Delta (B1.617.2) variant of SARS-CoV-2 induces severe neurotropic patterns in K18-hACE2 mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214516 | GEO | 2023/03/08
REPOSITORIES: GEO
Similar Datasets
Project description:A highly contagious virus, severe acute respiratory syndrome coronavirus 2, caused the coronavirus disease 19 (COVID-19) pandemic (SARS-CoV-2). SARS-CoV-2 genetic variants have been reported to circulate throughout the COVID-19 pandemic. COVID-19 symptoms include respiratory symptoms, fever, muscle pain, and breathing difficulty. In addition, up to 30% of COVID-19 patients experience neurological complications such as headaches, nausea, stroke, and anosmia. However, the neurotropism of SARS-CoV-2 infection remains largely unknown. This study investigated the neurotropic patterns between the B1.617.2 (Delta) and Hu-1 variants (Wuhan, early strain) in K18-hACE2 mice. Despite both the variants inducing similar pathogenic patterns in various organs, B1.617.2-infected K18-hACE2 mice demonstrated a higher range of disease phenotypes such as weight loss, lethality, and conjunctivitis when compared to those in Hu-1-infected mice. In addition, histopathological analysis revealed that B1.617.2 infects the brain of K18-hACE2 mice more rapidly and effectively than Hu-1. Finally, we discovered that, in B1.617.2-infected mice, the early activation of various signature genes involved innate cytokines and that the necrosis-related response was most pronounced than that in Hu-1-infected mice. The present findings indicate the neuroinvasive properties of SARS-CoV-2 variants in K18-hACE2 mice and link them to fatal neuro-dissemination during the disease onset.
| S-EPMC9970970 | biostudies-literature
Project description:The SARS-CoV-2 Delta variant is more contagious than WT and causes severe symptoms.To understand the elevated fusogenicity of Delta, we used LC-MS/MS to characterize the site specific N-linked glycan of spike protein in SARS-CoV-2 Delta variant virions.The glycan analysis revealed increased oligomannose-type glycosylation of native Delta spike over that of the Wuhan-Hu-1 spike.
2023-05-10 | PXD033342 | Pride
Project description:Obesity is a risk factor for developing severe COVID-19. However, the mechanism underlying obesity-accelerated COVID-19 remains unclear. Here, we report results from a study in which K18-hACE2 mice were fed an obesity-inducing western diet (WD) for over 3 months before intranasal infection with SARS-CoV2. After infection, the WD-fed K18-hACE2 mice lost more body weight and had more severe lung inflammation than normal chow (NC)-fed mice. Bulk RNAseq analysis of lungs and adipose tissue revealed that a diverse landscape of various immune cells, inflammatory markers, and pathways are upregulated in obese COVID-19 patients or the WD-fed K18-hACE2 mice when compared with their respective control groups. When compared with infected NC-fed mice in the lung, the infected WD-fed mice had upregulation of IL-6, a well-established marker for severe COVID-19. These results indicate that obesity-accelerated severe COVID-19 caused by SARS-CoV-2 infection in the K18-hACE2 mouse model can be used for dissecting the cellular and molecular mechanisms underlying pathogenesis. Furthermore, in the transcriptome analysis of the lung and adipose tissue obtained from deceased COVID-19 patients, we found upregulation of an array of genes and pathways associated with Inflammation. Both the K18-hACE2 mouse model and human COVID-19 patient data support a link between inflammation and an obesity-accelerated COVID-19 disease phenotype.
2024-05-21 | GSE267021 | GEO
Project description:We evaluate heterozygous transgenic mice expressing human ACE2 receptor driven by the epithelial cell promoter cytokeratin-18 promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of K18-hACE2 mice with SARS-CoV-2 results in high levels of infection in the lung parenchyma with spread to other organs.
2020-07-29 | GSE154104 | GEO
Project description:Mouse metagenome strain:K18-hACE2 Raw sequence reads
| PRJNA722991 | ENA
Project description:The COVID-19 pandemic is an infectious disease caused by SARS-CoV-2. The first step of SARS-CoV-2 infection is the recognition of angiotensin-converting enzyme 2 (hACE2) receptors by the receptor-binding domain (RBD) of the viral spike (S) glycoprotein. Although the molecular and structural bases of the SARS-CoV-2-RBD/hACE2 interaction have been thoroughly investigated in vitro, the relationship between hACE2 expression and in vivo infection is less understood. Here, we developed an efficient SARS-CoV-2-RBD binding assay suitable for super resolution microscopy and simultaneous hACE2 immunodetection and mapped the correlation between hACE2 receptor abundance and SARS-CoV-2-RBD binding, both in vitro and in human lung biopsies. Next, we explored the specific proteome of SARS-CoV-2-RBD/hACE2 through a comparative mass spectrometry approach. We found that only a minority of hACE2 positive spots are actually SARS-CoV-2-RBD binding sites, and that the relationship between SARS-CoV-2-RBD binding and hACE2 presence is variable, suggesting the existence of additional factors. Indeed, we found several interactors that are involved in receptor localization and viral entry and characterized one of them: SLC1A5, an amino acid transporter. High-resolution receptor-binding studies showed that co-expression of membrane-bound SLC1A5 with hACE2 predicted SARS-CoV-2 binding and entry better than hACE2 expression alone. Accordingly, SLC1A5 depletion reduces SARS-CoV-2 binding and entry. Notably, the Omicron variant is more efficient in binding hACE2 sites, but equally sensitive to SLC1A5 downregulation. We propose a method for mapping functional SARS-CoV-2 receptors in vivo. We confirm the existence of hACE2 co-factors that may contribute to differential sensitivity of cells to infection.
2023-01-09 | PXD038005 | Pride
Project description:hACE2 transgenic mice were infected with the original SARS-CoV-2 strain (B.1) and the Beta (B.1.351) variant. Lung and spleen samples were collected 1 day post infection (DPI), 3 DPI and 5 DPI, and mRNA was sequenced.
2023-09-22 | E-MTAB-13308 | biostudies-arrayexpress
Project description:Viral variant is one known risk factor associated with post-acute sequelae of COVID-19 (PASC), yet the pathogenesis is largely unknown. We studied SARS-CoV-2 Delta variant-induced PASC in K18-hACE2 mice. The virus replicated productively, induced robust inflammatory responses in lung and brain tissues, and caused weight loss and mortality during the acute infection. Longitudinal behavior studies, in surviving mice up to 4 months post-acute infection, revealed persistent abnormalities in neuropsychiatric state and motor behaviors, while reflex and sensory functions recovered over time. Surviving mice showed no detectable viral RNA in the brain and minimal neuroinflammation post-acute infection. Transcriptome analysis revealed persistent activation of immune pathways, including humoral responses, complement, and phagocytosis, and reduced levels of genes associated with ataxia telangiectasia, impaired cognitive function and memory recall, and neuronal dysfunction and degeneration. Furthermore, surviving mice maintained potent T helper 1 prone cellular immune responses and high neutralizing antibodies in the periphery for months post-acute infection. Overall, infection in K18-hACE2 mice recapitulates the persistent clinical symptoms reported in long COVID patients.
2024-04-15 | GSE260625 | GEO
Project description:Age-matched K18-hACE2 transgenic mice were passively transferred with human COVID-19 mRNA post-vaccination (post-vac) sera followed by the lethal challenge with different SARS-CoV-2 viruses via intranasal route, including (1) New York-PV09158/2020 (NY) of lineage B.1.3 bearing 614G, (2) Kappa (B.1.617.1) and (3) Delta (B.1.617.2). Mouse lungs were harvested on 5 days post infection (dpi). Total RNA was extracted using QIAgen RNeasy Plus Mini Kit and was reverse transcribed using the High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). Resultant cDNA was used as the template along with RT2 SYBR Green ROX qPCR Mastermix (Qiagen) to perform RT² Profiler™ PCR Array Mouse Hypoxia Signaling Pathway (Qiagen) real-time PCR in Stratagene MX3000p qPCR system.
2022-11-21 | GSE193839 | GEO
Project description:The development of tractable animal models that faithfully reproduce COVID-19 pathogenesis would arguably be a major benefit. Infection of transgenic mice expressing the human version of the SARS-CoV-2 receptor (hACE2) by intranasal instillation of a liquid SARS-CoV-2 suspension under deep anesthesia results in disproportionate high CNS infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the characterization of a novel COVID-19 mouse model based on an inhalation tower system that allows to expose unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction, but did not lead to fatal viral neuroinvasion. When compared to intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition and a transcriptional signature comparable to that observed in humans. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection) and therapeutic interventions.
2021-11-23 | GSE184657 | GEO