Ontology highlight
ABSTRACT:
PROVIDER: PRJNA875205 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21360700_1.fastq.gz | Fastqsanger.gz | |||
| SRR21360700_2.fastq.gz | Fastqsanger.gz | |||
| SRR21360701_1.fastq.gz | Fastqsanger.gz | |||
| SRR21360701_2.fastq.gz | Fastqsanger.gz | |||
| SRR21360702_1.fastq.gz | Fastqsanger.gz |
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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:Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19), with effective versus dysregulated responses influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the diverse genetic backgrounds of the Collaborative Cross founder strains crossed to K18-hACE2 mice that confers high susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 F1 progeny resulted in a spectrum of weight loss, survival, viral replication kinetics, histopathology, and cytokine profiles, some of which were sex-specific. Importantly, early kinetics of type I interferon (IFN) responses, and a regulated proinflammatory response were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to severe disease. Thus, dynamics of inflammatory responses observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding antiviral immunity.
2023-06-07 | GSE231711 | GEO
Project description:SARS-CoV-2 infection can cause persistent respiratory sequelae, as seen in long COVID. However, the underlying mechanisms remain unclear. To investigate pulmonary cellular and transcriptomic changes mediated by SARS-CoV-2 and influenza infection, we characterized the SARS-CoV-2-infected K18-hACE2 (K18) mice and compared their lung recovery with a mouse-adapted influenza model and verified the finding in SARS-CoV-2-infected nonhuman primates and in fatal human COVID-19 cases. K18-hACE2 mice infected with a sub-lethal dose of SARS-CoV-2 lost body weight from 1 - 8 days post-infection (DPI), and then gradually returned to baseline weight between 8 -13 DPI. Infected mice showed patchy pneumonia associated with histiocytic inflammation, collagen deposition, and increased pulmonary interferon and inflammatory response signature gene changes at 21 and 45 DPI. Transcriptomic analyses revealed that compared to influenza-infected mice, SARS-CoV-2-infected mice had reduced interferon-gamma/alpha responses at 4 DPI and failed to induce keratin 5 (Krt5) at 6 DPI in lung, a marker of nascent pulmonary progenitor cells. They also showed reduced activation of epithelial-to-mesenchymal transition and apical junction pathways compared to influenza (Flu)-infected mice. Histologically, influenza- but not SARS-CoV-2- infected mice showed extensive Krt5+ “pods” structure co-stained with stem cell markers Trp63/ NGFR proliferated in the pulmonary consolidation area at both 7 and 14 DPI, with regression at 21 DPI. These Krt5+ “pods” and proliferative stem cells were not observed in SARS-CoV-2 infection in the lungs of humans or nonhuman primates. These results suggest that SARS-CoV-2 infection fails to induce nascent Krt5+ cell proliferation in consolidated regions, leading to incomplete repair of the injured lung which may underlie the persistent clinical symptoms of long COVID.
2023-12-02 | GSE248775 | GEO
Project description:SARS-CoV-2 infection can cause persistent respiratory sequelae, as seen in long COVID. However, the underlying mechanisms remain unclear. To investigate pulmonary cellular and transcriptomic changes mediated by SARS-CoV-2 and influenza infection, we characterized the SARS-CoV-2-infected K18-hACE2 (K18) mice and compared their lung recovery with a mouse-adapted influenza model and verified the finding in SARS-CoV-2-infected nonhuman primates and in fatal human COVID-19 cases. K18-hACE2 mice infected with a sub-lethal dose of SARS-CoV-2 lost body weight from 1 - 8 days post-infection (DPI), and then gradually returned to baseline weight between 8 -13 DPI. Infected mice showed patchy pneumonia associated with histiocytic inflammation, collagen deposition, and increased pulmonary interferon and inflammatory response signature gene changes at 21 and 45 DPI. Transcriptomic analyses revealed that compared to influenza-infected mice, SARS-CoV-2-infected mice had reduced interferon-gamma/alpha responses at 4 DPI and failed to induce keratin 5 (Krt5) at 6 DPI in lung, a marker of nascent pulmonary progenitor cells. They also showed reduced activation of epithelial-to-mesenchymal transition and apical junction pathways compared to influenza (Flu)-infected mice. Histologically, influenza- but not SARS-CoV-2- infected mice showed extensive Krt5+ “pods” structure co-stained with stem cell markers Trp63/ NGFR proliferated in the pulmonary consolidation area at both 7 and 14 DPI, with regression at 21 DPI. These Krt5+ “pods” and proliferative stem cells were not observed in SARS-CoV-2 infection in the lungs of humans or nonhuman primates. These results suggest that SARS-CoV-2 infection fails to induce nascent Krt5+ cell proliferation in consolidated regions, leading to incomplete repair of the injured lung which may underlie the persistent clinical symptoms of long COVID.
2023-12-02 | GSE248773 | 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
Project description:Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using a Hutchinson-Gilford progeria syndrome (HGPS) mouse model with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SAR-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract bleeding, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a valuable tool for investigating COVID-19 pathogenesis in individuals with premature aging.
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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.
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Project description:In order to research the relationship between neurological sequelae of COVID-19 and acetylation of brain cortexes, we reported for the first time the acetylome in the brain cortex of the K18-hACE2 infected mouse model, and the difference between the SARS-CoV-2 infection group and the control group, which found the largest amount of acetylated proteins in the brain cortex of the mouse to date, greatly expanding the existing database of acetylome. Besides, it would also lay a foundation for the subsequent research on the pathogenesis and treatment of COVID-19 patients.
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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.
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Project description:Rapid emergence of antigenic distinct SARS-CoV-2 variants implies a greater risk of reinfection as viruses can escape neutralizing antibodies induced by vaccination or previous viral exposure. Disease severity during COVID-19 depends on many variables such as age-related comorbidities, host immune status and genetic variation. The host immune response during infection with SARS-CoV-2 may contribute to disease severity, which can range from asymptomatic to severe with fatal outcome. Furthermore, the extent of host immune response activation may rely on underlying genetic predisposition for disease or protection. To address these questions, we performed immune profiling studies in mice with different genetic backgrounds - transgenic K18-hACE2 and wild-type 129S1 mice – subjected to reinfection with the severe disease-causing SARS-CoV-2 B.1.351 variant, 30 days after experimental milder BA.1 infection. BA.1 preinfection conferred protection against B.1.351-induced morbidity in K18-hACE2 mice but aggravated disease in 129S1 mice. We found that he cytokine/chemokine profile in B.1.351 re-infected 129S1mice is similar to that during severe SARS-CoV-2 infection in humans and is characterized by a much higher level of IL-10, IL-1β, IL-18 and IFN-γ , whereas in B.1.351 re-infected K18-hACE2 mice, the cytokine profile echoes the signature of naïve mice undergoing viral infection for the first time. Interestingly, the enhanced pathology observed in 129S1 mice upon reinfection cannot be attributed to a less efficient induction of adaptive immune responses to the initial BA.1 infection, as both K18-hACE2 and 129S1 mice exhibited similar B and T cell responses at 30 DPI against BA.1, with similar anti-BA.1 or B.1.351 spike-specific ELISA binding titers, levels of germinal center B-cells, and SARS-CoV-2-Spike specific tissue-resident T-cells. Long-term effects of BA.1 infection are associated with differential transcriptional changes in bronchoalveolar lavage-derived CD11c+ immune cells from K18-hACE2 and 129S1, with K18-hACE2 CD11c+ cells showing a strong antiviral defense gene expression profile whereas 129S1 CD11c+ cells showed a more pro-inflammatory response. In conclusion, initial infection with BA.1 induces cross-reactive adaptive immune responses in both K18-hACE2 and 129S1 mice, however the different disease outcome of reinfection seems to be driven by differential responses of CD11c+ cells in the alveolar space.
2024-10-23 | GSE248984 | GEO