Corpus overview


MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ORF3a (1)

ORF6 (1)


SARS-CoV-2 Proteins
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    The K18- hACE2 HGNC Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 MESHD in Response to Infectious Dose of SARS-CoV-2 Virus


    doi:10.1101/2021.05.08.443244 Date: 2021-05-09 Source: bioRxiv

    A comprehensive analysis and characterization of a SARS-CoV-2 infection MESHD model that mimics non-severe and severe COVID-19 MESHD in humans is warranted for understating the virus and developing preventive and therapeutic agents. Here, we characterized the K18- hACE2 HGNC mouse model expressing human (h) ACE2 HGNC in mice, controlled by the human keratin 18 HGNC ( K18 HGNC) promoter, in epithelia, including airway epithelial cells where SARS-CoV-2 infections MESHD typically start. We found that intranasal inoculation with higher viral doses (2x103 and 2x104 PFU) of SARS-CoV-2 caused lethality of all mice and severe damage of various organs, including lungs, liver, and kidney MESHD, while lower doses (2x101 and 2x102 PFU) led to less severe tissue damage and some mice recovered from the infection. In this humanized hACE2 HGNC mouse model, SARS-CoV-2 infection MESHD damaged multiple tissues, with a dose-dependent effect in most tissues. Similar damage was observed in biopsy samples from COVID-19 MESHD patients. Finally, the mice that recovered after infection with a low dose of virus also survived rechallenge with a high dose of virus. Compared to other existing models, the K18- hACE2 HGNC model seems to be the most sensitive COVID-19 MESHD model reported to date. Our work expands the information available about this model to include analysis of multiple infectious doses and various tissues with comparison to human biopsy samples from COVID-19 MESHD patients. In conclusion, the K18- hACE2 HGNC mouse model recapitulates both severe and non-severe COVID-19 MESHD in humans and can provide insight into disease progression and the efficacy of therapeutics for preventing or treating COVID-19 MESHD.

    Contribution of SARS-CoV-2 accessory proteins to viral pathogenicity in K18 hACE2 HGNC transgenic mice


    doi:10.1101/2021.03.09.434696 Date: 2021-03-12 Source: bioRxiv

    Severe Acute Respiratory Syndrome coronavirus 2 MESHD (SARS-CoV-2) is the viral pathogen responsible for the current coronavirus disease 2019 MESHD ( COVID-19 MESHD) pandemic. To date, it is estimated that over 113 million individuals have been infected with SARS-CoV-2 and over 2.5 million human deaths have been recorded worldwide. Currently, three vaccines have been approved by the Food and Drug Administration for emergency use only. However much of the pathogenesis observed during SARS-CoV-2 infection MESHD remains elusive. To gain insight into the contribution of individual accessory open reading frame (ORF) proteins in SARS-CoV-2 pathogenesis, we used our recently described reverse genetics system approach to successfully engineer recombinant (r)SARS-CoV-2, where we individually removed viral 3a, 6, 7a, 7b, and 8 ORF proteins, and characterized these recombinant viruses in vitro and in vivo. Our results indicate differences in plaque morphology, with ORF deficient MESHD (DORF) viruses producing smaller plaques than those of the wild-type (rSARS-CoV-2/WT). However, growth kinetics of DORF viruses were like those of rSARS-CoV-2/WT. Interestingly, infection of K18 HGNC human angiotensin converting enzyme 2 HGNC ( hACE2 HGNC) transgenic mice with the DORF rSARS-CoV-2 identified ORF3a PROTEIN and ORF6 PROTEIN as the major contributors of viral pathogenesis, while DORF7a, DORF7b and DORF8 rSARS-CoV-2 induced comparable pathology to rSARS-CoV-2/WT. This study demonstrates the robustness of our reverse genetics system to generate rSARS-CoV-2 and the major role for ORF3a PROTEIN and ORF6 PROTEIN in viral pathogenesis, providing important information for the generation of attenuated forms of SARS-CoV-2 for their implementation as live-attenuated vaccines for the treatment of SARS-CoV-2 infection MESHD and associated COVID-19 MESHD.

    Fatal neuroinvasion of SARS-CoV-2 in K18- hACE2 HGNC mice is partially dependent on hACE2 HGNC expression

    Authors: Mariano Carossino; Paige Montanaro; Devin Kenney; Hans Gertje; Kyle Grosz; Susanna Kurnick; Markus Bosmann; Mohsan Saeed; Udeni Balasuriya; Florian Douam; Nicholas Crossland; Madison M Hebert; Scott W Benzinger; Koushik T Sinha; Keith T Gagnon; Rafael Rezende; Eduardo Cilli; Guilherme Malafaia; Nicholas Thomson; Caroline Buckee; Firdausi Qadri; Tahmina Shirin

    doi:10.1101/2021.01.13.425144 Date: 2021-01-13 Source: bioRxiv

    Animal models recapitulating the distinctive features of severe COVID-19 MESHD are critical to enhance our understanding of SARS-CoV-2 pathogenesis. Transgenic mice expressing human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) under the cytokeratin 18 promoter ( K18 HGNC- hACE2 HGNC) represent a lethal model of SARS-CoV-2 infection MESHD. However, the cause(s) and mechanisms of lethality in this mouse model remain unclear. Here, we evaluated the spatiotemporal dynamics of SARS-CoV-2 infection MESHD for up to 14 days post-infection. Despite infection and moderate inflammation MESHD in the lungs, lethality was invariably associated with viral neuroinvasion and neuronal damage MESHD (including spinal motor neurons). Neuroinvasion occurred following virus transport through the olfactory neuroepithelium in a manner that was only partially dependent on hACE2 HGNC. Interestingly, SARS-CoV-2 tropism MESHD was overall neither widespread among nor restricted to only ACE2-expressing cells. Although our work incites caution in the utility of the K18- hACE2 HGNC model to study global aspects of SARS-CoV-2 pathogenesis, it underscores this model as a unique platform for exploring the mechanisms of SARS-CoV-2 neuropathogenesis MESHD. SUMMARY COVID-19 MESHD is a respiratory disease MESHD caused by SARS-CoV-2, a betacoronavirus. Here, we show that in a widely used transgenic mouse model of COVID-19 MESHD, lethality is invariably associated with viral neuroinvasion and the ensuing neuronal disease MESHD, while lung inflammation MESHD remains moderate.

    SARS-CoV-2 infection MESHD in the lungs of human ACE2 HGNC transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

    Authors: Emma S Winkler; Adam L Bailey; Natasha M Kafai; Sharmila Nair; Broc T McCune; Jinsheng Yu; Julie M Fox; Rita E Chen; James T Earnest; Shamus P Keeler; Jon H Ritter; Liang-I Kang; Sarah Dort; Annette Robichaud; Richard Head; Michael J Holtzman; Michael S Diamond

    doi:10.1101/2020.07.09.196188 Date: 2020-07-10 Source: bioRxiv

    Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 MESHD ( COVID-19 MESHD) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection MESHD, none have recapitulated the severe lung disease MESHD phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 HGNC receptor driven by the epithelial cell cytokeratin-18 HGNC gene promoter ( K18 HGNC- hACE2 HGNC) as a model of SARS-CoV-2 infection MESHD. Intranasal inoculation of SARS-CoV-2 in K18- hACE2 HGNC mice results in high levels of viral infection MESHD in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia MESHD. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung MESHD tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18 HGNC- hACE2 HGNC model of SARS-CoV-2 infection MESHD recapitulates many features of severe COVID-19 MESHD infection in humans and can be used to define the mechanistic basis of lung disease MESHD and test immune and antiviral-based countermeasures.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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