Differing susceptibility of C57BL/6J and DBA/2J mice—parents of the murine BXD family, to severe acute respiratory syndrome coronavirus infection

Li, Kui; Shen, Yang; Miller, Mark A.; Stabenow, Jennifer; Williams, Robert W.; Lu, Lu

doi:10.1186/s13578-021-00656-8

Cited by 5 publications

(3 citation statements)

References 10 publications

(15 reference statements)

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“…We found that K18‐hACE2 mice treated with S/GFP EV had markedly reduced morbidity (early body weight loss) after infection with a lethal dose of SARS‐CoV‐2 (Figure 6c ). The apparent transiency of the weight loss, or rebound in surviving control mice is consistent with reported data (Falach et al., 2021 ; Li et al., 2021 ; Sun et al., 2021 ) and may represent a selection of more resilient animals in the group. Importantly, the overall survival of mice treated with S/GFP EVs was significantly increased to 65% compared to 20% in control mice, which received only GFP‐containing EVs (Figure 6d ).…”

Section: Resultssupporting

confidence: 89%

Quantitative proteomics and biological activity of extracellular vesicles engineered to express SARS‐CoV‐2 spike protein

Choi

Khan

Montermini

et al. 2022

J of Extracellular Bio

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SARS-CoV-2 viral infection led to the devastating COVID-19 pandemic, where illness stemmed from interactions between virions and recipient host cells resulting in multi-layered pathological consequences. The role of the infection portal is now understood to be the cellular angiotensin converting enzyme-2 (ACE2) receptor, which binds to viral spike (S) protein initiating virion internalisation process. Since SARS-CoV-2 virions bear some resemblance to endogenously produced small extracellular vesicles (sEVs) we reasoned that EVs engineered to express S protein (viral mimics) may interfere with viral infection. Here, we report generation of HEK293T cells producing sEVs enriched for transmembrane S-protein tagged with green fluorescent protein (S/GFP). Strikingly, S protein drove the GFP tag to the membrane of sEVs, while GFP alone was not efficiently included in the sEV cargo. Highthroughput quantitative proteomics revealed that S/GFP sEVs contained over 1000 proteins including canonical components of the exosomal pathway such as ALIX, syntenin-1, and tetraspanins (CD81, CD9), but depleted for calnexin and cytochrome c. We found that 84 sEV proteins were significantly altered by the presence of S/GFP. S protein expressing EVs efficiently adhered to target cells in an ACE2-dependent manner, but they were poorly internalised. Importantly, prolonged administration of S/GFP EV to K18-hACE2 mice provided a significant protection against SARS-CoV-2 infection. Thus, the generation of sEV containing S protein can be considered as a novel therapeutic approach in reducing the transmission of SARS-CoV-2.

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Section: Resultssupporting

confidence: 89%

Quantitative proteomics and biological activity of extracellular vesicles engineered to express SARS‐CoV‐2 spike protein

Choi

Khan

Montermini

et al. 2022

J of Extracellular Bio

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“…Thus careful studies are needed to verify the effectiveness and suitability of these strains as model organisms. Studies employing mouse-adapted SARS-CoV-2 strains have primarily been performed in BALB/c mice [ 6 , 8 , 9 , 13 , 14 ] and focused on a single sex or single age cohorts [ 3 , 10 , 12 , 15 , 16 ], or have employed highly adapted and virulent variants that limit the ability to comprehensively examine infection and recovery [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

A C57BL/6 Mouse Model of SARS-CoV-2 Infection Recapitulates Age- and Sex-Based Differences in Human COVID-19 Disease and Recovery

et al. 2022

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We present a comprehensive analysis of SARS-CoV-2 infection and recovery using wild type C57BL/6 mice and a mouse-adapted virus, and we demonstrate that this is an ideal model of infection and recovery that phenocopies acute human disease arising from the ancestral SARS-CoV-2. Disease severity and infection kinetics are age- and sex-dependent, as has been reported for humans, with older mice and males in particular exhibiting decreased viral clearance and increased mortality. We identified key parallels with human pathology, including intense virus positivity in bronchial epithelial cells, wide-spread alveolar involvement, recruitment of immune cells to the infected lungs, and acute bronchial epithelial cell death. Moreover, older animals experienced increased virus persistence, delayed dispersal of immune cells into lung parenchyma, and morphologic evidence of tissue damage and inflammation. Parallel analysis of SCID mice revealed that the adaptive immune response was not required for recovery from COVID disease symptoms nor early phase clearance of virus but was required for efficient clearance of virus at later stages of infection. Finally, transcriptional analyses indicated that induction and duration of key innate immune gene programs may explain differences in age-dependent disease severity. Importantly, these data demonstrate that SARS-CoV-2-mediated disease in C57BL/6 mice phenocopies human disease across ages and establishes a platform for future therapeutic and genetic screens for not just SARS-CoV-2 but also novel coronaviruses that have yet to emerge.

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“…It is observed that there is a myriad of disease manifestation among SARS-CoV-2 infected patients 27 . The use of humanized mice with variations in immune responses can represent diverse cohorts of people.…”

mentioning

confidence: 99%

Comparison of infection and human immune responses of two SARS-CoV-2 strains in a humanized hACE2 NIKO mouse model

Yong,

Anderson,

Zheng

et al. 2023

Sci Rep

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The COVID-19 pandemic has sickened millions, cost lives and has devastated the global economy. Various animal models for experimental infection with SARS-CoV-2 have played a key role in many aspects of COVID-19 research. Here, we describe a humanized hACE2 (adenovirus expressing hACE2) NOD-SCID IL2Rγ−/− (NIKO) mouse model and compare infection with ancestral and mutant (SARS-CoV-2-∆382) strains of SARS-CoV-2. Immune cell infiltration, inflammation, lung damage and pro-inflammatory cytokines and chemokines was observed in humanized hACE2 NIKO mice. Humanized hACE2 NIKO mice infected with the ancestral and mutant SARS-CoV-2 strain had lung inflammation and production of pro-inflammatory cytokines and chemokines. This model can aid in examining the pathological basis of SARS-CoV-2 infection in a human immune environment and evaluation of therapeutic interventions.

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Differing susceptibility of C57BL/6J and DBA/2J mice—parents of the murine BXD family, to severe acute respiratory syndrome coronavirus infection

Cited by 5 publications

References 10 publications

Quantitative proteomics and biological activity of extracellular vesicles engineered to express SARS‐CoV‐2 spike protein

Quantitative proteomics and biological activity of extracellular vesicles engineered to express SARS‐CoV‐2 spike protein

A C57BL/6 Mouse Model of SARS-CoV-2 Infection Recapitulates Age- and Sex-Based Differences in Human COVID-19 Disease and Recovery

Comparison of infection and human immune responses of two SARS-CoV-2 strains in a humanized hACE2 NIKO mouse model

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