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

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.

Download Full-text

Sex-Specific Modulation of Blood Pressure and the Renin-Angiotensin System by ACE (Angiotensin-Converting Enzyme) 2

Hypertension ◽

10.1161/hypertensionaha.120.15276 ◽

2020 ◽

Vol 76 (2) ◽

pp. 478-487 ◽

Cited By ~ 3

Author(s):

Hong Ji ◽

Aline M.A. de Souza ◽

Bilkish Bajaj ◽

Wei Zheng ◽

Xie Wu ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Protein Expression ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Male Mice ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Female Mice ◽

Induced Hypertension

We showed ACE (angiotensin-converting enzyme) 2 is higher in the kidney of male compared with female mice. To further investigate this sex difference, we examined the role of ACE2 in Ang-[1–8] (angiotensin [1–8])–induced hypertension and regulation of the renin-angiotensin system in the kidney of WT (wild type) and Ace2 KO (knockout) mice. Mean arterial pressure rose faster in WT male than WT female mice after Ang-[1–8] infusion. This sex difference was attenuated in ACE2 KO mice. Ang-[1–8] infusion reduced glomerular AT1R (angiotensin type 1 receptor) binding in WT female mice by 30%, and deletion of Ace2 abolished this effect. In contrast, Ang-[1–8] infusion increased glomerular AT1R binding in WT male mice by 1.2-fold, and this effect of Ang-[1–8] persisted in Ace2 KO male mice (1.3-fold). ACE2 also had an effect on renal protein expression of the neutral endopeptidase NEP (neprilysin), the enzyme that catabolizes Ang-[1–10] (angiotensin [1–10]), the precursor of Ang-[1–8]. Ang-[1–8] infusion downregulated NEP protein expression by 20% in WT male, whereas there was a slight increase in NEP expression in WT female mice. Deletion of Ace2 resulted in lowered NEP expression after Ang-[1-8] infusion in both sexes. These findings suggest sex-specific ACE2 regulation of the renin-angiotensin system contributes to female protection from Ang-[1–8]–induced hypertension. These findings have ramifications for the current coronavirus disease 2019 (COVID-19) pandemic, especially in hypertension since ACE2 is the SARS-CoV-2 receptor and hypertension is a major risk factor for poor outcomes.

Download Full-text

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

Nature Communications ◽

10.1038/s41467-020-19891-7 ◽

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.

Download Full-text

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

10.1101/2020.07.18.210179 ◽

2020 ◽

Cited By ~ 6

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.

Download Full-text

The Effects of Aβ1-42 Binding to the SARS-CoV-2 Spike Protein S1 Subunit and Angiotensin-Converting Enzyme 2

International Journal of Molecular Sciences ◽

10.3390/ijms22158226 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8226

Author(s):

John Tsu-An Hsu ◽

Chih-Feng Tien ◽

Guann-Yi Yu ◽

Santai Shen ◽

Yi-Hsuan Lee ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Viral Entry ◽

Negative Impact ◽

Spike Protein ◽

Infection Model ◽

Converting Enzyme ◽

Viral Receptor ◽

Angiotensin Converting Enzyme 2 ◽

People With Dementia ◽

The Impact

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer’s disease (AD), the major form of dementia, β-amyloid (Aβ) levels in the blood are increased; however, the impact of elevated Aβ levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aβ1-42, but not Aβ1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aβ1-42. Furthermore, Aβ1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aβ1-42 show that the clearance of Aβ1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aβ antibody. In conclusion, these findings suggest that the binding of Aβ1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aβ1-42 in the blood is beneficial to the fight against COVID-19 and AD.

Download Full-text

Do sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression explain increased severity and mortality of COVID-19 in males?

Diagnosis ◽

10.1515/dx-2020-0054 ◽

2020 ◽

Vol 7 (4) ◽

pp. 385-386 ◽

Cited By ~ 3

Author(s):

Jens Vikse ◽

Giuseppe Lippi ◽

Brandon Michael Henry

Keyword(s):

Mortality Rate ◽

Severe Acute Respiratory Syndrome ◽

Lung Injury ◽

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Immunomodulatory Treatment ◽

Angiotensin Converting Enzyme 2 ◽

Cytopathic Effects ◽

Severe Lung

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

Download Full-text

Association between angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin-II receptor 1 (AGTR1) polymorphisms and COVID-19 infection in the southeast of Iran: a preliminary case-control study

Translational Medicine Communications ◽

10.1186/s41231-021-00106-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Hamid Reza Kouhpayeh ◽

Farhad Tabasi ◽

Mohammad Dehvari ◽

Mohammad Naderi ◽

Gholamreza Bahari ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Severe Disease ◽

Renin Angiotensin System ◽

Iranian Population ◽

Converting Enzyme ◽

Angiotensin Ii Receptor ◽

Health Crisis ◽

Angiotensin Converting Enzyme 2 ◽

Pcr Rflp ◽

Severity Of The Disease

Abstract Background The COVID-19 pandemic remains an emerging public health crisis with serious adverse effects. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV--2) infection, targeting angiotensin-converting enzyme-2 (ACE2) receptor for cell entry. However, changes in the renin-angiotensin system (RAS) balance alter an individual’s susceptibility to COVID-19 infection. We aimed to evaluate the association between AGT rs699 C > T, ACE rs4646994 I/D, and AGTR1 rs5186 C > A variants and the risk of COVID-19 infection and the severity in a sample of the southeast Iranian population. Methods A total of 504 subjects, including 258 COVID-19 positives, and 246 healthy controls, were recruited. Genotyping of the ACE gene rs4646994, and AGT rs699, and AGTR1 rs5186 polymorphisms was performed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP), respectively. Results Our results showed that the II genotype of ACE rs4646994 and the I allele decreased the risk of COVID-19 infection. Moreover, we found that the TC genotype and C allele of AGT rs699 increased the risk of COVID-19 infection. The AGTR1 rs5186 was not associated with COVID-19 infection. Also, we did not find any association between these polymorphisms and the severity of the disease. However, we found a significantly higher age and prevalence of diabetes and hypertension in patients with severe disease than a non-severe disease. Conclusions These findings suggest that ACE rs4646994 and AGT rs699 polymorphisms increase the risk of COVID-19 infection in a southeast Iranian population.

Download Full-text