic continues to pose a global threat to the human population. Identifying animal species susceptible to infection with the SARS-CoV-2/HCoV-19 pathogen is essential for controlling the outbreak and for testing valid prophylactics or therapeutics based on animal model studies. Here,different aged Chinese tree shrews(adult group, 1 year old;old group, 5–6 years old), which are close relatives to primates, were infected with SARS-CoV-2. X-ray, viral shedding, laboratory, and histological analyses were performed on different days postinoculation(dpi). Results showed that Chinese tree shrews could be infected by SARS-CoV-2. Lung infiltrates were visible in X-ray radiographs in most infected animals. Viral RNA was consistently detected in lung tissues from infected animals at 3,5, and 7 dpi, along with alterations in related parameters from routine blood tests and serum biochemistry, including increased levels of aspartate aminotransferase(AST) and blood urea nitrogen(BUN). Histological analysis of lung tissues from animals at 3 dpi(adult group) and 7 dpi(old group) showed thickened alveolar septa and interstitial hemorrhage. Several differences were found between the two different aged groups in regard to viral shedding peak. Our results indicate that Chinese tree shrews have the potential to be used as animal models for SARS-CoV-2 infection.

关键词： SARS-CoV-2/HCoV-19 Treeshrews Animal model Susceptibility COVID-19

Infectivity of SARS-CoV-2 and protection against reinfection in rats

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Zoological Research 2022年第6期43卷 945-948页

作者： Dandan Yu Yanghaopeng Long Ling Xu jian-bao han Jiawei Xi jianlin Xu Lu-Xiu Yang Xiao-Li Feng Qing-Cui Zou Wang Qu jiangwei Lin Ming-Hua Li Yong-Gang Yao Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650201China Kunming National High-Level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China Kunming College of Life Science University of Chinese Academy of SciencesKunmingYunnan 650204China

DEAR EDITOR,The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) pandemic remains an important global public health issue. In this study, we unexpectedly found that wildtype Sprague-Dawley(SD) rats can be infected with the SARS-CoV-2 prototype. Our results showed direct experimental evidence of the infectivity of SARS-CoV-2 infection, subsequent pathogenicity, and protection against reinfection in rats.

关键词： infection rats acute

A recombinant receptor-binding domain in trimeric form generates protective immunity against SARSCoV-2 infection in nonhuman primates

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The Innovation 2021年第3期2卷 94-102页

作者： Limin Yang Deyu Tian jian-bao han Wenhui Fan Yuan Zhang Yunlong Li Wenqiang Sun Yanqiu Wei Xiaodong Tian Dan-dan Yu Xiao-li Feng Gong Cheng Yuhai Bi Yong-tang Zheng Wenjun Liu CAS Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyCenter for Influenza Research and Early Warning(CASCIRE)CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID)Chinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 101408China Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences Kunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Kunming National High-Level Biosafety Research Center for Nonhuman Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunming 650107China Institute of Infectious Diseases Shenzhen Bay LaboratoryShenzhen 518000China Tsinghua-Peking Center for Life Sciences School of MedicineTsinghua UniversityBeijing 100084China

A safe and effective vaccine is critical to combat the COVID-19 ***,we developed a trimeric SARS-CoV-2 receptor-binding domain(RBD)subunit vaccine candidate that simulates the natural structure of the spike(S)trimer *** with the RBD trimer-induced robust humoral and cellular immune responses,and a high level of neutralizing antibodies was maintained for at least 4.5 ***,the antibodies that were produced in response to the vaccine effectively cross-neutralized the SARS-CoV-2501Y.V2 variant(B.1.351).Of note,when the vaccine-induced antibodies dropped to a sufficiently low level,only one boost quickly activated the anamnestic immune response,conferring full protection against a SARSCoV-2 challenge in rhesus macaques without typical histopathological changes in the lung *** results demonstrated that the SARS-CoV-2 RBD trimer vaccine candidate is highly immunogenic and safe,providing long-lasting,broad,and significant immunity protection in nonhuman primates,thereby offering an optimal vaccination strategy against COVID-19.

关键词： COVID-19 SARS-CoV-2 RBD subunit vaccine NHPs variants

Northern pig-tailed macaques(Macaca leonina)infected with SARS-CoV-2 show rapid viral clearance and persistent immune response

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Zoological Research 2021年第3期42卷 350-353页

作者： Tian-Zhang Song Hong-Yi Zheng jian-bao han Xiao-Li Feng Feng-Liang Liu Xiang Yang Lin Jin Rong-Hua Luo Ren-Rong Tian Chao Liu Ming-Hua Li Hou-Rong Cai Yong-Tang Zheng Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China Kunming National High-Level Biosafety Research Center for Non-Human Primates Center for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China National Resource Center for Non-Human Primates and National Research Facility for Phenotypic&Genetic Analysis of Model Animals(Primate Facility)Kunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China Department of Respiratory and Critical Care Medicine Affiliated Drum Tower Hospital of Nanjing UniversityNanjingJiangsu 210008China

Coronavirus disease 2019(COVID-19),which is caused by severe acute respiratory syndrome coronavirus(SARS-CoV-2),has become an unprecedented global health *** present,SARS-CoV-2-infected nonhuman primates are considered the gold standard animal model for COVID-19 ***,we showed that northern pig-tailed macaques(Macaca leonina,NPMs)supported SARS-CoV-2 ***,compared with rhesus macaques,NPMs showed rapid viral clearance in lung tissues,nose swabs,throat swabs,and rectal swabs,which may be due to higher expression of interferon(IFN)-αin lung ***,the rapid viral clearance was not associated with good *** the second week post infection,NPMs developed persistent or even more severe inflammation and body injury compared with rhesus *** results suggest that viral clearance may have no relationship with COVID-19 progression and SARS-CoV-2-infected NPMs could be considered as a critically ill animal model in COVID-19 research.

关键词： infected lung interferon