Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI72110.15789/2220-7619-2019-5-6-639-647REVIEWSОБЗОРЫCurrent understanding of Bacillus anthracis toxin molecules organization and approaches for blocking their cytotoxic actionСовременное понимание организации молекул токсинов сибирской язвы и подходы к блокированию их цитотоксического действияhttps://orcid.org/0000-0002-9898-9894FirstovaV. V.ФирстоваВ. В.
Russian Federation

Victoria V. Firstova, PhD, MD (Biology), Head Researcher of Molecular Biology

142279, Moscow Region, Obolensk.

Phone: +7 (4967) 36-00-03. Fax: +7 (4967) 36-00-10.

Фирстова Виктория Валерьевна, д.б.н., главный научный сотрудник лаборатории молекулярной биологии 

142279, Московская область, п. Оболенск.

Тел.: 8 (4967) 36-00-03. Факс: 8 (4967) 36-00-10.

firstova@obolensk.orgShemyakinI. G.ШемякинИ. Г.
Russian Federation

PhD, MD (Biology), Professor, Deputy Director for Science

Obolensk, Moscow Region

д.б.н., профессор, зам. директора по науке 

п. Оболенск, Московская областьDyatlovI. A.ДятловИ. А.
Russian Federation

RAS Full Member, PhD, MD (Medicine), Professor, Director

Obolensk, Moscow Region

академик РАН, профессор, д.м.н., директор

п. Оболенск, Московская областьState Research Center for Applied Microbiology and BiotechnologyФБУН Государственный научный центр прикладной микробиологии и биотехнологии Роспотребнадзора0112201995-66396472507201815032019Copyright ©; 2019, Firstova V.V., Shemyakin I.G., Dyatlov I.A.Copyright ©; 2019, Фирстова В.В., Шемякин И.Г., Дятлов И.А.2019Firstova V.V., Shemyakin I.G., Dyatlov I.A.Фирстова В.В., Шемякин И.Г., Дятлов И.А.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/721

Here, we review the data on mechanisms inhibiting cytotoxic effect of anthrax toxin on the immune system cells. Various disease forms, immunopathogenesis and contemporary methods for anthrax treatment are discussed. In addition, an anthrax toxin was outlined, whereas structural and functional organization of the protective antigen, lethal and edema factors was detailed. A mechanism for association of a protective antigen and lethal factor, protective antigen and edema factor leading to formation of a lethal toxin and edema toxin, respectively, was described. Participation of protective antigen domains in the process of interaction with surface receptors of imunocompetent cells as well as features of binding a protective antigen with lethal factor and edema factor are discussed. A mechanism of endosomal toxin complex internalization and subsequent transfer of effector molecules to the cytosol are described. Effects of the lethal factor and the edema factor on components of eukaryotic cells as well as cytotoxicity mechanisms are analyzed. The approaches to block anthrax toxin action at various stages of toxicoemia have been analyzed based on previously uncovered sequential signs of cytotoxic activity for Bacillus anthracis toxins. Currently available chimeric and humanized monoclonal antibodies are capable of neutralizing B. anthracis toxins at diverse assembly stages, particularly considering the drugs inhibiting: inter-receptor interaction between protective antigen with eukaryotic cells; furin-like enzymes activating prepore assembly; protective antigen oligomerization; binding of the lethal factor or edema factor to the protective antigen; translocation of the lethal factor or the edema factor into cell cytosol; transport of protective antigen with lethal factor or edema factor from endosomes; enzymatic activity of lethal factor or edematous factor. The anti-toxin agents approved for anthrax prevention and treatment in Russia and worldwide are discussed. The limitations of anti-toxin agents and perspectives for their improvement are also described including inhibition of lethal factor activity, interference with integration of toxin components, blockade of interactions between toxic complexes and immune cell receptors.

В обзорной статье приводятся результаты разносторонних исследований механизмов ингибирования цитотоксического действия сибиреязвенного токсина на клетки иммунной системы. Рассмотрены различные формы заболевания, иммунопатогенез и современные методы лечения сибирской язвы. Описан сибиреязвенный токсин Bacillus anthracis. Детально описана структурно-функциональная организация протективного антигена, летального и отечного факторов. Представлен механизм ассоциации протективного антигена и летального фактора, приводящий к образованию летального токсина, а также описан процесс образования комплекса протективный антиген — отечный фактор, формирующего отечный токсин. Рассмотрено участие доменов протективного антигена в процессе взаимодействия с рецепторами на поверхности иммунокомпетентных клеток и охарактеризованы особенности связывания протективного антигена с летальным фактором и отечным фактором. Описаны механизмы интернализации комплексов токсинов в эндосому и последующая транлокация эффекторных молекул в цитозоль. Проанализированы направленность действия летального и отечного факторов на структуры эукариотических клеток, механизмы цитотоксичности. На основании описанной последовательности проявления цитотоксической активности токсинами B. anthracis проанализированы подходы к блокированию их действия на различных стадиях токсикоемии. Описаны полученные к настоящему времени химерные и гуманизированные моноклональные антитела, способные нейтрализовать токсины B. anthracis на разных этапах сборки. В частности, рассмотрены препараты, ингибирующие: межрецепторные взаимодействия протективного антигена с рецепторами эукариотической клетки; фуринподобные ферменты, активирующие сборку препоры; олигомеризацию протективного антигена; связывание летального или отечного факторов с протективным антигеном; транслокацию летального или отечного факторов сибирской язвы в цитозоль клетки; транскрипцию протективного антигена с летальным или отечным факторами из эндосом; ферментативную активность летального или отечного факторов. Рассмотрены препараты, утвержденные для профилактики и лечения сибирской язвы в России и за рубежом. Описаны имеющиеся недостатки используемых препаратов и направления по их совершенствованию. В состав перспективных направлений входят ингибирование ферментативной активности летального фактора, препятствие ассоциации компонентов токсинов, блокирование взаимодействия токсических комплексов с рецепторами клеток иммунной системы.

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