vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-49vavilov-3391Research ArticleТЕСТ-СИСТЕМЫ И ВАКЦИНОПРОФИЛАКТИКАСоздание трансгенных мышей, восприимчивых к коронавирусам: платформа изучения вирусного патогенеза и тестирования вакцинCreation of transgenic mice susceptible to coronaviruses: a platform for studying viral pathogenesis and testing vaccinesБаттулинН. Р.BattulinN. R.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-1056-2966СеровО. Л.SerovO. L.

Новосибирск

Novosibirsk

serov@bionet.nsc.ruФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian Federation202207072022264402408Copyright © Баттулин Н.Р., Серов О.Л., 20222022Баттулин Н.Р., Серов О.Л.Battulin N.R., Serov O.L.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3391

За последние 20 лет коронавирусы вызвали три эпидемии, SARS-CoV, MERS-CoV и SARS-CoV2, причем летальность первых двух была очень высокой: около 10 и 26 % соответственно. Последняя вспышка коронавирусной инфекции, вызванная SARS-CoV2 в 2019 г. в Китае, охватила всю планету, и она все еще продолжает распространяться. Источником этих вирусов у человека были животные: летучие мыши, гималайские циветы и верблюды. Геномы MERS-CoV, SARS-CoV и SARS-CoV2 имеют высокое сходство между собой. Установлено, что заражение коронавирусной инфекцией (SARS-CoV и SARS-CoV2) происходит посредством контакта вирусного белка S с рецептором легочного эпителия – ангиотензин-конвертирующим ферментом 2 (АСЕ2), благодаря чему вирус попадает в клетки. Наиболее привлекательной моделью для исследования особенностей развития этих заболеваний является лабораторная мышь, которая, однако, резистентна к коронавирусной инфекции. Резистентность объясняется различием аминокислотного состава белков Асе2 мыши и АСЕ2 человека. Поэтому при получении мышей, восприимчивых к коронавирусам SARS-CoV и SARS-CoV2, в их геном переносят ген АСЕ2 человека. Экзогенная ДНК конструкций встраивается в реципиентный геном случайным образом и с варьирующим числом копий. На основе этой технологии были получены линии трансгенных мышей, восприимчивых к интраназальной коронавирусной инфекции. Применение технологии адресной модификации геномов с помощью CRISPR/Cas9 позволило получить линии трансгенных животных с инсерцией гена АСЕ2 человека под контроль промотора эндогенного гена Асе2 мыши. Такая «гуманизация» гена Ace2 дает возможность получить животных, наиболее близко имитирующих коронавирусную инфекцию человека. Таким образом, к настоящему времени создана серия линий трансгенных мышей – животных, моделирующих коронавирусные инфекции человека и потенциально способных служить платформами для тестирования вакцин.

Over the past 20 years, coronaviruses have caused three epidemics: SARS-CoV, MERS-CoV, and SARS-CoV2, with the first two having a very high lethality of about 10 and 26 %, respectively. The last outbreak of coronavirus infection caused by SARS-CoV2 in 2019 in China has swept the entire planet and is still spreading. The source of these viruses in humans are animals: bats, Himalayan civets, and camels. The genomes of MERS-CoV, SARS-CoV and SARS-CoV2 are highly similar. It has been established that coronavirus infection (SARS-CoV and SARS-CoV2) occurs through the viral protein S interaction with the lung epithelium – angiotensin-converting enzyme receptor 2 (ACE2) – due to which the virus enters the cells. The most attractive model for studying the development of these diseases is a laboratory mouse, which, however, is resistant to coronavirus infection. The resistance is explained by the difference in the amino acid composition of mouse Ace2 and human ACE2 proteins. Therefore, to create mice susceptible to SARS-CoV and SARS-CoV2 coronaviruses, the human ACE2 gene is transferred into their genome. The exogenous DNA of the constructs is inserted into the recipient genome randomly and with a varying number of copies. Based on this technology, lines of transgenic mice susceptible to intranasal coronavirus infection have been created. In addition, the use of the technology of targeted genome modification using CRISPR/Cas9 made it possible to create lines of transgenic animals with the insertion of the human ACE2 gene under the control of the endogenous murine Ace2 gene promoter. This “humanization” of the Ace2 gene makes it possible to obtain animals susceptible to infection with coronaviruses. Thus, transgenic animals that simulate coronavirus infections and are potential platforms for testing vaccines have now been created.

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The authors declare that there are no conflicts of interest present.