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Immunobiology of COVID-19: Mechanistic and therapeutic insights from animal models

Zoological Research 2024年第4期45卷 747-766页

作者： hong-yi zheng Tian-Zhang Song Yong-Tang zheng State Key Laboratory of Genetic Evolution&Animal Models KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China 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

The distribution of the immune system throughout the body complicates in vitro assessments of coronavirus disease 2019(COVID-19)immunobiology,often resulting in a lack of reproducibility when extrapolated to the whole ***,developing animal models is imperative for a comprehensive understanding of the pathology and immunology of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)*** review summarizes current progress related to COVID-19 animal models,including non-human primates(NHPs),mice,and hamsters,with a focus on their roles in exploring the mechanisms of immunopathology,immune protection,and long-term effects of SARS-CoV-2 infection,as well as their application in immunoprevention and immunotherapy of SARS-CoV-2 *** among these animal models and their specific applications are also highlighted,as no single model can fully encapsulate all aspects of *** effectively address the challenges posed by COVID-19,it is essential to select appropriate animal models that can accurately replicate both fatal and non-fatal infections with varying courses and *** animal model libraries and associated research tools is key to resolving the global COVID-19 pandemic,serving as a robust resource for future emerging infectious diseases.

关键词： SARS-CoV-2 COVID-19 Animal models Infection immunology Immunotherapy

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隐喻语句的预设及其动态语义

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自然辩证法研究 2024年第1期40卷 38-45,132页

作者：洪峥怡黄华新浙江大学哲学学院杭州310058

隐喻语句在进行非字面义表达时,需要基于一定的前提信息,这些前提信息和字面表达的预设没有本质区别。但相较于字面表达的预设,隐喻的预设更为复杂,即使是最简形式的隐喻语句,也存在不同类型的预设;且隐喻的预设介于语义预设和语用预设... 详细信息

隐喻语句在进行非字面义表达时,需要基于一定的前提信息,这些前提信息和字面表达的预设没有本质区别。但相较于字面表达的预设,隐喻的预设更为复杂,即使是最简形式的隐喻语句,也存在不同类型的预设;且隐喻的预设介于语义预设和语用预设之间,它既有相对确定的形式,又高度依赖于语境,具有动态性。通过将一个隐喻语句所使用的预设区分为隐喻概念预设和源域性质预设两类,说明两者在层级上的差异,可以解释隐喻预设和一般预设在投射性和可取消性上的区别。继而遵循动态语义学传统,可以提供一种贯通表层语句结构和深层认知结构的方式,在同一框架下刻画两类预设投射的不同情形,揭示动态语境中的隐喻语义。

关键词：隐喻预设动态语义语境转化潜力

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Association of TRIMCyp and TRIM5α from assam macaques leads to a functional trade-off between HIV-1 and N-MLV inhibition

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Science China(Life Sciences) 2018年第8期61卷 954-965页

作者： Dan Mu Jia-Wu Zhu Feng-Liang Liu hong-yi zheng 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 Kunming Institute of Zoology Chinese Academy of Sciences Kunming 650223 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming 650204 China Kunming Primate Research Center Chinese Academy of Sciences Kunming 650223 China

TRIM5α restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TR1M5-cyclophilin A （TRIMCyp） proteins. Previously, we found that assam macaques express a TRIMCyp chimera （amTRIMCyp）, along with a TRIM5α allelic protein （amTRIM5α）. Herein, we investigated the antiviral activity of amTRIMCyp and amTRIM5α individually, as well as their interaction and joint effects. amTRIMCyp showed a divergent restriction pattern from amTRIM5αc Although both proteins potently restricted the replication of HIV-1, only amTRIM5αt inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when amTRIMCyp and amTRIM5αt were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous amTRIM50t/TRIMCyp showed stronger resistance to HIV-1 infection than those from amTRIM5a/TRIM5α homozygotes. The anti-HIV-1 synergistic effect was dependent on the amTRIMCyp-amTRIM5α interaction. In contrast, amTRIMCyp completely abrogated the anti-N-MLV activity mediated by amTRIM5α, showing a dominant-negative effect, indicating that the generation of amTRIMCyp was involved in the trade-off between divergent restriction activities. Our results provide a new paradigm to study functional trade-offs mediated by allelic proteins, a theoretical basis for utilizing animal models with various TRIM5 alleles, as well as novel HIV-1 gene therapy strategies.

关键词： TRIMCyp/TRIM5α assam macaque HIV-1 N-MLV functional trade-off

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Replication potentials of HIV-1/HSIV in PBMCs from northern pigtailed macaque （Macaca leonina）

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Zoological Research 2014年第3期35卷 186-195页

作者： Ai-Hua LEI Gao-hong ZHANG Ren-Rong TIAN Jia-Wu ZHU hong-yi zheng Wei PANG Yong-Tang zheng Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming 650223 China Kunming College of Life Sciences University of Chinese Academy of Sciences Kunming Yunnan 650204 China University of Science and Technology of China Hefei 230026 China Kunming Primate Research Center Kunming Institute of Zoology Chinese Academy of Sciences Kunming 650223 China

The northern pig-tailed macaque （Macaca leonina） has been identified as an independent species of Old World monkey, and we previously found that PBMCs from M. leonina were susceptible to human immunodeficiency virus type 1 （HIV-1）, which may be due to the absence of a TRIM5 protein restricting HIV-1 replication. Here we investigated the infection potentials of six laboratory adapted HIV-1 strains and three primary HIV-1 isolates in PBMCs from M. leonina. The results indicate that these strains are characterized by various but low replication levels, and among which, HIV-INL4-3 shows the highest replication ability. Based on the abundant evidence of species-specific interactions between restriction factors APOBEC3 and HIV/SIV-derived Vif protein, we subsequently examined the replication potentials of v/f-substituted HIV-1 （HSIV） in M. leonina PBMCs. Notably, HSIV-vifmac and stHIV-lsv chimeras, two HIV-1Ni.4-3-derived viruses encoding the viral infectivity factor （Vif） protein from SIVmac239, replicated robustly in cells from M. leonina, which suggests that HSIV could effectively antagonize the antiviral activity of APOBEC3 proteins expressed in cells of M. leonina. Therefore, our data demonstrate that M. leonina has the potential to be developed into a promising animal model for human AIDS.

关键词： HIV-1 HSIV Replication PBMC Northern pig-tailed macaque (Macaca leonina)

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Flow cytometric characterizations of leukocyte subpopulations in the peripheral blood of northern pig-tailed macaques （Macaca leonina）

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Zoological Research 2014年第6期35卷 465-473页

作者： hong-yi zheng Ming-Xu ZHANG Lin-Tao ZHANG Xiao-Liang ZHANG Wei PANG Long-Bao LYU Yong-Tang zheng Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China School of Life Sciences University of Science and Technology of China Hefei Anhui 230026 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming Yunnan 650204 China Faculty of Life Science and Technology Kunming University of Science and Technology Kunming Yunnan 650500 China Kunming Primate Research Center Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China

Pig-tailed macaques(Macaca nemistrina group) have been extensively used as non-human primate animal models for various human diseases in recent years, notably for AIDS research due to their sensitivity to HIV-1. Northern pig-tailed macaques(M. leonina) are distributed in China and other surrounding Southeast Asia countries. Although northern pig-tailed macaques have been bred on a large scale as experimental animals since 2012, the reference value of normal levels of leukocytes is not available. To obtain such information, 62 blood samples from male and female healthy northern pig-tailed macaques at different ages were collected. The normal range of major leukocyte subpopulations, such as T lymphocytes, B lymphocytes, natural killer(NK) cells, monocytes, and the expression levels of activation or differentiation related molecules(CD38, HLA-DR, CCR5, CD21, IgD, CD80 and CD86) on lymphocytes were analyzed by flow cytometry. The counts of B cells decreased with age, but those of CD8+ T cells and NK cells and the frequency of CD38+HLA-DR+CD4+ T cells were positively correlated with age. The counts of leukocyte subpopulations were higher in males than those in females except for CD4+ T cells. Males also showed higher expression levels of Ig D and CD21 within B cells. This study provides basic data about the leukocyte subpopulations of northern pig-tailed macaques and compares this species with commonly used Chinese rhesus macaques(M. mulatta), which is meaningful for the biomedical application of northern pig-tailed macaques.

关键词： Northern pig-tailed macaque Flow cytometry Leukocyte subpopulation Age Sex

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Longitudinal analysis reveals characteristically high proportions of bacterial vaginosis-associated bacteria and temporal variability of vaginal microbiota in northern pig-tailed macaques （Macaca leonina）

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Zoological Research 2015年第5期36卷 285-298页

作者： Lin ZHU Ai-Hua LEI hong-yi zheng Long-Bao LYU Zhi-Gang ZHANG Yong-Tang zheng Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China State Key Laboratory of Genetic Resources and Evolution Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan 650223 China Kunming College of Life Science University of Chinese Academy of Sciences Kunming Yunnan 650204 China School of Life Sciences University of Science and Technology of China Hefei Anhui 230026 China Kunming Primate Research Center Chinese Academy of Sciences Kunming Yunnan 650223 China

The complex and dynamic vaginal microbial ecosystem is critical to both health and disease of the host. Studies focusing on how vaginal microbiota influences HIV-1 infection may face limitations in selecting proper animal models. Given that northern pig-tailed macaques （Macaca leonina） are susceptible to HIV-1 infection, they may be an optimal animal model for elucidating the mechanisms by which vaginal microbiota contributes to resistance and susceptibility to HIV-1 infection. However, little is known about the composition and temporal variability of vaginal microbiota of the northern pig-tailed macaque. Here, we present a comprehensive catalog of the composition and temporal dynamics of vaginal microbiota of two healthy northern pig-tailed macaques over 19 weeks using 454-pyrosequencing of 16S rRNA genes. We found remarkably high proportions of a diverse array of anaerobic bacteria associated with bacterial vaginosis. Atopobium and Sneathia were dominant genera, and interestingly, we demonstrated the presence of Lactobacillus-dominated vaginal microbiota. Moreover, longitudinal analysis demonstrated that the temporal dynamics of the vaginal microbiota were considerably individualized. Finally, network analysis revealed that vaginal pH may influence the temporal dynamics of the vaginal microbiota, suggesting that inter-subject variability of vaginal bacterial communities could be mirrored in inter-subject variation in correlation profiles of species with each other and with vaginal pH over time. Our results suggest that the northern pig-tailed macaque could be an ideal animal model for prospective investigation of the mechanisms by which vaginal microbiota influence susceptibility and resistance to HIV-1 infection in the context of highly polymicrobial and Lactobacillus-dominated states.

关键词： Macaque Vaginal microbiome Bacterialvaginosis Temporal dynamics Networks

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Superior intestinal integrity and limited microbial translocation are associated with lower immune activation in SIVmac239-infected northern pig-tailed macaques(Macaca leonina)

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Zoological Research 2019年第6期40卷 522-531页

作者： Ming-Xu Zhang Tian-Zhang Song hong-yi zheng Xue-Hui Wang ying Lu Han-Dan Zhang Ting Li Wei Pang 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 National Kunming High Level Biosafety Research Center for Non-human PrimatesKIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunming Yunnan 650223China Kunming College of Life Science University of Chinese Academy of SciencesKunming Yunnan 650204China School of Life Sciences University of Science and Technology of ChinaHefei Anhui 230026China KIZ-SU Joint Laboratory of Animal Models and Drug Development College of Pharmaceutical SciencesSoochow UniversitySuzhou Jiangsu 215123China

Microbial translocation is a cause of systemic immune activation in HIV/SIV infection. In the present study, we found a lower CD8+ T cell activation level in Macaca leonina (northern pig-tailed macaques, NPMs) than in Macaca mulatta (Chinese rhesus macaques, ChRMs) during SIVmac239 infection. Furthermore, the levels of plasma LPS-binding protein and soluble CD14 in NPMs were lower than those in ChRMs. Compared with ChRMs, SIV-infected NPMs had lower Chiu scores, representing relatively normal intestinal mucosa. In addition, no obvious damage to the ileum or colon epithelial barrier was observed in either infected or uninfected NPMs, which differed to that found in ChRMs. Furthermore, no significant microbial translocation (Escherichia coli) was detected in the colon or ileum of infected or uninfected NPMs, which again differed to that observed in ChRMs. In conclusion, NPMs retained superior intestinal integrity and limited microbial translocation during SIV infection, which may contribute to their lower immune activation compared with ChRMs.

关键词： Immune activation Intestinal integrity Microbial translocation SIVmac239 Macaca leonina Northern pig-tailed macaques Macaca mulatta Chinese rhesus macaques

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Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients

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Cellular & Molecular Immunology 2020年第5期17卷 541-543页

作者： hong-yi zheng Mi Zhang Cui-Xian Yang Nian Zhang Xi-Cheng Wang Xin-Ping Yang Xing-Qi Dong 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 DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Yunnan Provincial Hospital of Infectious Diseases Kunming 650301China

The novel contagious primary atypical pneumonia epidemic,which broke out in Wuhan,China,in December 2019,is now formally called Coronavirus Disease 2019(COVID-19),with the causative virus named as Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2).1,2 Recent studies have shown that in addition to dyspnea,hypoxemia,and acute respiratory distress,lymphopenia,and cytokine release syndrome are also important clinical features in patients with severe SARS-CoV-2 infection.3 This suggests that homeostasis of the immune system plays an important role in the development of COVID-19 pneumonia.

关键词： patients distress homeostasis

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The Logarithmic Sobolev Inequality for a Submanifold in Manifolds with Nonnegative Sectional Curvature

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Chinese Annals of Mathematics,Series B 2024年第3期45卷 487-496页

作者： Chengyang yi Yu zheng School of Mathematical Sciences East China Normal UniversityShanghai 200241China

The authors prove a sharp logarithmic Sobolev inequality which holds for compact submanifolds without boundary in Riemannian manifolds with nonnegative sectional curvature of arbitrary dimension and *** the Michael-Simon Sobolev inequality,this inequality includes a term involving the mean *** extends a recent result of Brendle with Euclidean setting.

关键词： Logarithmic Sobolev inequality Nonnegative sectional curvature Submanifold

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Aging induces severe SIV infection accompanied by an increase in follicular CD8+T cells with overactive STAT3 signaling

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Cellular & Molecular Immunology 2022年第9期19卷 1042-1053页

作者： hong-yi zheng Xue-Hui Wang Xiao-Yan He Min Chen Ming-Xu Zhang Xiao-Dong Lian Jia-Hao Song Yan Hu Wei Pang Yun Wang zheng-Fei Hu Long-Bao Lv 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 DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan650223China School of Life Sciences University of Science and Technology of ChinaHefeiAnhui230026China Kunming College of Life Science University of Chinese Academy of SciencesKunmingYunnan650204China 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 SciencesKunmingYunnan650107China

The number of elderly people living with HIV is increasing globally,and the condition of this population is relatively complicated due to the dual effects of aging and HIV ***,the impact of HIV infection combined with aging on the immune homeostasis of secondary lymphoid organs remains ***,we used the simian immunodeficiency virus mac239(SIVmac239)strain to infect six young and six old Chinese rhesus macaques(ChRMs)and compared the infection characteristics of the two groups in the chronic stage through multiplex immunofluorescence staining of lymph *** results showed that the SIV production and CD4/CD8 ratio inversion in old ChRMs were more severe than those in young ChRMs in both the peripheral blood and the lymph nodes,especially when a large number of CD8+T cells infiltrated the follicles and germinal ***3 in these follicular CXCR5+CD8+T cells was highly activated,with high expression of granzyme B,which might be caused by the severe inflammatory milieu in the follicles of old *** study indicates that aging may be a cofactor involved in SIV-induced immune disorders in secondary lymphoid tissues,affecting the effective antiviral activity of highly enriched follicular CXCR5+CD8+cells.

关键词： SIV Aging Follicle CD8 T cells

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