SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains

Radvák, Peter; Kwon, Hyeok‐Jung; Košíková, Martina; Ortega-Rodriguez, Uriel; Xiang, Ruoxuan; Phue, Je-Nie; Shen, Rong-Fong; Rozzelle, James; Kapoor, Neeraj; Rabara, Taylor; Fairman, Jeff; Xie, Hang

doi:10.1038/s41467-021-26803-w

Cited by 85 publications

(87 citation statements)

References 60 publications

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“…However, other recent studies have shown that intranasal infection of K18-hACE2 mice with B.1.1.7 and B.1.351 variants resulted in distinct arrays of cytokine response than those induced by early SARS-CoV-2 strains. Several myeloid cell chemoattractants showed enhanced pulmonary secretions in K18-hACE2 mice following exposures to B.1.1.7 or B.1.351 variant [29,30]. These findings are consistent with previous studies in humans, which established a consistent link between the mutations exhibited by the B.1.351 lineage and a greater potential for infectivity and immune escape [4,6,24].…”

Section: Discussionsupporting

confidence: 89%

SARS-CoV-2 Variants of Concern Infect the Respiratory Tract and Induce Inflammatory Response in Wild-Type Laboratory Mice

Stone

Rothan

Natekar

et al. 2021

Viruses

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The emergence of new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern pose a major threat to public health, due to possible enhanced virulence, transmissibility and immune escape. These variants may also adapt to new hosts, in part through mutations in the spike protein. In this study, we evaluated the infectivity and pathogenicity of SARS-CoV-2 variants of concern in wild-type C57BL/6 mice. Six-week-old mice were inoculated intranasally with a representative virus from the original B.1 lineage, or the emerging B.1.1.7 and B.1.351 lineages. We also infected a group of mice with a mouse-adapted SARS-CoV-2 (MA10). Viral load and mRNA levels of multiple cytokines and chemokines were analyzed in the lung tissues on day 3 after infection. Our data show that unlike the B.1 virus, the B.1.1.7 and B.1.351 viruses are capable of infecting C57BL/6 mice and replicating at high concentrations in the lungs. The B.1.351 virus replicated to higher titers in the lungs compared with the B.1.1.7 and MA10 viruses. The levels of cytokines (IL-6, TNF-α, IL-1β) and chemokine (CCL2) were upregulated in response to the B.1.1.7 and B.1.351 infection in the lungs. In addition, robust expression of viral nucleocapsid protein and histopathological changes were detected in the lungs of B.1.351-infected mice. Overall, these data indicate a greater potential for infectivity and adaptation to new hosts by emerging SARS-CoV-2 variants.

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Section: Discussionsupporting

confidence: 89%

SARS-CoV-2 Variants of Concern Infect the Respiratory Tract and Induce Inflammatory Response in Wild-Type Laboratory Mice

Stone

Rothan

Natekar

et al. 2021

Viruses

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“…The B.1.351 variant, originally identified in South Africa, includes several mutations within the structural and nonstructural proteins raising significant concerns about alterations to viral fitness, transmission, and disease 44 . SARS-CoV-2 variants B.1.1.7 (alpha) and B.1.351 45 are reported to have increased transmission and resistance to antibody neutralization 46 . The SARS-CoV-2 Omicron variant B.1.1.529 harbors more than 30 changes to the spike protein and has an increased risk of reinfection compared to other VOCs.…”

Section: Introductionmentioning

confidence: 99%

Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay

et al. 2022

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SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.

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“…org/sars-cov-2/). In K18-hACE2 transgenic mice, alpha and beta VOCs induced pathogenic patterns and were 100-fold more lethal than early SARS-CoV-2 lineages (115). The European Centre for Disease Prevention and Control (ECDC), compared the COVID-19 severity cases between VOCs and non-VOCs, and observed that the beta variant was associated with a higher ratio for hospitalization (3.6) (60).…”

Section: Emerging Sars-cov-2 Variants Of Concernmentioning

confidence: 99%

Viral Load in COVID-19 Patients: Implications for Prognosis and Vaccine Efficacy in the Context of Emerging SARS-CoV-2 Variants

et al. 2022

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The worldwide spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an unprecedented public health crisis in the 21st century. As the pandemic evolves, the emergence of SARS-CoV-2 has been characterized by the emergence of new variants of concern (VOCs), which resulted in a catastrophic impact on SARS-CoV-2 infection. In light of this, research groups around the world are unraveling key aspects of the associated illness, coronavirus disease 2019 (COVID-19). A cumulative body of data has indicated that the SARS-CoV-2 viral load may be a determinant of the COVID-19 severity. Here we summarize the main characteristics of the emerging variants of SARS-CoV-2, discussing their impact on viral transmissibility, viral load, disease severity, vaccine breakthrough, and lethality among COVID-19 patients. We also provide a rundown of the rapidly expanding scientific evidence from clinical studies and animal models that indicate how viral load could be linked to COVID-19 prognosis and vaccine efficacy among vaccinated individuals, highlighting the differences compared to unvaccinated individuals.

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SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains

Cited by 85 publications

References 60 publications

SARS-CoV-2 Variants of Concern Infect the Respiratory Tract and Induce Inflammatory Response in Wild-Type Laboratory Mice

SARS-CoV-2 Variants of Concern Infect the Respiratory Tract and Induce Inflammatory Response in Wild-Type Laboratory Mice

Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay

Viral Load in COVID-19 Patients: Implications for Prognosis and Vaccine Efficacy in the Context of Emerging SARS-CoV-2 Variants

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