Биохимическая и молекулярно-биологическая характеристика штаммов микобактерий туберкулезного комплекса, распространенных в Санкт-Петербурге тема диссертации и автореферата по ВАК РФ 03.01.04, кандидат биологических наук Черняева, Екатерина Николаевна

• Черняева, Екатерина Николаевна
• кандидат биологических наук
• 2012

Оглавление диссертации кандидат биологических наук Черняева, Екатерина Николаевна

СПИСОК СОКРАЩЕНИЙ И ОБОЗНАЧЕНИЙ.

ВВЕДЕНИЕ.

Цель и задачи исследования.

Научная новизна и практическая значимость работы.

1. ОБЗОР ЛИТЕРАТУРЫ.

1.1. Общая характеристика микобактерий туберкулезного комплекса.

1.2. Геном микобактерий туберкулезного комплекса.

1.3. Методы анализа генома микобактерий туберкулезного комплекса.

1.4. Генетическое разнообразие штаммов микобактерий туберкулезного комплекса.

1.5. Семейства сполиготипов микобактерий туберкулезного комплекса. Распространенность различных сполиготипов микобактерий туберкулезного комплекса в разных регионах мира.

1.6. Молекулярные механизмы лекарственной устойчивости М. tuberculosis.

1.7. Проблема множественной и широкой лекарственной устойчивости.

1.8. Эпидемиологическая ситуация по туберкулезу в России и в мире.

1.9. Распространенность туберкулеза в различных социальных группах.

2. МАТЕРИАЛЫ И МЕТОДЫ.

2.1. Материалы.

2.2. Методы.

3. РЕЗУЛЬТАТЫ.

3.1. Анализ точечных мутаций, ассоциированных с устойчивостью М. tuberculosis к изониазиду, рифампицину и офлоксацину.

3.2. Сравнение сполиготипов офлоксацин-устойчивых штаммов М. tuberculosis, штаммов обладающих МЛУ и штаммов чувствительных ко всем ПТП.

3.3. Результаты анализа сполиготипов М. tuberculosis, обнаруженных у пациентов, принадлежащих к различным группам риска.

3.3. Анализ регионов различия генома МБТ.

3.4. Формирование коллекции геномной ДНК штаммов МБТ.

4. ОБСУЖДЕНИЕ.

4.1. Анализ точечных мутаций в генах katG, rpoB, gyrA и gyrB, ассоциированных с устойчивостью штаммов М. tuberculosis к противотуберкулезным препаратам.

4.2. Анализ сполиготипов офлоксацин-устойчивых штаммов М. tuberculosis, штаммов обладающих МЛУ и штаммов чувствительных ко всем ПТП.

4.3. Анализ сполиготипов М. tuberculosis, обнаруженных у пациентов, принадлежащих к различным группам риска.

5. ВЫВОДЫ.

Заключение диссертации по теме «Биохимия», Черняева, Екатерина Николаевна

5. ВЫВОДЫ

1. Секвенирование фрагментов генома санкт-петербургских изолятов M.tuberculosis показало:

- точечные мутации, обнаруженные в генах кatG и гроВ среди 93 и 88% INH-и RIF-устойчивых изолятов, соответственно, являются надежными маркерами устойчивости к данным препаратам;

- детекция мутаций в области QRDR гена gyrA позволяет обнаружить не менее 50% OFL-устойчивых изолятов;

- область QRDR гена gyrB не имела мутаций, ассоциированных с устойчивостью к OFL, в исследованной группе изолятов.

2. Генотипирование штаммов М. tuberculosis на основе полиморфизма области прямых повторов выявило доминирование генетического семейства Beijing во всех исследованных группах изолятов. Исследованные штаммы семейства Beijing достоверно чаще (р<0,05) обладали МЛУ, устойчивостью к OFL, а также значительно чаще преобладали среди пациентов, находящихся в местах лишения свободы, чем штаммы других генотипов.

3. Впервые показано распространение генетически сходных изолятов M.tuberculosis среди бездомных, ВИЧ-инфицированных и пациентов из общей популяции жителей Санкт-Петербурга. Сравнение сполиготипов исследованных штаммов МБТ обнаружило более низкое генетическое разнообразие бактериальных штаммов, выявленных среди заключенных, а также среди OFL-устойчивых изолятов.

4. Сформирована коллекция образцов геномной ДНК клинических штаммов M.tuberculosis, полученных от больных туберкулезом жителей Санкт-Петербурга, необходимая для создания кандидатного вакцинового препарата, направленного на профилактику и лечение туберкулезной инфекции. Данная коллекция образцов может быть использована для разработки тест-систем по обнаружению лекарственно-устойчивых штаммов МБТ.

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220. Номер изолята Код изолята на дендрограмме Год сбора образца Возбудитель Пол/возраст пациента Код сполиготипа в базе данных SpolDB4 Семейство сполиготипов Лекарственная устойчивость* Комментарии*

221. Нуклеотидная последовательность фрагмента гена katG, несущая мутации, ассоциированные с устойчивостью микобактерий к изониазиду.