Retinoid X Receptors

COVID-19 patients also show heightened IL-4 and IL-10 levels, cytokines associated with inhibitory inflammatory responses [41]

COVID-19 patients also show heightened IL-4 and IL-10 levels, cytokines associated with inhibitory inflammatory responses [41]. of lymphocytes in the 21 DPI lung composed of G. CD45+ B cells and H. CD3+ T cells. Magnification: a = 40x; b, c, f, g, h = 200x; d, e = 400x.(TIF) ppat.1009195.s002.tif (9.9M) GUID:?A44BA1C3-5DCE-4C26-95BA-516008AC668B S3 Fig: Multiplex analysis of cytokines/chemokines in K18-hACE mice challenged with SARS-CoV-2 measured at 3- and 7-days post inoculation. A. Individual animals are plotted, violin plots depict median and quantiles. Low dose = blue, high dose = red. B. Correlation between cytokine levels and viral RNA in the lungs. Significant correlations (p = 0.05) are shown and strength of correlation is depicted according to the colour bar, crossed bars are not significant. Abbreviations: DPI = days post inoculation, G-CSF = granulocyte colony-stimulating factor, GM-CSF = granulocyte-macrophage colony-stimulating factor, INF = interferon, IL = interleukin, KC = keratinocyte chemoattractant, MCP = monocyte chemoattractant protein, MIP = macrophage inflammatory protein, IP = interferon–inducible protein, TNF = tumour necrosis factor.(TIF) ppat.1009195.s003.tif (2.7M) GUID:?A3A4C975-99F3-4FBE-96E8-856AC0AECA1D S4 Fig: Depletion efficiency of NK-cell and Gr-1 depletion in SARS-CoV-2 infection in K18-hACE mice. A. Depletion efficiency Thbd was decided on 0, 3 and 7 DPI in blood and cis-Urocanic acid on 3 and 7 DPI in lung. Gr-1 population (bottom) was defined as CD45+ Gr-1+, NK1.1 population (top) as CD45+, CD3- and NK1.1+. Differences to control animals were determined by Kruskal-Wallis test.(TIF) ppat.1009195.s004.tif (2.7M) GUID:?F3905119-76FF-431B-A986-E85B7B4C72B4 S1 Table: Histologic findings in K18 hACE2 mice associated with SARS-CoV-2 contamination. (XLSX) ppat.1009195.s005.xlsx (15K) GUID:?51401F9A-28FB-41AF-9C3B-552CC2009A1A Data Availability StatementAll relevant data are within the manuscript and its Supporting Information files. Data is available at data repository: https://figshare.com/articles/dataset/K18-hACE2_mice_develop_respiratory_disease_resembling_severe_COVID-19/12836813. Abstract SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked cis-Urocanic acid medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that contamination resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 contamination resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract contamination with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 contamination resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of cis-Urocanic acid several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a moderate disease course can be simulated by low dose contamination with 102 TCID50 SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development. Author summary The disease manifestation of COVID-19 in humans ranges from asymptomatic to severe. While several moderate to moderate disease models have.

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