김동범 (한림대학교 의과대학)

한빛사논문

조회234

김동범Dongbum Kim

한림대학교 의과대학

J. Med. Virol., Feb 2024, 96 (2) | https://doi.org/10.1002/jmv.29459 A mouse xenograft long-term replication yields a SARS-CoV-2 Delta mutant with increased lethality

Dongbum Kim ¹, Minyoung Kim², Jinsoo Kim ¹, Kyeongbin Baek ², Heedo Park ³, Sangkyu Park ⁴, Bo Min Kang ², Suyeon Kim², Mo-Jong Kim ⁵, Mohd Najib Mostafa ^5,6, Sony Maharjan ¹, Ha-Eun Shin ⁴, Myeong-Heon Lee ⁴, Jin Il Kim³, Man-Seong Park ³, Yong-Sun Kim ^2,5, Eun-Kyoung Choi ^5,6, Younghee Lee ⁴, Hyung-Joo Kwon^1,2

¹Institute of Medical Science, College of Medicine, Hallym University, Chuncheon, Republic of Korea.

²Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.

³Department of Microbiology, Vaccine Innovation Center College of Medicine, Institute for Viral Diseases, Korea University, Seoul, Republic of Korea.

⁴Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Republic of Korea.

⁵Ilsong Institute of Life Science, Hallym University, Seoul, Republic of Korea.

⁶Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Republic of Korea.

Dongbum Kim, Minyoung Kim, Jinsoo Kim, and Kyeongbin Baek contributed equally to this study.

CORRESPONDING AUTHORS : Eun-Kyoung Choi, Younghee Lee, Hyung-Joo Kwon

Abstract

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta-10 and Delta-12, with both predominant mutations and some additional mutations. Delta-10 and Delta-12 showed lower replication capacity compared with SARS-CoV-2 Delta in cultured cells; however, Delta-12 was more lethal in K18-hACE2 mice compared with SARS-CoV-2 Delta and Delta-10. Mice infected with Delta-12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta-12 was associated with lung and brain pathology. Our long-term infection model can provide mutant viruses derived from SARS-CoV-2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-03-06)
연구진국내 연구진
분야 생명과학 > 생화학

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