Single amino acid mutation of nectin-1 provides remarkable resistance against lethal pseudorabies virus infection in mice
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- TOMIOKA Yukiko
- Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori, Japan
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- TAKEDA Keiko
- Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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- OZAKI Kinuyo
- Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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- INOUE Hiromi
- Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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- YAMAMOTO Sayo
- Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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- TAKEUCHI Takashi
- Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori, Japan
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- ONO Etsuro
- Department of Biomedicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
抄録
<p>An approach to genetically engineered resistance to pseudorabies virus (PRV) infection was examined by using a mouse model with defined point mutation in primary receptor for alphaherpesviruses, nectin-1, by the CRISPR/Cas9 system. It has become clear that phenylalanine at position 129 of nectin-1 is important for binding to viral glycoprotein D (gD), and mutation of phenylalanine 129 to alanine (F129A) prevents nectin-1 binding to gD and virus entry in vitro. Here, to assess the antiviral potential of the single amino acid mutation of nectin-1, F129A, in vivo, we generated genome-edited mutant mouse lines; F129A and 135 knockout (KO). The latter, 135 KO used as a nectin-1 knockout line for comparison, expresses a carboxy-terminal deleted polypeptide consisting of 135 amino acids without phenylalanine 129. In the challenge with 10 LD50 PRV via intranasal route, perfect protection of disease onset was induced by expression of the mutation of nectin-1, F129A (survival rate: 100% in F129A and 135 KO versus 0% in wild type mice). Neither viral DNA/antigens nor pathological changes were detected in F129A, suggesting that viral entry was prevented at the primary site in natural infection. In the challenge with 50 LD50 PRV, lower but still strong protective effect against disease onset was observed (survival rate: 57% in F129A and 75% in 135 KO versus 0% in wild type mice). The present results indicate that single amino acid mutation of nectin-1 F129A provides significant resistance against lethal pseudorabies.</p>
収録刊行物
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- Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ｖｅｔｅｒｉｎａｒｙ Ｍｅｄｉｃａｌ Ｓｃｉｅｎｃｅ
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Ｔｈｅ Ｊｏｕｒｎａｌ ｏｆ Ｖｅｔｅｒｉｎａｒｙ Ｍｅｄｉｃａｌ Ｓｃｉｅｎｃｅ 86 (1), 120-127, 2024
公益社団法人 日本獣医学会