Галектин-опосредованное связывание вируса гриппа с клетками-мишенями тема диссертации и автореферата по ВАК РФ 02.00.10, кандидат химических наук Черный, Евгений Станиславович

• Черный, Евгений Станиславович
• кандидат химических наук
• 2013

Оглавление диссертации кандидат химических наук Черный, Евгений Станиславович

СОДЕРЖАНИЕ

Стр

Список использованных сокращений

1 ВВЕДЕНИЕ

2 ОБЗОР ЛИТЕРАТУРЫ

Глава 1 Структурные компоненты вируса гриппа

1 1 Структура нейраминидазы 1 2 Гликозилирование нейраминидазы 1 3 Структура гемагглютинина

1 4 Гликозилирование гемагглютинина

Глава 2 Сборка и отпочковывание (баддинг) вируса гриппа

2 1 Липидный состав вируса гриппа

2 2 Роль НА и ИА в сборке и баддинге вирионов

2 3 Роль М1 и М2 в сборке и баддинге вирионов

Глава 3 Структурная организация вируса гриппа

3 1 Современные методы изучения морфологии вируса гриппа 3 2 Размеры и форма вирионов

3 3 Поверхность вируса гриппа

Глава 4 Галектины

4 1 Структура галектинов

4 2 Биологическая роль галектинов 4 3 Куриные галектины

3 МАТЕРИАЛЫ И МЕТОДЫ

4 РЕЗУЛЬТАТЫ И ОБСУЖДЕНИЕ

1 Проверка первых двух гипотез Роль белков в составе вириона

1 1 Поиски белков клетки-хозяина

1 2 Поиск «неклассических» углеводных рецепторов

для вируса гриппа

2 Взаимодействие вируса гриппа с галектинами

2 1 Изучение связывания вируса гриппа с галектинами

с помощью твердофазного анализа 2 2 Влияние галектинов на функционирование НА и

КА вируса гриппа 3 Ингибирование галектинами связывания антител с вирусом

3 1 Ингибирование связывания поликлональных

антител с вирусом гриппа 3 2 Ингибирование галектинами связывания сыворотки больных гриппом с вирусом гриппа

3 3 Ингибирование галектинами связывания

внутривенного иммуноглобулина с вирусом гриппа 4 Роль галектинов на стадии адгезии вирионов на клетке

4 1 Расположение галектинов и вируса гриппа на поверхности клетки 4 2 Изучение влияния галектинов на связывание вируса гриппа

с клетками

4 3 Проверка влияния флуоресцентной метки на связывание

вируса с галектинами 4 4 Действие галектинов при нагрузке на вирионы 4 5 Ингибирование взаимодействия галектинов с вирусом 4 6 Влияние на адгезию гликома вируса и клеточной поверхности

4 7 Связывание вируса с десиалилированными клетками

в присутствии галектинов

5 Мечение вирусов гриппа с помощью флуоресцентного липида

127

6 Исследование полного цикла заражения вируса в присутствии галектинов 6 1 Влияние галектинов на заражение монослоя клеток вирусом 6 2 Действие галектинов на эффект заражения клеток вирусом гриппа,

132

сравнение разных условий проведения эксперимента

7 О возможности участия галектинов в инфекционном процессе вируса гриппа

142

5 ЗАКЛЮЧЕНИЕ

6 ВЫВОДЫ

7 Благодарности

8 СПИСОК ЛИТЕРАТУРЫ

146

147

148

Список использованных сокращений

АЭК - аминоэтилкарбазол FITC - флуоресцеинизотиоционат ДСН - додецилсульфат натрия Fluo-DOPE - флуоресцентный липид ГАЕ - гемагглютинирующая единица М - матриксный белок НА - гемагглютинин

НВ-сайт - гемоадсорбционный сайт нейраминидазы РГА - реакция гемагглютинации ТФА - твердофазный анализ РНП - рибонуклеопротеин

MDCK - линия клеток Madin-Darby Canine Kidney

NA - нейраминидаза

NP - нуклеопротеин

NS - неструктурный белок

CG - Куриные галектины

hG - Человеческие галектины

УСД - углевод связывающий домен

Сахариды, конъюгаты и субстраты NA:

Glyc-PAA-biot - биотинилированный гликоконъюгат конъюгат на основе полиакриламида

Neu5Ac - N-ацетилнейраминовая кислота

3'SL - Neu5Aca2-3Gaipi-4Glc

3'SLN - Neu5Aca2-3Gaipi-4GlcNAc

6'SLN - Neu5Aca2-6Gaipi-4GlcNAc

Lex - Gaipi-4(Fucal-3)GlcNAcp

B,ri- Galal-3(Fucal-2)Galp

Fs-2 - GalNAcal-3GalNAcp

Tn - aGalNAc

LacNAc - Gaipi-4GlcNAc

А тип 1 -GalNAcal-3(Fucal-2)Galpl-3GlcNAc

А тип 2 - GalNAcal -3(Fuca 1 -2)Gaip 1 -4GlcNAc

В тип 1 - Gala 1 -3 (Fuca 1 -2)Gaip 1 -3 GlcNAc

В тип 2 - Galal-3(Fucal -2)Gaipi -4GlcNAc

H тип 1 -Fucal-2Gaipi-3GlcNAc

H тип 2 - Fucal-2Gaipi-4GlcNAc

MU-NANA - метилумбеллиферил N-ацетилнейраминовая кислота BODIPY - 6-((4,4-дифторо-5,7-диметил-4-бора-За,4а-даиза-5-индацин-3-пропионил)амино)гексаноилвая кислота сукцинимидный эфир

Введение диссертации (часть автореферата) на тему «Галектин-опосредованное связывание вируса гриппа с клетками-мишенями»

1. ВВЕДЕНИЕ

Вирус гриппа - один из наиболее изученных объектов среди возбудителей опасных заболеваний человека. Тем не менее, в начале 21 века человечество фактически не имеет ни надежного лекарства против него, ни системы вакцинации, способной гарантированно предотвратить заболевание. Поэтому расширение представлений о структурной организации, рецепторной специфичности и репликации вируса в организме хозяина, с целью разработки принципиально новых подходов к терапии и предупреждению этого заболевания, является крайне актуальной задачей.

Стадии первичного связывания и проникновения вируса гриппа в заражаемую клетку по-прежнему являются предметами активного изучения. На сегодняшний день, устоявшиеся представления о том, что единственным рецептором вируса гриппа являются сиалогликаны, регулярно подвергаются сомнению, и высказываются предположения о существовании дополнительных факторов, участвующих в адгезии вирионов на поверхности клетки (Stray and others 2000; Rapoport and others 2006; M L Yang and others 2011). В связи с этим, исследования в данном направлении являются актуальной задачей, решение которой может привести к разработке нового поколения лекарственных препаратов - блокаторов адгезии вируса гриппа. Кроме того, детальное изучение комплексных процессов, протекающих в организме при иммунном ответе на вторжение вируса, и, прежде всего, реакция к поверхностным гликопротеинам вирионов как антигенам, открывает возможности для разработки новых иммунотерапевтических подходов.

Цели и задачи исследования.

Целью данной кандидатской диссертации являлось обнаружение дополнительных факторов, участвующих в рецепции вируса гриппа на начальной стадии заражения клеток.

Предполагалось решить следующие задачи:

1. Изучить возможность связывания вируса гриппа с несиалилированными углеводными лигандами.

2. Экспериментально проверить гипотезу о возможности связывания галектинов с вирусом гриппа и установить роль этих белков во взаимодействии вирусных частиц с клеткой-мишенью.

3. Изучить влияние галектинов на связывание антител с вирусом гриппа.

Научная новизна.

• большая часть представителей семейства куриных и человеческих галектинов специфично связываются с вирусом гриппа;

• галектины, несмотря на способность увеличивать адгезию вируса

5

гриппа на клетке-мишени, выступают как ингибиторы процесса заражения;

• при отсутствии основного сиало-рецептора, галектины могут обеспечивать высокий уровень адгезии вируса на клетке;

• связывание галектинов с вирусом гриппа не приводит к изменению функциональных свойств гемагглютинина и нейраминидазы, но маскирует их антигенные детерминанты.

Практическая значимость.

^ Обнаруженная компенсаторная роль галектинов при отсутствии сиалорецепторов на клетке заставляет по-новому относиться к терапевтическим методам, нацеленным на ингибирование сиало-опосредованного заякоревания вируса гриппа, а именно, учитывать этот фактор при испытании антиадгезионных препаратов.

^ Галектин-опосредованную адгезию вируса гриппа на клетке необходимо учитывать в производстве живых вакцин, которые получают наращиванием вируса в клеточных культурах.

^ Найденный эффект ингибирования галектинами протективных антивирусных антител открывает новую возможную область для совершенствования анти-вирусной иммунотерапии.

2. ОБЗОР ЛИТЕРАТУРЫ

Заключение диссертации по теме «Биоорганическая химия», Черный, Евгений Станиславович

6. выводы

1. Обнаружена способность галектинов связываться с вирусом гриппа. Нагрузка галектинов на поверхность вируса не изменяет функциональную активность гемагглютинина и нейраминидазы.

2. Связывание с галектинами маскирует антигенные детерминанты поверхности вируса гриппа, предохраняя его от присоединения антител.

3. Галектины в отсутствие сиалозидов способны обеспечивать адгезию вируса гриппа на клетке-мишени. На галектин-опосредованную адгезию влияет углеводный состав как вируса, так и клетки.

4. Галектины ингибируют инфицирование, несмотря на то, что способствуют адгезии вируса гриппа на клетке.

5. Предложен новый метод мечения вируса гриппа с помощью введения гидрофобной флуоресцентной метки в состав липидной мембраны вирионов.

7. Благодарности

Автор крайне признателен A.C. Гамбарян (Институт полиомиелита и вирусных энцефалитов им. М.П.Чумакова РАМН, Москва) за помощь в выращивании вирусов, Е.М. Рапопорт (ИБХ РАН, Москва) за помощь в клеточной работе, Е.Ю. Корчагиной (ИБХ РАН, Москва) за синтез Fluo-DOPE и обсуждение работы, Л.В. Кордюковой (НИИ ФХБ, Москва) за рекомендации в проведении ряда экспериментов, Т. Гардеру (Институт Фридриха-Леффлера, Грайфсвальд, Германия) за сотрудничество в проведении ряда экспериментов, М.Н. Матросовичу (Университет имени Филиппа, Марбург, Германия) за предоставление культуры MDCK6SIAT, Е.И. Бурцевой (НИИ Вирусологии, Москва) за предоставление вируса H1N1 Москва и человеческой сыворотки и Г.-И. Габиусу (Университет имени Максимилиана, Мюнхен, Германия) за предоставление галектинов.

5. ЗАКЛЮЧЕНИЕ

Несмотря на то, что вирус гриппа является одним из самых хорошо изученных вирусов, он, по-прежнему, представляет опасность для здоровья человека. Лекарственные препараты, которые доступны на сегодняшний день, направлены на подавление активности нейраминидазы или М2 белка вируса гриппа. Между тем, эти компоненты являются минорными, в то время как большую часть поверхности вируса занимает гемагглютинин. Однако, лекарственных средств направленного действия против гемагглютинина пока не существует. Выявленные в данной работе закономерности делают более полным понимание процесса адгезии вируса на клетке-мишени. Полученные результаты могут способствовать разработке терапевтического подхода, объединяющего блокирование гемагглютинина и галектина. Еще одним средством борьбы с вирусом гриппа является вакцинация. Несмотря на огромные усилия по разработке синтетических вакцин, реально действующими и надежными остаются вакцины, основанные на целых вирионах, которые по современным технологиям нарабатываются в клеточной культуре. Обнаруженные в данном исследовании факты влияния галектинов на адгезию вирусов к клетке и на процесс заражения, несомненно, внесут определенные коррективы в будущие разработки новых противогриппозных вакцин.

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