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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-323719

ABSTRACT

The SARS-CoV-2 has led to a worldwide health crisis. The ACE2 has been identified as the entry receptor in a species-specific manner. Classic laboratory mice were insusceptible since the virus cannot use murine ACE2 orthologue. Animal models rely on gene modification on the virus or the host. However, these mice were restricted in limited genetic backgrounds and did not support natural infection. Here we showed two wild-type inbred lines (CAST and FEW) from Genetic Diversity mice supported authentic SARS-CoV-2 infection, and developed mild to moderate interstitial pneumonia, along with infiltrating inflammatory cells. Particularly, FEW featured age-dependent damages, while CAST charactered by pulmonary fibrosis. Genome and transcriptome comparative analysis suggested the mutated ACE2 was not responsible for SARS-CoV-2 infection in CAST and FEW, and the differential gene expressions in immune response and immune cell may be risk factors for the infection. In summary, the GD mice, derived from the multi-parental panel, provided promising murine models for exploring sophisticated pathogenesis in SARS-CoV-2.

2.
Signal Transduct Target Ther ; 7(1): 29, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1655546

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.


Subject(s)
COVID-19/metabolism , Lung/metabolism , Macrophages, Alveolar/metabolism , Metabolome , Mink/virology , SARS-CoV-2/metabolism , Amino Acids/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/pathology , Disease Models, Animal , Female , Humans , Lung/pathology , Lung/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/virology , Melatonin/metabolism , Metabolic Networks and Pathways/genetics , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sterols/metabolism , Virulence , Virus Replication/genetics
3.
Animal Model Exp Med ; 4(1): 2-15, 2021 03.
Article in English | MEDLINE | ID: covidwho-1122088

ABSTRACT

Background: Cardiovascular diseases (CVDs) and diabetes mellitus (DM) are top two chronic comorbidities that increase the severity and mortality of COVID-19. However, how SARS-CoV-2 alters the progression of chronic diseases remain unclear. Methods: We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice. SARS-CoV-2's impacts on pathogenesis of chronic diseases were studied through histopathological, virologic and molecular biology analysis. Results: Pre-existing CVDs resulted in viral invasion, ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection. Viral infection increased fasting blood glucose and reduced insulin response in DM model. Bone mineral density decreased shortly after infection, which associated with impaired PI3K/AKT/mTOR signaling. Conclusion: We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases. Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection, which further aggravated the pre-existing diseases. This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.


Subject(s)
COVID-19/complications , COVID-19/physiopathology , Cardiovascular Diseases/complications , Cardiovascular Diseases/physiopathology , Diabetes Complications/physiopathology , Animals , Comorbidity , Diabetes Mellitus , Disease Models, Animal , Male , Mice , SARS-CoV-2
4.
J Infect Dis ; 223(8): 1313-1321, 2021 04 23.
Article in English | MEDLINE | ID: covidwho-1091239

ABSTRACT

Domestic cats, an important companion animal, can be infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This has aroused concern regarding the ability of domestic cats to spread the virus that causes coronavirus disease 2019. We systematically demonstrated the pathogenesis and transmissibility of SARS-CoV-2 in cats. Serial passaging of the virus between cats dramatically attenuated the viral transmissibility, likely owing to variations of the amino acids in the receptor-binding domain sites of angiotensin-converting enzyme 2 between humans and cats. These findings provide insight into the transmissibility of SARS-CoV-2 in cats and information for protecting the health of humans and cats.


Subject(s)
COVID-19/transmission , COVID-19/veterinary , SARS-CoV-2/pathogenicity , Amino Acids/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/metabolism , Cats , Cell Line , Chlorocebus aethiops , Female , Humans , Male , Vero Cells
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