Рекомбинантные миниантитела человека в формате scFv к энтеротоксину A стафилококков: получение и характеристика тема диссертации и автореферата по ВАК РФ 03.01.03, кандидат биологических наук Фурсова, Ксения Константиновна

• Фурсова, Ксения Константиновна
• кандидат биологических наук
• 2013

Оглавление диссертации кандидат биологических наук Фурсова, Ксения Константиновна

ВВЕДЕНИЕ

ГЛАВА 1. ОБЗОР ЛИТЕРАТУРЫ

1.1. Энтеротоксины стафилококков

1.1.1. Стафилококки - условно-патогенные микроорганизмы

1.1.2. Энтеротоксины стафилококков

1.1.3. Молекулярная структура стафилококкового энтеротоксина А

1.1.4. Механизм действия энтеротоксинов стафилококков

1.1.5. Методы молекулярной детекции стафилококковых энтеротоксинов

1.2. Антитела

1.2.1. Структура иммуноглобулинов

1.2.2. Разнообразие форматов антител

1.2.3. Методы и технологии получения бсЕу

1.2.4. Экспрессия бсГу

1.2.5. Применение антител

1.3. Продукция рекомбинантных белков в клетках Е.соИ

1.3.1. Основные аспекты рефолдинга

1.3.2. Выделение телец включения

1.3.3. Способы рефолдинга белка

1.3.4. Добавки при рефолдинге

1.3.5. Вклад дисульфидных связей в белковый фолдинг

ГЛАВА 2. ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ

2.1. Материалы исследования

2.2. Методы

2.2.1. Аффинная селекция миниантител из фаговой библиотеки

2.2.2. Скрининг индивидуальных продуцентов из фаговой библиотеки

2.2.3. Выделение фаговых частиц

2.2.4. ИФА бсГу в фаговом формате

2.2.5. ИФА эсЕу-фрагментов

2.2.6. «Сэндвич»-иммуноанализ на иммунопланшетах

2.2.7. Иммуно-ПЦР в фаговом формате

2.2.8. Клонирование генов миниантител в экспрессионный вектор

2.2.9. Трансформация и анализ клонов Е.соИ

2.2.10. Экспрессия всЕу в клетках Е.соИ

2.2.11. Анализ уровня синтеза всЕу

2.2.12. Экспрессия и выделение эсЕу из телец включения

2.2.13. Экспрессия и выделение растворимых бсЕу

2.2.14. Рефолдинг миниантител с помощью металл-хелатной хроматографии

2.2.15. Рефолдинг миниантител гель фильтрацией

2.2.16. Определение аргинина с помощью тонкослойной хроматографии

2.2.17. Электрофоретический анализ белковых препаратов в нативных условиях

2.2.18. Регистрация спектров кругового дихроизма

2.2.19. Определение констант диссоциации

2.2.20. Эпитопный анализ стафилококкового энтеротоксина А

2.2.21. Иммуно-блот анализ

2.2.22. Лиофилизация миниантител

ГЛАВА 3. РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ

3.1. Миниантитела в фаговом формате

3.1.1. Получение всЕу фрагментов в составе фаговой частицы

3.1.2. Использование фаговых миниантител для детекции

3.2. Миниантитела всЕу

3.2.1. Анализ уровня синтеза миниантител

3.2.1.1. Выделение миниантител из растворимой фракции

3.2.1.2. Выделение миниантител в денатурирующих условиях

3.3. Оценка стабильности миниантител при различных условиях хранения

3.4. Характеристика миниантител

3.4.1. Аффинность миниантител в отношении SEA

3.4.2. Анализ взаимодействия миниантител с родственными стафилококковыми энтеротоксинами

3.4.3. Эпитопный анализ стафилококкового энтеротоксина А

ВЫВОДЫ

СПИСОК СОКРАЩЕНИЙ

СПИСОК ЛИТЕРАТУРЫ

Введение диссертации (часть автореферата) на тему «Рекомбинантные миниантитела человека в формате scFv к энтеротоксину A стафилококков: получение и характеристика»

ВВЕДЕНИЕ

Актуальность темы исследования

Бактерии рода Staphylococcus являются одной из основных причин пищевых отравлений и аутоиммунных расстройств. К причинам патогенности Staphylococcus aureus относятся факторы вирулентности вырабатываемые бактерией - это и факторы адгезии, и разнообразные ферменты, играющие роль факторов «агрессии и защиты», и комплекс секретируемых экзотоксинов (Becker et al., 2003). Около 6% синтезируемого клеткой белка составляют энтеротоксины (Thomas et al., 2007; Lowy, 1998). На сегодняшний день описано более 20 энтеротоксинов, среди которых SEA один из наиболее распространенных.

Энтеротоксины - семейство белков с молекулярной массой 23-29 кД, взаимодействующих с антигенами гистосовместимости (MHC-II) и Т-клеточным рецептором (TCR) (Thomas et al., 2009). В результате такого взаимодействия является образование комплекса из двух видов клеток и антигена, провоцирующий гипериммунный ответ (Profit, Fraser, 2003).

Отравление пищевыми продуктами, содержащими энтеротоксины стафилококков, широко распространено и находится на втором месте после отравлений, вызываемых сальмонельными инфекциями (Lowy, 1998; Le Louir et al., 2003). При пищевых отравлениях возможны различные осложнения, включая развитие пневмонии (Cheng et al., 2012), аутоиммунных заболеваний, таких как ревматоидный артрит (Howell et al.,1991.), атопический дерматит (Ikezawa et al., 2010; Niebuhr et al., 2010), и аллергические заболевания. Синтезируемые бактериями энтеротоксины могут проникать в кровоток не только через ткани желудочно-кишечного тракта, но и через эпителиальные ткани дыхательных путей и кожных покровов (Balaban, Rasooly, 2000; Peterson et al., 2005).

Таким образом, задача детекции и нейтрализации токсинов является актуальной в здравоохранении, и представляет интерес для современной науки. Вакцинация пациентов природным антигеном осложняется ответной

гиперреакцией организма. Применение рекомбинантных аналогов энтеротоксина и конкурентных молекул, блокирующих взаимодействие токсинов с рецепторами на компетентных клетках оказалось малоэффективно (Bavari et al., 1996; Bavari et al., 1999). Показано, что антитела иммунных доноров способны нейтрализовывать энтеротоксины при пассивной вакцинации. Поэтому получение нейтрализующих антител или искусственных конструктов на их основе может быть одним из решений данной задачи и представляет несомненный интерес.

Один из основных способов получения антител человека - это конструирование библиотек антител на основе генетического материала антителопродуцирующих клеток доноров и отбор из этих библиотек антител с заданными свойствами.

Цель данной работы: получение рекомбинантных миниантител человека в формате scFv против стафилококкового энтеротоксина А с помощью технологии фагового дисплея и характеристика их взаимодействия с антигеном. В задачи работы входило:

1. провести аффинное обогащение фаговой библиотеки на стафилококковом энтеротоксине А и определить уровень детекции SEA с помощью фаговых антител;

2. экспрессировать антитела в клетках Е. coli и выделить очищенные препараты миниантител в активной форме;

3. разработать способ хранения полученного препарата миниантител;

4. определить основные характеристики полученных миниантител: аффинность, специфичность;

5. провести картирование эпитопов SEA, распознаваемых полученными миниантител ами.

Научная новизна работы

В настоящей работе впервые были получены миниантитела человека в формате scFv против стафилококкового энтеротоксина А. На основе полученных фаговых антител разработан способ детекции SEA с

использованием фагового иммуно-ПЦР. Разработан способ выделения и ренатурации миниантител из телец включения методом гельфильтрации через слой раствора аргинина. Впервые показана возможность хранения лиофилизованного препарата фаговых миниантител. Установлены эпитопы взаимодействия полученных антител со стафилококковым энтеротоксином А.

Научно-практическая значимость работы

Полученные антитела возможно использовать для создания диагностического набора на основе твердофазного ИФА или ПЦР метода, а также терапевтического препарата с токсин-нейтрализующей активностью. Антитела могут быть перспективным инструментом для структурно-функциональных исследований стафилококковых энтеротоксинов.

Методология работы состояла из набора молекулярно-биологических методов, таких как технология фагового дисплея, молекулярное клонирование, экспрессия и выделение рекомбинантных белков, ПЦР. Характеристика антител проводилась с помощью физико-химических и иммунохимических методов: белковый электрофорез, спектроскопия кругового дихроизма, иммуно-ферментный анализ и иммуноблоттинг. Для установления эпитопов использовались базы данных и пакеты программ NCBI/BLAST, Chromas, GeneRunner 3.05, ClustalW, UCSF Chimera 1.6.2.

Положения, выносимые на защиту

1. Используя библиотеку миниантител, сконструированную на основе неиммунных доноров с помощью методов аффинной селекции возможно получить миниантитела к стафилококковому энтеротоксину А. Разработан способ детекции SEA с использованием полученных миниантител с помощью метода иммуно-ПЦР в фаговом формате.

2. Полученные рекомбинантные антитела эффективно экспрессируются в клетках Е. coli. Миниантитела синтезируются как в виде растворимого клеточного белка, так и виде телец включения. Полученные миниантитела успешно подвергаются рефолдингу телец включения с помощью метода

гельфильтрации через слой аргинина. Участие аргинина в данном процессе способствует повышению выхода ренатурированного препарата. 3. Полученные рекомбинантные антитела распознают разные эпитопы молекулы стафилококкового энтеротоксина А. Эпитопы представляют собой линейные участки длиной 5-7 аминокислот, локализованные на поверхности молекулы SEA.

Апробация работы

Материалы диссертации были представлены на международных конференциях: зимняя молодёжная научная школа «Перспективные направления физико-химической биологии и биотехнологии» (Москва, 2013), 9th IST Asia Pacific meeting on animal, plant and microbial toxins (Владивосток, 2011), 10-ом съезде Научного общества гастроэнтерологов России «Российские научные школы. Технологии качества» (Москва, 2010), на ежегодных Пущинских школах-конференциях молодых ученых «Биология - наука XXI века» (Пущино, 2010, 2011, 2012), V Международная конференция «Наука и образование для целей биобезопасности» (Пущино, 2008).

Диссертационная работа была апробирована на межлабораторном семинаре ФБУН ФИБХ РАН, и семинаре секции "Молекулярная биология" Ученого совета ФГУП ГосНИИгенетика.

Основные результаты по теме диссертации изложены в 10 работах: 4 статьи в журналах, входящих в перечень периодических изданий, рекомендованных ВАК; 6 - представлено в виде материалов конференций.

Заключение диссертации по теме «Молекулярная биология», Фурсова, Ксения Константиновна

выводы

1. С помощью технологии фагового дисплея получены миниантитела человека в формате бсБу к стафилококковому энтеротоксину А. Разработан способ детекции стафилококкового энтеротоксина А в фемптомолярных концентрациях методом иммуно-ПЦР в фаговом формате.

2. Предложены условия экспрессии миниантител в растворимом виде и в виде телец включения. Разработан способ рефолдинга одноцепочных миниантител в присутствии раствора аргинина с помощью метода гельфильтрации. Метод позволяет отделять мономерную активную форму мининатител от агрегированной. Эффективность рефолдинга составляет 5080%.

3. Подобраны условия хранения миниантител. Показано, что миниантитела, экспонированные в виде слитного БсРу-рШ белка на фаговой частице, так и свободные миниантитела сохраняют свою активность после лиофилизации в присутствии 0,1 М трегалозы.

4. Исследована специфичность взаимодействия полученных миниантител с энтеротоксинами стафилококков. Константы диссоциации миниантител при взаимодействии со стафилококковым энтеротоксином А

7 ^ составляют 10 - 10 .

5. Установлены последовательности распознаваемых миниантителами эпитопов. Показано, что миниантитела распознают линейные эпитопы, локализованные на разных доменах стафилокококкового энтеротоксина А.

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