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1.
Zool Res ; 43(1): 1-2, 2022 01 18.
Article in English | MEDLINE | ID: covidwho-1627787
2.
EBioMedicine ; 75: 103803, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1587923

ABSTRACT

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has been a great threat to global public health since 2020. Although the advance on vaccine development has been largely achieved, a strategy to alleviate immune overactivation in severe COVID-19 patients is still needed. The NLRP3 inflammasome is activated upon SARS-CoV-2 infection and associated with COVID-19 severity. However, the processes by which the NLRP3 inflammasome is involved in COVID-19 disease remain unclear. METHODS: We infected THP-1 derived macrophages, NLRP3 knockout mice, and human ACE2 transgenic mice with live SARS-CoV-2 in Biosafety Level 3 (BSL-3) laboratory. We performed quantitative real-time PCR for targeted viral or host genes from SARS-CoV-2 infected mouse tissues, conducted histological or immunofluorescence analysis in SARS-CoV-2 infected mouse tissues. We also injected intranasally AAV-hACE2 or intraperitoneally NLRP3 inflammasome inhibitor MCC950 before SARS-CoV-2 infection in mice as indicated. FINDINGS: We have provided multiple lines of evidence that the NLRP3 inflammasome plays an important role in the host immune response to SARS-CoV-2 invasion of the lungs. Inhibition of the NLRP3 inflammasome attenuated the release of COVID-19 related pro-inflammatory cytokines in cell cultures and mice. The severe pathology induced by SARS-CoV-2 in lung tissues was reduced in Nlrp3-/- mice compared to wild-type C57BL/6 mice. Finally, specific inhibition of the NLRP3 inflammasome by MCC950 alleviated excessive lung inflammation and thus COVID-19 like pathology in human ACE2 transgenic mice. INTERPRETATION: Inflammatory activation induced by SARS-CoV-2 is an important stimulator of COVID-19 related immunopathology. Targeting the NLRP3 inflammasome is a promising immune intervention against severe COVID-19 disease. FUNDING: This work was supported by grants from the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to Y.G.Y.), the key project of the CAS "Light of West China" Program (to D.Y.) and Yunnan Province (202001AS070023 to D.Y.).


Subject(s)
COVID-19 , Lung , Macrophages , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Disease Models, Animal , Humans , Lung/immunology , Lung/pathology , Lung/virology , Macrophages/immunology , Macrophages/pathology , Macrophages/virology , Male , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , SARS-CoV-2/genetics , THP-1 Cells
3.
Zool Res ; 42(6): 834-844, 2021 11 18.
Article in English | MEDLINE | ID: covidwho-1515719

ABSTRACT

Understanding the zoonotic origin and evolution history of SARS-CoV-2 will provide critical insights for alerting and preventing future outbreaks. A significant gap remains for the possible role of pangolins as a reservoir of SARS-CoV-2 related coronaviruses (SC2r-CoVs). Here, we screened SC2r-CoVs in 172 samples from 163 pangolin individuals of four species, and detected positive signals in muscles of four Manis javanica and, for the first time, one M. pentadactyla. Phylogeographic analysis of pangolin mitochondrial DNA traced their origins from Southeast Asia. Using in-solution hybridization capture sequencing, we assembled a partial pangolin SC2r-CoV (pangolin-CoV) genome sequence of 22 895 bp (MP20) from the M. pentadactyla sample. Phylogenetic analyses revealed MP20 was very closely related to pangolin-CoVs that were identified in M. javanica seized by Guangxi Customs. A genetic contribution of bat coronavirus to pangolin-CoVs via recombination was indicated. Our analysis revealed that the genetic diversity of pangolin-CoVs is substantially higher than previously anticipated. Given the potential infectivity of pangolin-CoVs, the high genetic diversity of pangolin-CoVs alerts the ecological risk of zoonotic evolution and transmission of pathogenic SC2r-CoVs.


Subject(s)
COVID-19/veterinary , Evolution, Molecular , Pangolins/virology , SARS-CoV-2/genetics , Animals , Genome, Viral , Phylogeny , RNA, Viral/genetics
4.
Signal Transduct Target Ther ; 5(1): 294, 2020 12 24.
Article in English | MEDLINE | ID: covidwho-997816

ABSTRACT

Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for improving treatment. Here, we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell (PBMC) samples from 18 patients with coronavirus disease 2019 (COVID-19) during their treatment, convalescence, and rehabilitation. After analyzing the regulatory networks of differentially expressed messenger RNAs (mRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) between the different clinical stages, we found that humoral immunity and type I interferon response were significantly downregulated, while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19. The formation of this T cell immune response might be driven by the activation of activating protein-1 (AP-1) related signaling pathway and was weakly affected by other clinical features. These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.


Subject(s)
COVID-19/genetics , Immunity, Humoral/genetics , T-Lymphocytes/metabolism , Transcriptome/genetics , COVID-19/epidemiology , COVID-19/pathology , Female , Humans , Immunity, Humoral/immunology , Leukocytes, Mononuclear/metabolism , Male , MicroRNAs , RNA, Long Noncoding/genetics , RNA-Seq , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , T-Lymphocytes/pathology , Transcription Factor AP-1/genetics
5.
Zool Res ; 41(5): 517-526, 2020 Sep 18.
Article in English | MEDLINE | ID: covidwho-671953

ABSTRACT

The coronavirus disease 2019 (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 post-inoculation (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.


Subject(s)
Betacoronavirus/growth & development , Coronavirus Infections/diagnosis , Disease Models, Animal , Lung/pathology , Pneumonia, Viral/diagnosis , Tupaiidae/physiology , Age Factors , Animals , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/transmission , Coronavirus Infections/virology , Female , Humans , Lung/virology , Male , Pandemics , Pneumonia, Viral/transmission , Pneumonia, Viral/virology , SARS-CoV-2 , Tupaiidae/virology , Virus Shedding/physiology
6.
Zool Res ; 41(3): 213-219, 2020 May 18.
Article in English | MEDLINE | ID: covidwho-210902

ABSTRACT

The ongoing pandemic of coronavirus disease 2019 (COVID-19), caused by infection with human coronavirus 2019 (HCoV-19 / SARS-CoV-2 / 2019-nCoV), is a global threat to the human population. Here, we briefly summarize the available data for the zoonotic origins of HCoV-19, with reference to the other two epidemics of highly virulent coronaviruses, SARS-CoV and MERS-CoV, which cause severe pneumonia in humans. We propose to intensify future efforts for tracing the origins of HCoV-19, which is a very important scientific question for the control and prevention of the pandemic.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/transmission , Pneumonia, Viral/transmission , Zoonoses , Animals , COVID-19 , Coronavirus Infections/virology , Disease Reservoirs , Humans , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
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