COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice

Lutz, Cathleen; Maher, Leigh; Lee, Charles; Kang, Wonyoung

doi:10.1186/s40246-020-00272-6

Cited by 67 publications

(84 citation statements)

References 127 publications

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“…As has recently been reported in studies using K18-hACE2 transgenic mice 23,30 , pathology revealed brain involvement in some of the SARS-CoV-2 singly infected and coinfected mice at day 10 which manifested as non-suppurative meningoencephalitis predominantly affecting the midbrain and brainstem. Previous studies using K18-hACE2 mice focusing on SARS-CoV have shown that the virus spreads throughout the brain around 3 days post intranasal inoculation 21,23,31 however the mechanism of entry is unclear as one study reported abundant infection of the olfactory bulb 31 while the other showed little involvement 21 .…”

Section: Discussionsupporting

confidence: 71%

Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19

Clark

Penrice-Randal

Sharma

et al. 2020

Preprint

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COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that has rapidly caused a pandemic. Coalescence of a second wave of this virus with seasonal respiratory viruses, particularly influenza virus is a possible global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although, SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, these mice had a more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary manifestations associated with SARS-CoV-2. This included a more severe encephalitis. Taken together, the data suggest that the concept of “twinfection” is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.

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Section: Discussionsupporting

confidence: 71%

Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19

Clark

Penrice-Randal

Sharma

et al. 2020

Preprint

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show abstract

“…Until now, studies based on RBD domain analysis ruled out the probability of mice, rats, and rabbit's involvement in the SARS-CoV-2 cycle [52]. The findings on ferrets, orangutans, and monkeys showed a higher affinity of ACE2 with the RBD domain of SARS-CoV-2 S protein [53].…”

Section: Transmission Of Sars-cov-2 From Covid-19 Positive Persons Tomentioning

confidence: 99%

Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to animals: an updated review

et al. 2020

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COVID-19 caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in Wuhan (Hubei province, China) during late 2019. It has spread across the globe affecting nearly 21 million people with a toll of 0.75 million deaths and restricting the movement of most of the world population during the past 6 months. COVID-19 became the leading health, economic, and humanitarian challenge of the twenty-first century. In addition to the considerable COVID-19 cases, hospitalizations, and deaths in humans, several cases of SARS-CoV-2 infections in animal hosts (dog, cat, tiger, lion, and mink) have been reported. Thus, the concern of pet owners is increasing. Moreover, the dynamics of the disease requires further explanation, mainly concerning the transmission of the virus from humans to animals and vice versa. Therefore, this study aimed to gather information about the reported cases of COVID-19 transmission in animals through a literary review of works published in scientific journals and perform genomic and phylogenetic analyses of SARS-CoV-2 isolated from animal hosts. Although many instances of transmission of the SARS-CoV-2 have been reported, caution and further studies are necessary to avoid the occurrence of maltreatment in animals, and to achieve a better understanding of the dynamics of the disease in the environment, humans, and animals. Future research in the animal–human interface can help formulate and implement preventive measures to combat the further transmission of COVID-19.

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“…In response to the need for small animal models to study SARS-CoV, several laboratories produced transgenic animals expressing the hACE2 gene under the control of various promotors, including the CMV, HFH4 epithelial cell promotor or the endogenous murine ACE2 promotor (27)(28)(29)(30)(31). Many of these animals develop severe disease upon infection by SARS-CoV, but severity largely depends upon expression levels and tissue distribution of the hACE2 transgene.…”

Section: Introductionmentioning

confidence: 99%

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

Golden

Cline

Zeng

et al. 2020

Preprint

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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.

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COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice

Cited by 67 publications

References 127 publications

Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19

Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19

Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to animals: an updated review

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

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