Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice

Thieulent, Côme; Dittmar, Wellesley; Balasuriya, Udeni B. R.; Crossland, Nicholas A.; Xue, Wei; Richt, Jürgen A.; Carossino, Mariano

doi:10.1128/msphere.00558-22

Cited by 13 publications

(11 citation statements)

References 81 publications

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“…Regarding the mouse-adapted SARS-CoV-2 MA10, 39 the virus acquired pulmonary tropism compared to its parental strain during adaptation into mice, leading to efficient replication in the lungs. 45 As shown in Figure 5 E, Akaluc signals were detected not in nasal cavity but in the lungs of the MA10-infected mouse. Collectively, these data indicate that the AkaBLI can also be utilized to assess viral tissue tropism in vivo .…”

Section: Discussionmentioning

confidence: 99%

Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection

Tamura,

Ito,

Torii

et al. 2024

iScience

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Section: Discussionmentioning

confidence: 99%

Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection

Tamura,

Ito,

Torii

et al. 2024

iScience

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“…Since the C57BL/6 mouse is widely used as a genetic background for genetically modified mice in studies of various human diseases [ 24 ], a C57BL/6J model that develops severe pneumonia similar to that seen in COVID-19 patients is highly desirable. Several mouse-adapted (MA) strains of SARS-CoV-2 developed through serial passaging in mice and/or reverse genetics have been shown to cause severe pneumonia in C57BL/6J mice [ 25 , 26 , 27 ]; however, mouse-adapted reporter SARS-CoV-2 strains that are pathogenic to C57BL/6J mice and express fluorescent proteins in infected cells have not been established.…”

Section: Introductionmentioning

confidence: 99%

Development of a Mouse-Adapted Reporter SARS-CoV-2 as a Tool for Two-Photon In Vivo Imaging

Ueki,

Kiso,

Furusawa

et al. 2024

Viruses

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) often causes severe viral pneumonia. Although many studies using mouse models have examined the pathogenicity of SARS-CoV-2, COVID-19 pathogenesis remains poorly understood. In vivo imaging analysis using two-photon excitation microscopy (TPEM) is useful for elucidating the pathology of COVID-19, providing pathological insights that are not available from conventional histological analysis. However, there is no reporter SARS-CoV-2 that demonstrates pathogenicity in C57BL/6 mice and emits sufficient light intensity for two-photon in vivo imaging. Here, we generated a mouse-adapted strain of SARS-CoV-2 (named MASCV2-p25) and demonstrated its efficient replication in the lungs of C57BL/6 mice, causing fatal pneumonia. Histopathologic analysis revealed the severe inflammation and infiltration of immune cells in the lungs of MASCV2-p25-infected C57BL/6 mice, not unlike that observed in COVID-19 patients with severe pneumonia. Subsequently, we generated a mouse-adapted reporter SARS-CoV-2 (named MASCV-Venus-p9) by inserting the fluorescent protein-encoding gene Venus into MASCV2-p25 and sequential lung-to-lung passages in C57BL/6 mice. C57BL/6 mice infected with MASCV2-Venus-p9 exhibited severe pneumonia. In addition, the TPEM of the lungs of the infected C57BL/6J mice showed that the infected cells emitted sufficient levels of fluorescence for easy observation. These findings suggest that MASCV2-Venus-p9 will be useful for two-photon in vivo imaging studies of the pathogenesis of severe COVID-19 pneumonia.

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“…Rabbits, raccoon dogs, fruit bats, and skunks have been shown to be susceptible to experimental infection ( 26 – 29 ). In contrast, wild-type mice [i.e., mice that do not express the human angiotensin-converting enzyme 2 (ACE2)] and rats are not naturally permissive to natural or experimental infection by ancestral, Wuhan-like SARS-CoV-2 strains ( 30 – 32 ). However, SARS-CoV-2 strains, including mouse-adapted strains (e.g., MA10) and various VOCs that carry the N501Y mutation in the viral spike protein are able to infect wild-type mice and rats ( 32 – 34 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the transgenic K18-hACE2 mouse model, distribution analysis of human ACE2 (hACE2) expression determined its localization within the olfactory neuroepithelium, bronchiolar epithelium, scattered alveolar type 2 (AT2) cells, and neurons ( 48 ). Tmprss2 mRNA is enriched throughout the airway epithelia and sporadically in alveolar type 1 (AT1) and AT2 cells ( 31 ). A recent study performed in our laboratory comparing the ancestral, Wuhan-like strain USA-WA1/2020 and its derivative mouse-adapted MA10 strain in K18-hACE2, C57BL/6J, and BALB/c mice, demonstrated a decline in mouse Ace2 rather than hACE2 mRNA transcript abundance following infection ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

ACE2 and TMPRSS2 distribution in the respiratory tract of different animal species and its correlation with SARS-CoV-2 tissue tropism

Carossino,

Izadmehr,

Trujillo

et al. 2024

Microbiol Spectr

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A wide range of animal species show variable susceptibility to SARS-CoV-2; however, host factors associated with varied susceptibility remain to be defined. Here, we examined whether susceptibility to SARS-CoV-2 and virus tropism in different animal species are dependent on the expression and distribution of the virus receptor angiotensin-converting enzyme 2 ( ACE2 ) and the host cell factor transmembrane serine protease 2 ( TMPRSS2 ). We cataloged the upper and lower respiratory tract of multiple animal species and humans in a tissue-specific manner and quantitatively evaluated the distribution and abundance of ACE2 and TMPRSS2 mRNA in situ . Our results show that: (i) ACE2 and TMPRSS2 mRNA are abundant in the conduction portion of the respiratory tract, (ii) ACE2 mRNA occurs at a lower abundance compared to TMPRSS2 mRNA, (iii) co-expression of ACE2-TMPRSS2 mRNAs is highest in those species with the highest susceptibility to SARS-CoV-2 infection (i.e., cats, Syrian hamsters, and white-tailed deer), and (iv) expression of ACE2 and TMPRSS2 mRNA was not altered following SARS-CoV-2 infection. Our results demonstrate that while specific regions of the respiratory tract are enriched in ACE2 and TMPRSS2 mRNAs in different animal species, this is only a partial determinant of susceptibility to SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 infects a wide array of domestic and wild animals, raising concerns regarding its evolutionary dynamics in animals and potential for spillback transmission of emerging variants to humans. Hence, SARS-CoV-2 infection in animals has significant public health relevance. Host factors determining animal susceptibility to SARS-CoV-2 are vastly unknown, and their characterization is critical to further understand susceptibility and viral dynamics in animal populations and anticipate potential spillback transmission. Here, we quantitatively assessed the distribution and abundance of the two most important host factors, angiotensin-converting enzyme 2 and transmembrane serine protease 2, in the respiratory tract of various animal species and humans. Our results demonstrate that while specific regions of the respiratory tract are enriched in these two host factors, they are only partial determinants of susceptibility. Detailed analysis of additional host factors is critical for our understanding of the underlying mechanisms governing viral susceptibility and reservoir hosts.

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Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice

Abstract: The COVID-19 pandemic, caused by SARS-CoV-2, is still significantly impacting health care systems around the globe. Refined animal models are needed to study SARS-CoV-2 pathogenicity as well as efficacy of vaccines and therapeutics.

Cited by 13 publications

References 81 publications

Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection

Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection

Development of a Mouse-Adapted Reporter SARS-CoV-2 as a Tool for Two-Photon In Vivo Imaging

ACE2 and TMPRSS2 distribution in the respiratory tract of different animal species and its correlation with SARS-CoV-2 tissue tropism

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