Антигенное картирование молекулы гемагглютинина вируса гриппа H5N1 и влияние изменения антигенной структуры на вирулентность тема диссертации и автореферата по ВАК РФ 03.01.03, кандидат биологических наук Крылов, Петр Сергеевич

• Крылов, Петр Сергеевич
• кандидат биологических наук
• 2010

Введение диссертации (часть автореферата) на тему «Антигенное картирование молекулы гемагглютинина вируса гриппа H5N1 и влияние изменения антигенной структуры на вирулентность»

Актуальность темы.6

Цели исследования.9

Научная новизна и практическое значение работы.11

Основные положения, выносимые на защиту.:.12

Часть I. Обзор литературы.14

Часть I. Обзор литературы.14

Заключение диссертации по теме «Молекулярная биология», Крылов, Петр Сергеевич

Выводы

1. Впервые осуществлено антигенное картирование молекулы гемагглютинина (НА) высокопатогенного вируса гриппа H5N1 с использованием трехмерной модели гемагглютинина подтипа Н5 посредством селекции эскейп-мутантов моноклональными антителами с последующим секвенированием мутантных генов НА и определения их перекрестной реактивности с моноклональными антителами.

2. Определена локализация, протяженность и структура двух антигенных сайтов в трехмерной структуре молекулы НА вируса A/Vietnam/1203/04 (H5N1).

3. Выявлены особенности моноклональных антител против НА вируса A/Vietnam/1203/04 (H5N1), отличающие их от охарактеризованных ранее моноклональных антител против НА подтипа Н5. Идентифицированы 4 ранее не описанные аминокислотные позиции в НА подипа Н5, распознаваемые моноклональными антителами. В Зх других позициях выявлены ранее не описанные аминокислотные замены, меняющие антигенную специфичность НА.

4. Впервые выявлена способность некоторых моноклональных антител против НА подтипа Н5 распознавать аминокислотные позиции, локализованные в двух разных антигенных сайтах.

5. У двух эскейп-мутантов, имеющих аминокислотную замену S145F в НА, выявлено резкое снижение вирулентности для мышей. Реадаптация низковирулентных эскейп-мутантов посредством пассажей на мышах при интраназальном заражении приводила к восстановлению вирулентности.

6. Реассортационный анализ, проведенный с использованием скрещивания и с применением сайт-специфического мутагенеза, показал, что снижение вирулентности эскейп-мутантов, имеющих замену S145F в НА, вызвано именно этой заменой. Восстановление вирулентности при пассировании низковирулентных эскейп-мутантов может быть обусловлено как дополнительными мутациями в гене НА, так и изменениями в других генах.

7. Аминокислотные замены в НА эскейп-мутантов вируса АЛ/1е1:пат/1203/04 (Н5Ш), совпадают с аминокислотными заменами у природных высокопатогенных изолятов Н5№, относящихся к разным ветвям филогенетического дерева. Это указывает на существенное значение вариаций антигенных сайтов, идентифицированных и охарактеризованных в настоящей работе, для эволюции иммунологических свойств и вирулентности вирусов подтипа Н5]Ч1.

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