Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19

Sun, Cheng‐Pu; Jan, Jia-Tsrong; Wang, I-Hsuan; Ma, Hsiu-Hua; Ko, Hui-Ying; Wu, Ping-Yi; Kuo, Tzu-Jiun; Liao, Hsin-Ni; Lan, Yu-Hua; Sie, Zong-Lin; Chen, Yen‐Hui; Ko, Yi-An; Liao, Chun-Che; Chen, Liang-Yu; Lee, I-Jung; Tsung, Szu-I; Lai, Yun‐Ju; Chiang, Ming‐Tsai; Liang, Jian-Jong; Liu, Wen-Chun; Wang, Jing‐Rong; Yuan, Joyce Pei-Yi; Lin, Yin-Shiou; Tsai, Yi-Ching; Hsieh, Shie Liang; Li, Chia-Wei; Wu, Han‐Chung; Ko, Tai‐Ming; Lin, Yi-Ling; Tao, Mi‐Hua

doi:10.1371/journal.ppat.1009758

Cited by 22 publications

(27 citation statements)

References 81 publications

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“…It is known that SARS-CoV-2 S with Furin cleavage site mutation and S-2P substitutions is stabilized in the prefusion state to stimulate better immune responses ( 11 , 31 ). The R682G and R682G-S813Y mutants have lower sensitivity to enzymatic processes ( 14 , 32 ), which might enhance their potency during vaccination. To test the hypothesis, hamsters were immunized with R682G or R682G-S813Y mutants, and their immune responses were analyzed at two weeks post-immunization ( Figure 7A ).…”

Section: Resultsmentioning

confidence: 99%

“…For SARS-CoV-2 challenge tests, immunized hamsters were intranasally inoculated with 1×10 5 TCID 50 of SARS-CoV-2 (hCoV-19/Taiwan/4/2020). K18-human ACE2 transgenic mice ( 32 ) were imported from the Jackson Laboratory and bred at BioLASCO Taiwan and NHRI. The transgenic mice were immunized with 1×10 8 ffu or pfu of recombinant VSV viruses with boost doses at a 3 weeks interval.…”

Section: Methodsmentioning

confidence: 99%

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Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

et al. 2022

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An effective COVID-19 vaccine against broad SARS-CoV-2 variants is still an unmet need. In the study, the vesicular stomatitis virus (VSV)-based vector was used to express the SARS-CoV-2 Spike protein to identify better vaccine designs. The replication-competent of the recombinant VSV-spike virus with C-terminal 19 amino acid truncation (SΔ19 Rep) was generated. A single dose of SΔ19 Rep intranasal vaccination is sufficient to induce protective immunity against SARS-CoV-2 infection in hamsters. All the clones isolated from the SΔ19 Rep virus contained R682G mutation located at the Furin cleavage site. An additional S813Y mutation close to the TMPRSS2 cleavage site was identified in some clones. The enzymatic processing of S protein was blocked by these mutations. The vaccination of the R682G-S813Y virus produced a high antibody response against S protein and a robust S protein-specific CD8+ T cell response. The vaccinated animals were protected from the lethal SARS-CoV-2 (delta variant) challenge. The S antigen with resistance to enzymatic processes by Furin and TMPRSS2 will provide better immunogenicity for vaccine design.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

et al. 2022

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“…Mice were anesthetized and transduced with 3 × 10 11 vg of AAV6/hACE2 intratracheally and 1 × 10 12 vg AAV9/hACE2 intraperitoneally 2 weeks after immunization [ 19 ]. The transduced mice were then challenged with 2 × 10 5 TCID 50 of SARS-CoV-2 (wild-type, hCoV-19/Taiwan/4/2020) intranasally.…”

Section: Methodsmentioning

confidence: 99%

A booster dose of Delta × Omicron hybrid mRNA vaccine produced broadly neutralizing antibody against Omicron and other SARS-CoV-2 variants

Lee

Sun²,

Wu³

et al. 2022

J Biomed Sci

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Background With the continuous emergence of new SARS-CoV-2 variants that feature increased transmission and immune escape, there is an urgent demand for a better vaccine design that will provide broader neutralizing efficacy. Methods We report an mRNA-based vaccine using an engineered “hybrid” receptor binding domain (RBD) that contains all 16 point-mutations shown in the currently prevailing Omicron and Delta variants. Results A booster dose of hybrid vaccine in mice previously immunized with wild-type RBD vaccine induced high titers of broadly neutralizing antibodies against all tested SARS-CoV-2 variants of concern (VOCs). In naïve mice, hybrid vaccine generated strong Omicron-specific neutralizing antibodies as well as low but significant titers against other VOCs. Hybrid vaccine also elicited CD8+/IFN-γ+ T cell responses against a conserved T cell epitope present in wild type and all VOCs. Conclusions These results demonstrate that inclusion of different antigenic mutations from various SARS-CoV-2 variants is a feasible approach to develop cross-protective vaccines.

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“…We have used recombinant adeno-associated virus to introduce human ACE2 (hACE2) into wild type mice to establish a SARS-CoV-2 infection model system [31]. To evaluate the roles of CLEC5A and TLR2 in SARS-CoV-2-induced thromboinflammation, the AAV-hACE2 was introduced to wild-type littermates (WT) and clec5a -/- tlr2 -/- mice to address this question.…”

Section: Resultsmentioning

confidence: 99%

“…Virus preparation and inoculation of SARS-CoV-2 into C57BL/6 and clec5a -/- tlr2 -/- mice were as described [31]. Lung tissue was collected at 3 days and 5 days post-infection for further analysis.…”

Section: Methodsmentioning

confidence: 99%

CLEC5A and TLR2 are critical in SARS-CoV-2-induced NET formation and lung inflammation

Sung

Yang

Peng

et al. 2022

Preprint

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Coronavirus-induced disease 19 (COVID-19) infects more than three hundred and sixty million patients worldwide, and people with severe symptoms frequently die of acute respiratory distress syndrome (ARDS). Autopsy demonstrates the presence of thrombosis and microangiopathy in the small vessels and capillaries. Recent studies indicated that excessive neutrophil extracellular traps (NETs) contributed to immunothrombosis, thereby leading to extensive intravascular coagulopathy and multiple organ dysfunction. Thus, understanding the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced NET formation would be helpful to reduce thrombosis and prevent ARDS. It has been shown that sera from individuals with COVID-19 triggered NET release in vitro, and spleen tyrosine kinase (Syk) inhibitor R406 inhibited NETosis caused by COVID-19 plasma. However, the serum components responsible for NET formation are still unknown. In this study, we found that virus-free extracellular vesicles (EVs) from COVID-19 patients (COVID-19 EVs) induced robust NET formation via Syk-coupled C-type lectin member 5A (CLEC5A). Blockade of CLEC5A inhibited COVID-19 EVs-induced NETosis, and simultaneous blockade of CLEC5A and TLR2 further suppressed SARS-CoV-2-induced NETosis in vitro. Moreover, thromboinflammation and lung fibrosis were attenuated dramatically in clec5a-/-/tlr2-/- mice. These results suggest that COVID-19 EVs play critical roles in SARS-CoV-2-induced immunothrombosis, and blockade of CLEC5A and TLR2 is a promising strategy to inhibit SARS-CoV-2-induced intravascular coagulopathy and reduce the risk of ARDS in COVID-19 patients.

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Rapid generation of mouse model for emerging infectious disease with the case of severe COVID-19

Cited by 22 publications

References 81 publications

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

Furin and TMPRSS2 Resistant Spike Induces Robust Humoral and Cellular Immunity Against SARS-CoV-2 Lethal Infection

A booster dose of Delta × Omicron hybrid mRNA vaccine produced broadly neutralizing antibody against Omicron and other SARS-CoV-2 variants

CLEC5A and TLR2 are critical in SARS-CoV-2-induced NET formation and lung inflammation

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