microbeПроблемы особо опасных инфекцийProblems of Particularly Dangerous Infections0370-10692658-719XRussian Research Anti-Plague Institute “Microbe”10.21055/0370-1069-2012-2(112)-69-74microbe-800Research ArticleИММУНОЛОГИЯ, ПАТОГЕНЕЗIMMUNOLOGY, PATHOGENESISФормирование внеклеточных ловушек - эффективный механизм защиты организма от патогенаFormation of Extracellular Traps - the Effective Mechanism of Organism Protection from PathogenКравцовА. Л.KravtsovA. L.rusrapi@microbe.ruРоссийский научно-исследовательский противочумный институт «Микроб»РоссияRussian Research Anti-Plague Institute MicrobeRussian Federation20122004201202(112)6974Copyright © Кравцов А.Л., 20122012Кравцов А.Л.Kravtsov A.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.microbe.ru/jour/article/view/800

В обзоре обобщены и проанализированы современные литературные данные о способности клеток, реализующих механизмы врожденного иммунитета (нейтрофилов, эозинофилов и тучных клеток), формировать внеклеточные ловушки для захвата и киллинга патогенных микроорганизмов путем секреции ДНК и содержимого бактерицидных гранул в экстрацеллюлярное пространство. Эффективность улавливания и обезвреживания патогенов во внеклеточных ловушках выше, чем при фагоцитозе, и предполагают, что механизм внеклеточной бактерицидности играет важную роль в защите организма от бактерий, обладающих устойчивостью к лейкоцитарному фагоцитозу.

Summarized and analyzed are modern literature data on capability of cells (neutrophils, eosinophils and labrocytes) realizing the mechanisms of innate immunity, to form extracellular traps that capture and kill pathogens by secretion of DNA and antibacterial granules content into extracellular space. The efficiency of capture and bacterial clearance is higher in extracellular traps than that in phagocytosis. The mechanism of extracellular bactericidal activity is supposed to play an important role in protection of organism from bacteria which are resistant to phagocytosis by leukocytes.

внеклеточные ловушкиврожденный иммунитетбактериальная инфекциясекреция ДНКсекреторная дегрануляциялейкоцитарные протеазыантибактериальные пептидыextracellular spaceinnate immunitybacterial infectionDNA secretionsecretory degranulationleukocyte proteasesantibacterial peptidesReferencesДолгушин И.И., Андреева Ю.С., Савочкина А.Ю. Нейтрофильные внеклеточные ловушки и методы оценки функционального статуса нейтрофилов. М.: Изд-во РАМН; 2009. 208 с.Dolgushin I.I., Andreeva Yu.S., Savochkina A.Yu. [ Neutrophil Extracellular Taps and Methods of Assessment of Neutrophils Functional Status]. M.: RAMS; 2009. 208 p.Исачкова Л.М., Плехова Н.Г. К развитию представлений об антиинфекционной резистентности. Эпидемиол. и инф. бол. 2002; 1:11-5.Isachkova L.M., Plekhova N.G. [To the development of view about anti-infective resistance]. Epidemiol. Infek. Bol. 2002; 1:11–5.Козинец Г.И., Высоцкий В.В., Погорелов В.М. и др. Кровь и инфекция. М.: Триада-Фарм; 2001. 456 с.Kozinets G.I., Vysotsky V.V., Pogorelov V.M. et al. [Blood and Infection]. M.; 2001. 456 p.Кравцов А.Л., Гребенюкова Т.П., Тараненко Т.М., Кузнецов О.С., Храмченкова Т.А., Наумов А.В. Проточно-цитофлуориметрический мониторинг за развитием азурофильной дегрануляции нейтрофилов в цельной крови человека в ответ на эндотоксин Yersinia pestis. Пробл. особо опасных инф. 1999; 79:81-9.Kravtsov A.L., Grebenyukova T.P., Taranenko T.M., Kuznetsov O.S., Chramchenkova T.A., Naumov A.V. [Flow cytofluorimetric monitoring for the development of neutrophil degranulation (azurophil) in the whole human blood as a response to endotoxin of Yersinia pestis]. Probl. Osobo Opasn. Infek. 1999; 79:81–9.Кравцов А.Л., Шмелькова Т.П. Секреторная дегрануляция нейтрофилов как триггер воспаления и регулятор иммунного ответа: роль сериновых лейкоцитарных протеаз и протеолитически активируемых рецепторов. Эпидемиол. и вакцинопрофилакт. 2011; 1(56):79-87.Kravtsov A.L., Shmel’kova T.P. [Secretory degranulation of neutro- phils as a trigger of inflammation and regulator of immune response: the role of serine leukocyte proteases and protease-activated receptors]. Epidemiol. Vaktsinoprofilakt. 2011; 1(56):79–87.Кравцов А.Л., Шмелькова Т.П., Щуковская Т.Н. Влияние противочумной вакцинации на функциональную активность клеток врожденного иммунитета человека. Пробл. особо опасных инф. 2011; 1(107):77-80.Kravtsov A.L., Shmel’kova T.P., Shchukovskaya T.N. [Influence of the anti-plague vaccination on the functional activity of human innate immu- nity cells]. Probl. Osobo Opasn. Infek. 2011; 1(107):77–80.Семенов Б.Ф., Зверев В.В. Концепция создания быстрой иммунологической защиты от патогенов. Журн. эпидемиол, микробиол. и иммунобиол. 2007; 4:93-100.Semenov B.F., Zverev V.V. [Concept of construction of rapid immu- nological protection from pathogens]. Zh. Microbiol. Epidemiol. Immunobiol. 2007; 4:93–100.Фрадкин В.А. Диагностика аллергии реакциями нейтрофилов крови. М.: Медицина; 1985. 176 с.Fradkin V.A. [Diagnostics of Allergy by Blood Neutrophil Reactions]. M.: Meditsina; 1985. 176 p.Шишкова Ю.С., Савочкина А.Ю., Рыжкова А.И., Мезенцева Е.А. Влияние препарата «пирогенал» на образование нейтрофильных внеклеточных ловушек. Мед. наука и образование Урала. 2009; 10(3):23-4.Shishkova Yu.S., Savochkina A.Yu., Ryzhkova A.I., Mezentseva E.A. [Influence of “Pirogenalum” preparation on formation of neutrophils extracel- lular traps]. Med. Nauka Obraz. Urala. 2009; 10(3):23–4.Яглова Н.В. Тучные клетки и врожденный иммунитет. Иммунология. 2009; 2:139-42.Yaglova N.V. [Mast cells and innate immunity]. Immunologia. 2009; 139–42.Baker V.S., Imade G.E., Molta N.B. et al. Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age. Malar. J. 2008; 7:41.Baker V.S., Imade G.E., Molta N.B. et al. Cytokine-associated neutrophil extracellular traps and antinuclear antibodies in Plasmodium falciparum infected children under six years of age. Malar. J. 2008; 7:41.Bianchi M., Hakkim A., Brinkmann V. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009; 114(13):2619-22.Bianchi M., Hakkim A., Brinkmann V. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood. 2009; 114(13):2619-22.Bischoff S.C., Kamer S. Human mast cells, bacteria, and intestinal immunity. Immunol. Rev. 2007; 217:329-37.Bischoff S.C., Kamer S. Human mast cells, bacteria, and intestinal immunity. Immunol. Rev. 2007; 217:329-37.Brinkmann V., Reichard U., Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303:1532-5.Brinkmann V., Reichard U., Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303:1532-5.Buchanan J.T., Simpson A.J., Aziz R.K. et al. Dnase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 2006; 16:396-400.Buchanan J.T., Simpson A.J., Aziz R.K. et al. Dnase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr. Biol. 2006; 16:396-400.Chromy B.A., Perkins J., Heidbrink J.L. et al. Proteomic characterization of host response to Yersinia pestis and near neighbors. Biochem. Biophys. Res. Commun. 2004; 320:474-9.Chromy B.A., Perkins J., Heidbrink J.L. et al. Proteomic characterization of host response to Yersinia pestis and near neighbors. Biochem. Biophys. Res. Commun. 2004; 320:474-9.Clark S.R., Ma A.C., Tavener S.A. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 2007; 13:463-9.Clark S.R., Ma A.C., Tavener S.A. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 2007; 13:463-9.Cole A.M., Shi J., Ceccarelli A. et al. Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds. Blood. 2001; 97(1):297-304.Cole A.M., Shi J., Ceccarelli A. et al. Inhibition of neutrophil elastase prevents cathelicidin activation and impairs clearance of bacteria from wounds. Blood. 2001; 97(1):297-304.Eggers C.T., Murray I.A., Delmar V.A. et al. The periplasmic serine protease inhibitor ecotin protects bacteria against neutrophil elastase. Biochem. J. 2004; 379 (Pt.1):107-18.Eggers C.T., Murray I.A., Delmar V.A. et al. The periplasmic serine protease inhibitor ecotin protects bacteria against neutrophil elastase. Biochem. J. 2004; 379 (Pt.1):107-18.Ermert D., Urban CF., Laube B. et al. Mouse neutrophil extracellular traps in microbial infections. J. Innate Immun. 2009; 1:181-93.Ermert D., Urban CF., Laube B. et al. Mouse neutrophil extracellular traps in microbial infections. J. Innate Immun. 2009; 1:181-93.Fuchs T.A., Abed U., Goosmann C. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 2007; 176:231-41.Fuchs T.A., Abed U., Goosmann C. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 2007; 176:231-41.Fuchs T.A., Brill A., Duerschmied D. et al. Extracellular DNA traps promote trombosis. Proc. Natl Acad. Sci. USA. 2010; 107(36): 15880-5.Fuchs T.A., Brill A., Duerschmied D. et al. Extracellular DNA traps promote trombosis. Proc. Natl Acad. Sci. USA. 2010; 107(36): 15880-5.Garcia R., Gusmani L., Murgia R. et al. Elastase is the only human neutrophil granule protein that alone is responsible for in vitro killing of Borrelia durgdorferi. Infec. Immunity.1998; 66(4): 1408-12.Garcia R., Gusmani L., Murgia R. et al. Elastase is the only human neutrophil granule protein that alone is responsible for in vitro killing of Borrelia durgdorferi. Infec. Immunity.1998; 66(4): 1408-12.Guimaraes-Costa A.B., Nascimento M.T., Froment G.S. et al. Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc. Natl Acad. Sci. USA. 2009; 106: 6748-53.Guimaraes-Costa A.B., Nascimento M.T., Froment G.S. et al. Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc. Natl Acad. Sci. USA. 2009; 106: 6748-53.Hakkim A., Furnrohr B.G., Amann K. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA. 2010; 107(21):9813-8.Hakkim A., Furnrohr B.G., Amann K. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA. 2010; 107(21):9813-8.Hickey M.J., Kubes P. Intravascular immunity: the host-pathogen encounter in blood vessels. Nature Rev. Immunology. 2009; 6:364-74.Hickey M.J., Kubes P. Intravascular immunity: the host-pathogen encounter in blood vessels. Nature Rev. Immunology. 2009; 6:364-74.Hirche T.O., Benabid R., Delslee G. et al. Netrophil elastase mediates innate host protection against Pseudomonas aeruginosa. J. Immunology. 2008; 181:4945-54.Hirche T.O., Benabid R., Delslee G. et al. Netrophil elastase mediates innate host protection against Pseudomonas aeruginosa. J. Immunology. 2008; 181:4945-54.Hong W., Juneau R.A., Pang B., Swords W.E. Survival bacterial biofilms within neutrophil extracellular traps promotes nontypeable Haemophilus influenzae persistence in the chinchilla model otitis media. J. Innate Immun. 2009; 1:215-24.Hong W., Juneau R.A., Pang B., Swords W.E. Survival bacterial biofilms within neutrophil extracellular traps promotes nontypeable Haemophilus influenzae persistence in the chinchilla model otitis media. J. Innate Immun. 2009; 1:215-24.Kravtsov A.L., Grebenyukova T.P., Bobyleva E.V. et al. Flow cytofluorometric assay of human whole blood leukocyte DNA degradation in response to Yersinia pestis and Staphylococcus aureus. Proc. SPIE. 2001; 4241:260-6.Kravtsov A.L., Grebenyukova T.P., Bobyleva E.V. et al. Flow cytofluorometric assay of human whole blood leukocyte DNA degradation in response to Yersinia pestis and Staphylococcus aureus. Proc. SPIE. 2001; 4241:260-6.Kravtsov A.L., Bobyleva E.V., Grebenyukova T.P. et al. Flow microfluorometric analysis of phagocyte degranulation in bacteria infected whole blood cell cultures. Proc. SPIE. 2002; 4707: 395-402.Kravtsov A.L., Bobyleva E.V., Grebenyukova T.P. et al. Flow microfluorometric analysis of phagocyte degranulation in bacteria infected whole blood cell cultures. Proc. SPIE. 2002; 4707: 395-402.Lauth X., von Köckritz-Blickwede M., McNamara C.W. et al. M1 protein allows group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J. Innate Immun. 2009; 1:202-14.Lauth X., von Köckritz-Blickwede M., McNamara C.W. et al. M1 protein allows group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J. Innate Immun. 2009; 1:202-14.Lee W.L., Grinstain S. The tangled webs that neutrophils weave. Science. 2004; 303:1477-8.Lee W.L., Grinstain S. The tangled webs that neutrophils weave. Science. 2004; 303:1477-8.Lopez-Boado Y.S., Espinola M., Bahr S., Belaaouaj A. Neutrophil serine proteinases cleave bacterial flagellin, abrogating its host response-inducing activity. J. Immunol. 2004; 172:509-15.Lopez-Boado Y.S., Espinola M., Bahr S., Belaaouaj A. Neutrophil serine proteinases cleave bacterial flagellin, abrogating its host response-inducing activity. J. Immunol. 2004; 172:509-15.Ma A.C., Kubes P. Platelets, neutrophils and neutrophil extracellular traps in sepsis. J. Thromb. Haemost. 2007; 6:415-20.Ma A.C., Kubes P. Platelets, neutrophils and neutrophil extracellular traps in sepsis. J. Thromb. Haemost. 2007; 6:415-20.Martinelli S., Urosevis M., Daryadel A. et al. Induction of genes mediating interferon-dependent extracelular trap formation during neutrophil differentiation. J. Biol. Chem. 2004; 279:44123-32.Martinelli S., Urosevis M., Daryadel A. et al. Induction of genes mediating interferon-dependent extracelular trap formation during neutrophil differentiation. J. Biol. Chem. 2004; 279:44123-32.Medina E. Neutrophil extracelular traps: a strategic tactic to defeat pathogens with potential consequences for the host. J. Innate immun. 2009; 1(3):176-80.Medina E. Neutrophil extracelular traps: a strategic tactic to defeat pathogens with potential consequences for the host. J. Innate immun. 2009; 1(3):176-80.Mizgerd J.P. Mechanisms of disease acute lower respiratory tract infection. N. Engl. J. Med. 2008; 358:716-27.Mizgerd J.P. Mechanisms of disease acute lower respiratory tract infection. N. Engl. J. Med. 2008; 358:716-27.Oehmske S., Morgelin M., Hervald H. Activation of the human contact system on neutrophil extracellular traps. J. Innate Immun. 2009; 1:225-30.Oehmske S., Morgelin M., Hervald H. Activation of the human contact system on neutrophil extracellular traps. J. Innate Immun. 2009; 1:225-30.Papayannopoulos V., Metzler K.D., Hakkim A. et al. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 2010; 191:677-91.Papayannopoulos V., Metzler K.D., Hakkim A. et al. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 2010; 191:677-91.Ramos-Kichik V., Mondragon-Flores R., Mondragon M. et al. Neutrophil extracellular traps are induced by Mycobacterium tuberculosis. Tuberculosis (Edinb). 2008; 89:29-37.Ramos-Kichik V., Mondragon-Flores R., Mondragon M. et al. Neutrophil extracellular traps are induced by Mycobacterium tuberculosis. Tuberculosis (Edinb). 2008; 89:29-37.Silva M.T. When two is better then one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J. Leukoc. Biol. 2010; 87:1-14.Silva M.T. When two is better then one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J. Leukoc. Biol. 2010; 87:1-14.Urban C.F., Reichard U., Brinkmann V. et al. Neutrophil extracellular traps cupture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006; 8:668-76Urban C.F., Reichard U., Brinkmann V. et al. Neutrophil extracellular traps cupture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006; 8:668-76von Köckritz-Blickwede M., Goldmann O., Thulin P. et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular traps formation. Blood. 2008; 111:3070-80.von Köckritz-Blickwede M., Goldmann O., Thulin P. et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular traps formation. Blood. 2008; 111:3070-80.von Köckritz-Blickwede M., Nizet V. Innate immunity turned inside-out: antimicrobial defense by phagocyte extracelular traps. J. Mol. Med. 2009; 87(8):775-83.von Köckritz-Blickwede M., Nizet V. Innate immunity turned inside-out: antimicrobial defense by phagocyte extracelular traps. J. Mol. Med. 2009; 87(8):775-83.Wartha F., Beiter K., Albiger B. et al. Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol. 2007; 9:1162-71.Wartha F., Beiter K., Albiger B. et al. Capsule and D-alanylated lipoteichoic acids protect Streptococcus pneumoniae against neutrophil extracellular traps. Cell Microbiol. 2007; 9:1162-71.Weinrauch Y., Drujan D., Shapiro S.D. et al. Neutrophil elastase targets virulence factors of enterobacteria. Nature. 2002; 417:91-4.Weinrauch Y., Drujan D., Shapiro S.D. et al. Neutrophil elastase targets virulence factors of enterobacteria. Nature. 2002; 417:91-4.Yost C.C, Cody M.J., Harris E.S. et al. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009; 113 (25):6419-27.Yost C.C, Cody M.J., Harris E.S. et al. Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood. 2009; 113 (25):6419-27.Yousefi S., Gold J.A., Andina N. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 2008; 14:949-53.Yousefi S., Gold J.A., Andina N. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 2008; 14:949-53.

The authors declare that there are no conflicts of interest present.