The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus

Dong, Wenjuan; Mead, Heather; Tian, Lei; Park, Jun-Gyu; García, Juan Ignacio García; Jaramillo, Sierra A; Barr, Tasha; Kollath, Daniel S; Coyne, Vanessa K; Stone, Nathan E.; Jones, Ashley; Zhang, Jianying; Li, Aimin; Wang, Li‐Shu; Milanes‐Yearsley, Martha; Torrelles, Jordi B.; Martínez-Sobrido, Luis; Keim, Paul; Barker, Bridget; Caligiuri, Michael A.; Yu, Jianhua

doi:10.1128/jvi.00964-21

Cited by 118 publications

(124 citation statements)

References 37 publications

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“…2,3). K18-hACE2 mice express human ACE2 driven by a cytokeratin promotor in epithelia, including airway epithelia cells where SARS-2 infections often start and recapitulate severe COVID-19 upon infection with SARS-2 (40)(41)(42). Viral challenges of K18-hACE2 mice result in extensive weight loss, and death usually results from SARS-2 or SARS-1 infection (41).…”

Section: Resultsmentioning

confidence: 99%

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Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models

Cohen

Doremalen

Greaney

et al. 2022

Preprint

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To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

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Section: Resultsmentioning

confidence: 99%

“…To compare the efficacies of mosaic and homotypic RBD-mi3 nanoparticle immunizations, we evaluated immune responses and protection from viral challenge in K18-human ACE2 (K18-hACE2) transgenic mice ( 40 ) (Fig. 2,3).…”

Section: Resultsmentioning

confidence: 99%

Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models

Cohen

Doremalen

Greaney

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…The K18-hACE2 transgenic model has been extensively utilized to evaluate the vaccine efficacy and effectiveness in preventing COVID-19 in the preclinical setting (Arce and Costoya, 2021; Dong et al, 2021; Radvak et al, 2021; Winkler et al, 2020). Two key metrics to determine the severity of pathogenesis are the virus titer in the lung tissue and body weight loss following virus infection.…”

Section: Resultsmentioning

confidence: 99%

Chimeric mRNA based COVID-19 vaccine induces protective immunity against Omicron and Delta

Zhao

Shaabani

et al. 2022

Preprint

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The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the efficacy and effectiveness of the two FDA-approved mRNA vaccines currently in use. Here, we explored various strategies to develop mRNA vaccines that offer potentially safer and wider coverage of VOCs. The initial mouse vaccination results showed that the individual VOC mRNAs carrying furin cleavage mutation induced the generation of neutralizing antibody in a VOC-specific manner. Moreover, we discovered that the antibodies produced from mice immunized with Beta-Furin and Washington (WA)-Furin mRNAs cross-reacted with other VOCs. The broad spectrum of generated nAb was further confirmed when vaccinated mice were challenged with the respective live viruses. However, neither WA-Furin nor Beta-Furin mRNA elicited potent neutralizing activity against the omicron variant. Interestingly, in a mix-and-match booster experiment, omicron-Furin and WA-Furin mRNA elicited comparable protection against omicron. Finally, we tested the concept of bivalent vaccine by introducing the RBD of Delta strain into the intact S antigen of Omicron. The chimeric mRNA induces potent and broadly acting nAb against Omicron and Delta, which paves the way to develop vaccine candidate to target emerging variants in the future.

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“…A widely used mouse model of SARS-CoV-2 infection and COVID-19 disease is the K18-hACE2 mouse, where the human angiotensin-converting enzyme 2 (hACE2) is expressed as a transgene from the keratin 18 (K18) promoter. These mice develop a robust respiratory disease that histologically resembles severe COVID-19 (19)(20)(21). These mice have been widely used for evaluation of new interventions (22)(23)(24)(25)(26)(27), and for virology and immunopathology studies (28,29).…”

Section: Introductionmentioning

confidence: 99%

Mouse models of COVID-19 recapitulate inflammatory pathways rather than gene expression

Bishop

Dumenil

Rawle

et al. 2022

Preprint

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BACKGROUND: How well mouse models recapitulate the transcriptional profiles seen in humans remains debatable, with both conservation and diversity identified in various settings. The K18-hACE2 mouse model has been widely used for evaluation of new interventions for COVID-19. METHOD. Herein we use RNA-Seq data and bioinformatics approaches to compare the transcriptional responses in the SARS-CoV-2 infected lungs of K18-hACE2 mice with those seen in humans. RESULTS: Overlap in differentially expressed genes was generally poor (≈20-30%), even when multiple studies were combined. The overlap was not substantially improved when a second mouse model was examined wherein hACE was expressed from the mouse ACE2 promoter. In contrast, analyses of immune signatures and inflammatory pathways illustrated highly significant concordances between the species. CONCLUSION: As immunity and immunopathology are the focus of most studies, these hACE2 transgenic mouse models can thus be viewed as representative and relevant models of COVID-19.

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The K18-Human ACE2 Transgenic Mouse Model Recapitulates Non-severe and Severe COVID-19 in Response to an Infectious Dose of the SARS-CoV-2 Virus

Cited by 118 publications

References 37 publications

Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models

Mosaic RBD nanoparticles protect against multiple sarbecovirus challenges in animal models

Chimeric mRNA based COVID-19 vaccine induces protective immunity against Omicron and Delta

Mouse models of COVID-19 recapitulate inflammatory pathways rather than gene expression

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