The K18-hACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to Infectious Dose of SARS-CoV-2 Virus

Yu, Jianhua; Dong, Wenjuan; Li, Aimin; Zhang, Jianying; Caligiuri, Michael A.; Jaramillo, Sierra A; Mead, Heather; Stone, Nathan E.; Jones, Ashley; Kollath, Daniel R.; Coyne, Vanessa K; Yearsley, Martha; Wang, Li‐Shu; Barker, Bridget; Keim, Paul; Barr, Tasha

doi:10.1101/2021.05.08.443244

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…In contrast, mice infected with Alpha exhibited low RNA levels at day 2 and a 2-fold increase at day 6, suggesting an increase in viral replication in the brain over time (Fig 2C). These observations suggest that Delta at a challenge dose of 10 3 PFU replicates efficiently in the airway in a manner similar to Alpha but Delta appears to have lower brain localization previously observed in K18-hACE2-mice [41,[44][45][46]. Viral RNA burden of disease-associated tissues was quantified using nucleocapsid qPCR.…”

Section: Plos Onementioning

confidence: 78%

“…We observed that 10 3 PFU challenge with Delta variant does not cause the dramatic weight loss and hypothermia reported in models of Alpha and Beta challenge [ 17 ]. One well known caveat of the K18-hACE2-mouse model is the fact that WA-1, Alpha and Beta strains enter the brain [ 44 , 46 , 58 – 64 ]. However, it appears that the Delta variant remains more localized in the lungs of challenged mice ( Fig 3 ).…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

et al. 2022

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The COVID-19 pandemic has been fueled by SARS-CoV-2 novel variants of concern (VOC) that have increased transmissibility, receptor binding affinity, and other properties that enhance disease. The goal of this study is to characterize unique pathogenesis of the Delta VOC strain in the K18-hACE2-mouse challenge model. Challenge studies suggested that the lethal dose of Delta was higher than Alpha or Beta strains. To characterize the differences in the Delta strain’s pathogenesis, a time-course experiment was performed to evaluate the overall host response to Alpha or Delta variant challenge. qRT-PCR analysis of Alpha- or Delta-challenged mice revealed no significant difference between viral RNA burden in the lung, nasal wash or brain. However, histopathological analysis revealed high lung tissue inflammation and cell infiltration following Delta- but not Alpha-challenge at day 6. Additionally, pro-inflammatory cytokines were highest at day 6 in Delta-challenged mice suggesting enhanced pneumonia. Total RNA-sequencing analysis of lungs comparing challenged to no challenge mice revealed that Alpha-challenged mice have more total genes differentially activated. Conversely, Delta-challenged mice have a higher magnitude of differential gene expression. Delta-challenged mice have increased interferon-dependent gene expression and IFN-γ production compared to Alpha. Analysis of TCR clonotypes suggested that Delta challenged mice have increased T-cell infiltration compared to Alpha challenged. Our data suggest that Delta has evolved to engage interferon responses in a manner that may enhance pathogenesis. The in vivo and in silico observations of this study underscore the need to conduct experiments with VOC strains to best model COVID-19 when evaluating therapeutics and vaccines.

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Section: Plos Onementioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

et al. 2022

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“…The value of R changes with the type of activity but is currently uncertain. Also, the value of I may change independently since the dose may change with the severity of the COVID-19 disease [54,55]; age has also been suggested to influence disease severity [56,57]. Moreover, it has been suggested that some SARS-CoV-2 variants, such as the Delta variant, are more infectious corresponding to higher values of I [58].…”

Section: Modelling Frameworkmentioning

confidence: 99%

Predicting the spatio-temporal infection risk in indoor spaces using an efficient airborne transmission model

et al. 2022

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We develop a spatially dependent generalization to the Wells–Riley model, which determines the infection risk due to airborne transmission of viruses. We assume that the infectious aerosol concentration is governed by an advection–diffusion–reaction equation with the aerosols advected by airflow, diffused due to turbulence, emitted by infected people, and removed due to ventilation, inactivation of the virus and gravitational settling. We consider one asymptomatic or presymptomatic infectious person breathing or talking, with or without a mask, and model a quasi-three-dimensional set-up that incorporates a recirculating air-conditioning flow. We derive a semi-analytic solution that enables fast simulations and compare our predictions to three real-life case studies—a courtroom, a restaurant, and a hospital ward—demonstrating good agreement. We then generate predictions for the concentration and the infection risk in a classroom, for four different ventilation settings. We quantify the significant reduction in the concentration and the infection risk as ventilation improves, and derive appropriate power laws. The model can be easily updated for different parameter values and can be used to make predictions on the expected time taken to become infected, for any location, emission rate, and ventilation level. The results have direct applicability in mitigating the spread of the COVID-19 pandemic.

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“…To evaluate the potential effect of FXa in vivo, we used humanized K18-hACE2 mice as an infection model of SARS-CoV-2 23,24 .…”

Section: Fxa Cleavage Reduces the Binding Between S Protein And Ace2mentioning

confidence: 99%

Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection

et al. 2023

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Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.

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The K18-hACE2 Transgenic Mouse Model Recapitulates Non-Severe and Severe COVID-19 in Response to Infectious Dose of SARS-CoV-2 Virus

Cited by 11 publications

References 31 publications

SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

SARS-CoV-2 Delta variant induces enhanced pathology and inflammatory responses in K18-hACE2 mice

Predicting the spatio-temporal infection risk in indoor spaces using an efficient airborne transmission model

Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection

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