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Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE184657 | GEO | 2021/11/23

REPOSITORIES: GEO

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

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

Modelling SARS-CoV-2 Infection in Mice Using Lentiviral hACE2 Vectors Suggests Two Modes of Immune Responses to SARS-CoV-2 Infection

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2021-12-07 | GSE186167 | GEO

Infiltrating Monocytes Drive Cardiac Dysfunction in a Cardiomyocyte-Restricted Model of SARS-CoV-2 Infection

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2023-12-31 | GSE239372 | GEO

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2023-01-09 | PXD038005 | Pride

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2022-06-30 | GSE174382 | GEO

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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

COVID-19 and influenza infections mediate distinct pulmonary cellular and transcriptomic changes [RNA-seq]

2023-12-02 | GSE248773 | GEO

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Project description:The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity in male animals. In order to identify other mechanisms by which SCFAs influence the outcome of SARS-CoV-2 infection, we performed RNA-seq on lungs from male GF mice given control or SCFA water for two weeks. We identified a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria that might be leveraged as pan-coronavirus therapeutics to dampen viral entry and hypercoagulation and promote adaptive anti-viral immunity.

2022-08-02 | GSE189792 | GEO

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2022-08-02 | GSE189791 | GEO

Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19.

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

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