scholarly journals Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice

2020 ◽  
Author(s):  
Fatai S. Oladunni ◽  
Jun-Gyu Park ◽  
Paula Pino Tamayo ◽  
Olga Gonzalez ◽  
Anwari Akhter ◽  
...  
Keyword(s):  
Animal Model ◽  
Transgenic Mice ◽  
Angiotensin Converting Enzyme ◽  
Small Animal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Suitable Animal Model ◽  
The Brain ◽  
Identification And Characterization

ABSTRACTVaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease currently lacks a validated small animal model. Here, we show that transgenic mice expressing human angiotensin converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2-transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2-transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 4. K18 hACE2-transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

scholarly journals Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Fatai S. Oladunni ◽  
Jun-Gyu Park ◽  
Paula A. Pino ◽  
Olga Gonzalez ◽  
Anwari Akhter ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Angiotensin Converting Enzyme ◽  
Small Animal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Suitable Animal Model ◽  
Small Animal Models ◽  
The Brain ◽  
Identification And Characterization

AbstractVaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

scholarly journals Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

2020 ◽  
Author(s):  
Joseph W. Golden ◽  
Curtis R. Cline ◽  
Xiankun Zeng ◽  
Aura R. Garrison ◽  
Brian D. Carey ◽  
...  
Keyword(s):  
Lung Injury ◽  
Transgenic Mice ◽  
Angiotensin Converting Enzyme ◽  
Small Animal ◽  
Infection Model ◽  
Converting Enzyme ◽  
Male Mice ◽  
Health Crisis ◽  
Angiotensin Converting Enzyme 2 ◽  
Female Mice

ABSTRACTThe emergence of SARS-CoV-2 has created an international health crisis. Small animal models mirroring SARS-CoV-2 human disease are essential for medical countermeasure (MCM) development. Mice are refractory to SARS-CoV-2 infection due to low affinity binding to the murine angiotensin-converting enzyme 2 (ACE2) protein. Here we evaluated the pathogenesis of SARS-CoV-2 in male and female mice expressing the human ACE2 gene under the control of the keratin 18 promotor. In contrast to non-transgenic mice, intranasal exposure of K18-hACE2 animals to two different doses of SARS-CoV-2 resulted in acute disease including weight loss, lung injury, brain infection and lethality. Vasculitis was the most prominent finding in the lungs of infected mice. Transcriptomic analysis from lungs of infected animals revealed increases in transcripts involved in lung injury and inflammatory cytokines. In the lower dose challenge groups, there was a survival advantage in the female mice with 60% surviving infection whereas all male mice succumbed to disease. Male mice that succumbed to disease had higher levels of inflammatory transcripts compared to female mice. This is the first highly lethal murine infection model for SARS-CoV-2. The K18-hACE2 murine model will be valuable for the study of SARS-CoV-2 pathogenesis and the assessment of MCMs.

Angiotensin Converting Enzyme 2 (ACE2) Expression in the Visual System

2021 ◽  
Author(s):  
James M. Hill ◽  
Christian Clement ◽  
L. Arceneaux ◽  
Walter Lukiw
Keyword(s):  
Signal Processing ◽  
Angiotensin Converting Enzyme ◽  
Occipital Lobe ◽  
Cell Types ◽  
Receptor Expression ◽  
Host Cells ◽  
Visual Signal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The Brain

Abstract Background: Multiple lines of evidence currently indicate that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)gains entry into human host cells via a high-affinity interaction with the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor. Research has further shown the widespread expression of the ACE2 receptor on the surface of many different immune, non-immune and neural host cell types, and that SARS-CoV-2 has there markable capability to attack many different types of human-host cells simultaneously. One principal neuroanatomical region for highACE2 expression patterns occurs in the brainstem, an area of the brain containing regulatory centers for respiration, and this may in part explain the predisposition of many COVID-19 patients to respiratory distress. Early studies also indicated extensive ACE2 expression in the whole eye and the brain’s visual circuitry. In this study we analyzed ACE2 receptor expression at the mRNA and protein level in multiple cell types involved in human vision, including cell types of the external eye and several deep brain regions known to be involved in the processing of visual signals.Methods: ACE2 mRNA and protein analysis; multiple eye and brain cells and tissues; gamma32P-adenosine tri-phosphate ([γ-32P]dATP) radiolabeled probes; Northern analysis; ELISA.Results: The four main findings were: (i)that many different optical and neural cell types of the human visual system provide receptors essential for SARS-CoV-2 invasion; (ii)the remarkable ubiquity of ACE2 presence in cells of the eye and anatomical regions of the brain involved in visual signal processing; (iii)that ACE2 receptor expression in different ocular cell types and visual processing centers of the brain provide multiple compartments for SARS-CoV-2 infiltration; and (iv)a gradient of increasing ACE2 expression from the anterior surface of the eye to the visual signal processing areas of the occipital lobe and the primary visual neocortex.Conclusion: A gradient of ACE2 expression from the eye surface to the occipital lobe provide the SARS-CoV-2 virus a novel pathway from the outer eye into deeper anatomical regions of the brain involved in vision. These findings may explain, in part, the many recently reported neuro-ophthalmic manifestations of SARS-CoV-2infection in COVID-19 affected patients.

scholarly journals Differential Virological and Immunological Outcome of Severe Acute Respiratory Syndrome Coronavirus Infection in Susceptible and Resistant Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2

2009 ◽  
Vol 83 (11) ◽  
pp. 5451-5465 ◽  
Author(s):  
Naoko Yoshikawa ◽  
Tomoki Yoshikawa ◽  
Terence Hill ◽  
Cheng Huang ◽  
Douglas M. Watts ◽  
...  
Keyword(s):  
T Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Viral Infection ◽  
Inflammatory Responses ◽  
Fatal Outcome ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Inflammatory Infiltrates ◽  
The Brain

ABSTRACT We previously reported that transgenic (Tg) mice expressing human angiotensin-converting enzyme 2 (hACE2), the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), were highly susceptible to SARS-CoV infection, which resulted in the development of disease of various severity and even death in some lineages. In this study, we further characterized and compared the pathogeneses of SARS-CoV infection in two of the most stable Tg lineages, AC70 and AC22, representing those susceptible and resistant to the lethal SARS-CoV infection, respectively. The kinetics of virus replication and the inflammatory responses within the lungs and brains, as well as the clinical and pathological outcomes, were assessed in each lineage. In addition, we generated information on lymphocyte subsets and mitogen-mediated proliferation of splenocytes. We found that while both lineages were permissive to SARS-CoV infection, causing elevated secretion of many inflammatory mediators within the lungs and brains, viral infection appeared to be more intense in AC70 than in AC22 mice, especially in the brain. Moreover, such infection was accompanied by a more profound immune suppression in the former, as evidenced by the extensive loss of T cells, compromised responses to concanavalin A stimulation, and absence of inflammatory infiltrates within the brain. We also found that CD8+ T cells were partially effective in attenuating the pathogenesis of SARS-CoV infection in lethality-resistant AC22 mice. Collectively, our data revealed a more intense viral infection and immunosuppression in AC70 mice than in AC22 mice, thereby providing us with an immunopathogenic basis for the fatal outcome of SARS-CoV infection in the AC70 mice.

scholarly journals Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

JCI Insight ◽  
2020 ◽  
Vol 5 (19) ◽  
Author(s):  
Joseph W. Golden ◽  
Curtis R. Cline ◽  
Xiankun Zeng ◽  
Aura R. Garrison ◽  
Brian D. Carey ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Angiotensin Converting Enzyme ◽  
Respiratory Disease ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

scholarly journals Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2

Cell ◽  
2020 ◽  
Vol 182 (1) ◽  
pp. 50-58.e8 ◽  
Author(s):  
Ren-Di Jiang ◽  
Mei-Qin Liu ◽  
Ying Chen ◽  
Chao Shan ◽  
Yi-Wu Zhou ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2

scholarly journals Severe Acute Respiratory Syndrome Coronavirus Infection of Mice Transgenic for the Human Angiotensin-Converting Enzyme 2 Virus Receptor

2006 ◽  
Vol 81 (3) ◽  
pp. 1162-1173 ◽  
Author(s):  
Chien-Te K. Tseng ◽  
Cheng Huang ◽  
Patrick Newman ◽  
Nan Wang ◽  
Krishna Narayanan ◽  
...  
Keyword(s):  
Weight Loss ◽  
Severe Acute Respiratory Syndrome ◽  
Transgenic Mice ◽  
Angiotensin Converting Enzyme ◽  
Virus Replication ◽  
Clinical Manifestations ◽  
Converting Enzyme ◽  
Sars Coronavirus ◽  
Angiotensin Converting Enzyme 2 ◽  
Coronavirus Infection

ABSTRACT Animal models for severe acute respiratory syndrome (SARS) coronavirus infection of humans are needed to elucidate SARS pathogenesis and develop vaccines and antivirals. We developed transgenic mice expressing human angiotensin-converting enzyme 2, a functional receptor for the virus, under the regulation of a global promoter. A transgenic lineage, designated AC70, was among the best characterized against SARS coronavirus infection, showing weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection. High virus titers were detected in the lungs and brains of transgene-positive (Tg+) mice on days 1 and 3 after infection. Inflammatory mediators were also detected in these tissues, coinciding with high levels of virus replication. Lower virus titers were also detected in other tissues, including blood. In contrast, infected transgene-negative (Tg−) mice survived without showing any clinical illness. Pathologic examination suggests that the extensive involvement of the central nervous system likely contributed to the death of Tg+ mice, even though viral pneumonia was present. Preliminary studies with mice of a second lineage, AC63, in which the transgene expression was considerably less abundant than that in the AC70 line, revealed that virus replication was largely restricted to the lungs but not the brain. Importantly, despite significant weight loss, infected Tg+ AC63 mice eventually recovered from the illness without any mortality. The severity of the disease that developed in these transgenic mice—AC70 in particular—makes these mouse models valuable not only for evaluating the efficacy of antivirals and vaccines, but also for studying SARS coronavirus pathogenesis.

scholarly journals Purification and characterization of angiotensin converting enzyme 2 (ACE2) from murine model of mesangial cell in culture

2011 ◽  
Vol 49 (1) ◽  
pp. 79-84 ◽  
Author(s):  
Danielle S. Aragão ◽  
Tatiana S. Cunha ◽  
Danielle Yuri Arita ◽  
Maria Claudina C. Andrade ◽  
Adriana B. Fernandes ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Murine Model ◽  
Mesangial Cell ◽  
Converting Enzyme ◽  
Purification And Characterization ◽  
Angiotensin Converting Enzyme 2
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