Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI38110.15789/2220-7619-2016-1-7-24REVIEWSОБЗОРЫCOXIELLA BURNETII PATHOGENICITY MOLECULAR BASISМОЛЕКУЛЯРНЫЕ ОСНОВЫ ПАТОГЕННОСТИ COXIELLA BURNETIIPanferovaYu. A.ПанфероваЮ. А.
Russian Federation

Junior Researcher, Laboratory of Zoonoses, St. Petersburg Pasteur Institute, St. Petersburg, Russian Federation 197101, Russian Federation, St. Petersburg, Mira str., 14, Phone: +7 (812) 232-21-36 (office). Fax: +7 (812) 232-92-17.

младший научный сотрудник лаборатории зооантропонозных инфекций ФБУН НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург, Россия 197101, Россия, Санкт-Петербург, ул. Мира, 14, Тел.: (812) 232-21-36 (служебн.). Факс: (812) 232-92-17.

panferova.jul@gmail.comSt. Petersburg Pasteur InstituteФБУН НИИ эпидемиологии и микробиологии имени Пастера, Санкт-Петербург, Россия09062016617240906201609062016Copyright ©; 2016, Panferova Y.A.Copyright ©; 2016, Панферова Ю.А.2016Panferova Y.A.Панферова Ю.А.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/381

Coxiella burnetii is an obligate intracellular gram-negative bacterial pathogen, an ethiological agent of Q-fever, a zoonotic disease, elapsing as an acute (mostly atypical pneumonia) or a chronic (mostly endocarditis) form. The host range is represented by wide range of mammal, avian and arthropod species, but the main source of human infection are farm animals. The main route of infection is aerosolic. In case of contact with organism pathogen binds with phagocytal monocytic-macrophagal cell line. C. burnetii promotes maturation of specific phagolysosome-like compartment in host cell, called coxiella-containing vacuole, within this vacuole pathogen becames metabolically activated and actively replicates. Coxiella persists as metabolically inactive spore-like form in environment. Internalisation of C. burnetii occurs using actin-mediated phagocytosis and zipper mechanism. After internalization of bacteria maturation of phagolysosome-like compartment and large coxiella-containing vacuole formation occure, and vacuole can occupy nearly the whole cytoplasm of the host cell. Survivance of infected cells is important for chronic infection with C. burnetii. C. burnetii elongate the viability of host cell by two ways: it actively inhibits apoptotic signal cascades and induce pro-survival factors. Exceptthat C. burnetii involves autophagic pathway during coxiella-containing vacuole formation, and induction of autophagy promotes pathogen replication. During infection C. burnetii translocates effector substrates from bacterial cytosole to euca ryotic host cell cytosole using type IV secretion system, where effectors modulate host cell proteins. Overall approximately 130 secreted effectors of type IV transport system, but function of most of them remains unknown to date. Specific sec reted proteins for variety of strains and isolates were identified, confirmed that certain pathotypes of C. burnetii can exist. Identification and characterization of novel virulence factors it is now possible through axenic media for C. burnetii cultivation and development of site-specific mutagenesis and other genetic technics, which is important for research of C. burnetii molecular pathogenesis.

Coxiella burnetii — облигатный внутриклеточный грамотрицательный бактериальный патоген, возбудитель Ку-лихорадки — природно-очагового заболевания, протекающего в острой (преимущественно в виде атипичной пневмонии) или хронической (чаще всего в виде эндокардита) форме. Хозяевами коксиелл в природе являются многие виды млекопитающих, птиц и членистоногих, основной источник инфекции для человека — сельскохозяйственные животные. Основной путь передачи инфекции — аэрозольный. При попадании в организм человека патоген связывается с фагоцитирующими клетками моноцитарно-макрофагального ряда. Внутри клетки хозяина C. burnetii способствует созреванию специфического, подобного фаголизосоме, компартмента, известного как коксиелла-содержащая вакуоль, внутри которого происходит метаболическая активация и репликация бактерий. Во внешней среде коксиелла существует в виде метаболически неактивной спороподобной формы. В процессе внедрения в клетку хозяина C. burnetii использует актинзависимый фагоцитоз и механизм «застежки-молнии». После интернализации бактерии происходит созревание фаголизосомоподобного компартмента и формирование крупной коксиелла-содержащей вакуоли, занимающей почти всю цитоплазму клетки хозяина. Выживание инфицированных клеток является важным для поддержания хронической коксиеллезной инфекции. Коксиелла продлевает жизнеспособность хозяйской клетки двумя способами: она активно ингибирует апоптотический сигнальный каскад и индуцирует способствующие выживанию факторы. Помимо этого, коксиелла активно задействует компоненты аутофагии в формировании коксиелла-содержащей вакуоли, и индукция аутофагии способствует внутриклеточной репликации патогена. В процессе инфекции коксиелла с помощью секреторной системы IV типа транслоцирует эффекторные субстраты из бактериального цитозоля напрямую в цитозоль эукариотной клетки, где они взаимодействуют с белками хозяина. Всего идентифицировано около 130 секретируемых эффекторов транспортной системы IV типа, функция большинства из них на данный момент неизвестна. Обнаружены специфические для ряда штаммов и изолятов секретируемые белки, что подтверждает существующую гипотезу о наличии отдельных патотипов C. burnetii. Идентификация и характеристика новых факторов вирулентности стала возможной пос ле появления бесклеточной среды для культивирования и развития методов сайт-специфического мутагенеза и других генетических манипуляций, что является важной вехой в исследовании молекулярного патогенеза C. burnetii.

Coxiella burnetiiQ-fevermolecular pathogenesisvirulencetransport systemsecreted effectorsCoxiella burnetiiКу-лихорадкамолекулярный патогенезвирулентностьтранспортная системасекретируемые эффекторы1. Aguilera M., Salinas R., Rosales E., Carminati S., Colombo M.I., Beron W. Actin dynamics and Rho GTPases regulate the size and formation of parasitophorous vacuoles containing Coxiella burnetii. Infect. Immun., 2009, vol. 77, no. 10, pp. 4609–4620. doi: 10.1128/IAI.00301-092. Alvarez-Martinez C.E., Christie P.J. Biological diversity of prokaryotic type IV secretion systems. Microbiol. Mol. Biol. Rev., 2009, vol. 73, no. 4, pp. 775–808. doi: 10.1128/MMBR.00023-093. Amano K., Williams J.C., Missler S.R., Reinhold V.N. Structure and biological relationships of Coxiella burnetii lipopolysaccharide. J. Biol. Chem., 1987, vol. 262, no. 10, pp. 4740–4747.4. Ashida H., Mimuro H., Ogawa M., Kobayashi T., Sanada T., Kim M., Sasakawa C. Cell death and infection: a double-edged sword for host and pathogen survival. J. Cell. Biol., 2011, vol. 195, no. 6, pp. 931–942. doi: 10.1083/jcb.2011080815. Baca O.G., Scott T.O., Akporiaye E.T., De Blassie R., Crissman H.A. Cell cycle distribution patterns and generation times of L929 fibroblast cells persistently infected with Coxiella burnetii. Infect. Immun., 1985, vol. 47, no. 2, pp. 366–369.6. Baca O.J., Klassen D.A., Aragon A.S. Entry of Coxiella burnetii into host cells. Acta Virol., 1993, vol. 37, no. 2–3, pp. 143–155.7. Banga S., Gao P., Shen X., Fiscus V., Zong W.X., Chen L., Luo Z.Q. Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family. Proc. Natl. Acad. Sci. USA, 2007, vol. 104, no. 12, pp. 5121–5126.8. Bartra S.S., Gong X., Lorica C.D., Jain C., Nair M.K., Schifferli D., Qian L., Li Z., Plano G.V., Schlesser K. The outer membrane protein A (OmpA) of Yersinia pestis promotes intracellular survival and virulence in mice. Microb. Pathog., 2012, vol. 52, no. 1, pp. 41–46. doi: 10.1016/j.micpath.2011.09.0099. Beare P.A., Unswoth N., Andoh M., Voth D.E., Omsland A., Gilk S.D., Williams K.P., Sobral B.V., Kupko J.J. 3rd, Porcella S.F., Samuel J.E., Heinzen R.A. Comparative genomics reveal extensive transposon-mediated genomic plasticity and diversity among potential effector proteins within the genus Coxiella. Infect. Immun., 2009, vol. 77, no. 2, pp. 642–656. doi: 10.1128/IAI.01141-0810. Beare P.A., Gilk S.D., Larson C.L., Hill J., Stead C.M., Omsland A., Cockrell D.C., Howe D., Voth D.E., Heinzen R.A. Dot/Icm type IVB secretion system requirements for Coxiella burnetii growth in human macrophages. MBio, 2011, vol. 2, no. 4, e0017511. doi: 10.1128/mBio.00175-1111. Beare P.A., Sandoz K.M., Larson C.L., Howe D., Kronmiller B., Heinzen R.A. Essential role for the response regulator PmeA in Coxiella burnetii type IVB secretion and colonization of mammalian host cells. J. Bacteriol., 2014, vol. 196, no. 11, pp. 1925–1940. doi: 10.1128/JB.01532-1412. Beare P.A., Larson C.L., Gilk S.D., Heinzen R.A. Two systems for targeted gene deletion in Coxiella burnetii. Appl. Environ. Microbiol., 2012, vol. 78, no. 13, pp. 4580–4589. doi: 10.1128/AEM.00881-1213. Benoit M., Barbarat B., Bernard A., Olive D., Mege J.L. Coxiella burnetii, the agent of Q fever, stimulates an atypical M2 activation program in human macrophages. Eur. J. Immunol., 2008, vol. 38, no. 4, pp. 1065–1070. doi: 10.1002/eji.20073806714. Berens C., Bisle S., Klingenbeck L., Luhrmann A. Applying an inducible expression system to study interference of bacterial virulence factors with intracellular signaling. J. Vis. Exp., 2015, vol. 100, e52903. doi: 10.3791/52903.15. Brennan R.E., Russell K., Zhang G.E., Samuel J. Both inducible nitric oxide synthase and NADPH oxidase contribute to the control of virulent phase I Coxiella burnetii infections. Infect. Immun., 2004, vol. 72, no. 11, pp. 6666–6675.16. Campodonico E.M., Chesnel L., Roy C.R. A yeast genetic system for the identification and characterization of substrate proteins transferred into host cells by the Legionella pneumophila Dot/Icm system. Mol. Microbiol., 2005, vol. 56, no. 4, pp. 918–933.17. Campoy E.M., Zoppino F.C., Colombo M.I. The early secretory pathway contributes to the growth of the Coxiella-replicative niche. Infect. Immun., 2011, vol. 79, no. 1, pp. 402–413. doi: 10.1128/IAI.00688-1018. Capo C., Lindberg F.P., Meconi S., Zaffran Y., Tardei G., Brown E.J., Raoult D., Mege J.L. Subversion of monocyte functions by Coxiella burnetii: impairment of the cross-talk between αvβ3 integrin and CR3. J. Immunol., 1999, vol. 163, no. 11, pp. 6078–6085.19. Carey K.L., Newton H., Luhrmann A.J., Roy C.R. The Coxiella burnetii Dot/Icm system delivers a unique repertoire of type IV effectors into host cells and is required for intracellular replication. PLoS Pathog., 2011, vol. 7, no. 5, e1002056. doi: 10.1371/journal.ppat.100205620. Chen C., Banga S., Mertens K., Weber M.M., Gorbaslieva I., Tan Y., Luo Z.Q., Samuel J.E. Large-scale identification and translocation of type IV secretion substrates by Coxiella burnetii. Proc. Natl. Acad. Sci. USA, 2010, vol. 107, no. 50, pp. 21755–21760. doi: 10.1073/pnas.101048510721. Coleman S.A., Fischer E.R., Howe D., Mead D.J., Heinzen R.A. Temporal analysis of Coxiella burnetii morphological differentiation. J. Bacteriol., 2004, vol. 186, no. 21, pp. 7344–7352.22. Datta D., Vaidehi N., Floriano W.B., Kim K.S., Prasadarao N.V., Goddard W.A. 3rd. Interaction of E. coli outer-membrane protein A with sugars on the receptors of the brain microvascular endothelial cells. Proteins, 2003, vol. 50, no. 2, pp. 213–221.23. De Felipe K.S., Pampou S., Jovanovic O.S., Pericone C.D., Ye S.F., Kalachikov S., Shuman H.A. Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer. J. Bacteriol., 2005, vol. 187, no. 22, pp. 7716–7726.24. De Felipe K.S., Glover R.T., Charpentier X., Anderson O.R., Reyes M., Pericone C.D., Shuman H.A. Legionella eukaryotic-like type IV substrates interfere with organelle trafficking. PLoS Pathog., 2008, vol. 4, no. 8, e1000117. doi: 10.1371/journal.ppat.100011725. De Fougerolles A.R., Koteliansky V.E. Regulation of monocyte gene expression by the extracellular matrix and its functional implications. Immunol. Rev., 2002, vol. 186, pp. 208–220.26. Dellacasagrande J., Capo C., Raoult D., Mege J.L. IFN-γ-mediated control of Coxiella burnetii survival in monocytes: the role of cell apoptosis and TNF. J. Immunol., 1999, vol. 162, no. 4, pp. 2259–2265.27. Dellacasagrande J., Ghigo E., Machergui-El S., Hammami S.M., Toman R., Raoult D., Capo C., Mege J.L. αvβ3 integrin and bacterial lipopolysaccharide are involved in Coxiella burnetii-stimulated production of tumor necrosis factor by human monocytes. Infect. Immun., 2000, vol. 68, no. 10, pp. 5673–5678.28. Eckart R.A., Bisle S., Schulze-Luehrmann J., Wittman I., Jantsch J., Schmid B., Berens C., Luhrmann A. Antiapoptotic activi ty of Coxiella burnetii effector protein AnkG is controlled by p32-dependent trafficking. Infect. Immun., 2014, vol. 82, no. 7, pp. 2763–2771. doi: 10.1128/IAI.01204-1329. Espenshade P.J., Hughes A.L. Regulation of sterol synthesis in eukaryotes. Annu. Rev. Genet., 2007, vol. 41, pp. 401–427.30. Flannagan R.S., Jaumouillé V., Grinstein S. The cell biology of phagocytosis. Annu. Rev. Pathol., 2012, vol. 7, pp. 61–98. doi: 10.1146/annurev-pathol-011811-13244531. Fu Y., Galan J.E. Salmonella protein antagonizes Rac1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature, 1999, vol. 401, pp. 293–297. doi: 10.1038/4582932. Ge J., Xu H., Li T., Zhou Y., Zhang Z., Li S., Liu L., Shao F. A Legionella type IV effector activates the NFκB pathway by phosphorylating the IκB family of inhibitors. Proc. Natl Acad. Sci. USA, 2009, vol. 106, no. 33, pp. 13725–13730. doi: 10.1073/pnas.090720010633. Graham J.J., Winchell C.J., Sharma U.M., Voth D.E. Identification of ElpA, a Coxiella burnetii pathotype-specific Dot/Icm type IV secretion system substrate. Infect. Immun., 2015, vol. 83, no. 3, pp. 1190–1198. doi: 10.1128/IAI.02855-1434. Gutierrez M.G., Vazques C.L., Munafo D.B., Zoppino F.C., Beron W., Rabinovitch M., Colombo M.I. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell Microbiol., 2005, vol. 7, no. 7, pp. 981–993. doi: 10.1111/j.1462-5822.2005.00527.x35. Hill J., Samuel J.E. Coxiella burnetii acid phosphatase inhibits the release of reactive oxygen intermediates in polymorphonuclear leukocytes. Infect. Immun., 2011, vol. 79, no. 1, pp. 414–420. doi: 10.1128/IAI.01011-1036. Hirschfeld M., Ma Y., Weis J.H., Vogel S.N., Weis J.J. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2. J. Immunol., 2000, vol. 165, no. 2, pp. 618–622. doi: 10.4049/jimmunol.165.2.61837. Honstettre A., Ghigo E., Moynault A., Capo C., Toman R., Akira S., Takeuchi O., Lepidi H., Raoult D., Mege J.L. Lipopolysaccharide from Coxiella burnetii is involved in bacterial phagocytosis, filamentous actin reorganization, and inflammatory responses through Toll-like receptor 4. J. Immunol., 2004, vol. 172, no. 6, pp. 3695–703. doi: 10.4049/jimmunol.172.6.369538. Howe D., Mallavia L.P. Coxiella burnetii exhibits morphological change and delays phagolysosomal fusion after internalization by J774A.1 cells. Infect. Immun., 2000, vol. 68, no. 7, pp. 3815–3821. doi: 10.1128/IAI.68.7.3815-3821.200039. Howe D., Heinzen R.A. Coxiella burnetii inhabits a cholesterol-rich vacuole and influences cellular cholesterol metabolism. Cell. Microbiol., 2006, vol. 8, no. 3, pp. 496–507. doi: 10.1111/j.1462-5822.2005.00641.x40. Howe D., Melnicakova J., Barak I., Heinzen R.A. Maturation of the Coxiella burnetii parasitophorous vacuole requires bacterial protein synthesis but not replication. Cell. Microbiol., 2003, vol. 5, no. 7, pp. 469–480. doi: 10.1046/j.1462-5822.2003.00293.x41. Howe D., Heinzen R.A. Replication of Coxiella burnetii is inhibited in CHO K-1 cells treated with inhibitors of cholesterol metabolism. Ann. NY Acad. Sci., 2005, vol. 1063, pp. 123–129. doi: 10.1196/annals.1355.02042. Huang L., Boyd D., Amyot W.M., Hempstaed A.D., Luo Z.Q., O’Connor T.J., Chan C., Machner M., Montminy T., Isberg R.R. The E Block motif is associated with Legionella pneumophila translocated substrates. Cell. Microbiol., 2011, vol. 13, no. 2, pp. 227–245. doi: 10.1111/j.1462-5822.2010.01531.x43. Hussain S.K., Broederdorf L.J., Sharma U.M., Voth D.E. Host kinase activity is required for Coxiella burnetii parasitophorous vacuole formation. Front. Microbiol., 2010, vol. 1:137. doi: 10.3389/fmicb.2010.0013744. Kinchen J.M., Ravichandran K.S. Phagosome maturation: going through the acid test. Nat. Rev. Mol. Cell Biol., 2008, vol. 9, no. 10, pp. 781–795. doi: 10.1038/nrm251545. Klingenbeck L., Eckart R.A., Berens C., Luhrmann A. The Coxiella burnetii type IV secretion system substrate CaeB inhibits intrinsic apoptosis at the mitochondrial level. Cell. Microbiol., 2013, vol. 15, no. 4, pp. 675–687. doi: 10.1111/cmi.1206646. Kubori T., Shinzawa N., Kanuka H., Nagai H. Legionella metaeffector exploits host proteasome to temporally regulate cognate effector. PLoS Pathog., 2011, vol. 6, no. 12, e1001216. doi: 10.1371/journal.ppat.100121647. Laguna R.K., Creasey E.A., Li Z., Valtz N., Isberg R.R. A Legionella pneumophila – translocated substrate that is required for growth within macrofages and protection from host cell death. Proc. Natl. Acad. Sci. USA, 2006, vol. 103, no. 49, pp. 18745–18750. doi: 10.1073/pnas.060901210348. Larson C.L., Beare P., Howe D.A., Heinzen R.A. Coxiella burnetii effector protein subverts clathrin-mediated vesicular trafficking for pathogen vacuole biogenesis. Proc. Natl. Acad. Sci. USA, 2013, vol. 110, no. 49, E4770–4779. doi: 10.1073/pnas.130919511049. Lifshitz Z., Burstein D., Peeri M., Zusman T., Schwartz K., Shuman H.A., Pupko T., Segal G. Computational modeling and experimental validation of the Legionella and Coxiella virulence-related type-IVB secretion signal. Proc. Natl. Acad. Sci. USA, 2013, vol. 110, no. 8, E707–715. doi: 10.1073/pnas.121527811050. Lifshitz Z., Burstein D., Schwatz K., Shuman H.A., Pupko T., Segal G. Identification of novel Coxiella burnetii Icm/Dot effectors and genetic analysis of their involvement in modulating a mitogen-activated protein kinase pathway. Infect. Immun., 2014, vol. 82, no. 9, pp. 3740–3752. doi: 10.1128/IAI.01729-1451. Luhrmann A., Roy C.R. Coxiella burnetii inhibits activation of host cell apoptosis through a mechanism that involves preventing cytochrome c release from mitochondria. Infect. Immun., 2007, vol. 75, no. 11, pp. 5282–5289. doi: 10.1128/IAI.00863-0752. Luhrmann A., Nogueira C.V., Carey K.L., Roy C.R. Inhibition of pathogen-induced apoptosis by a Coxiella burnetii type IV effector protein. Proc. Natl. Acad. Sci. USA, 2010, vol. 107, no. 44, pp. 18997–19001. doi: 10.1073/pnas.100438010753. MacDonald L.J., Kurten R.C., Voth D.E. Coxiella burnetii alters cyclic AMP-dependent protein kinase signalling during growth in macrophage. Infect. Immun., 2012, vol. 80, no. 6, pp. 1980–1986. doi: 10.1128/IAI.00101-1254. MacDonald L.J., Graham J.J., Kurten R.C., Voth D.E. Coxiella burnetii exploits host cAMP-dependent protein kinase signalling to promote macrophage survival. Cell. Microbiol., 2014, vol. 16, no. 1, pp. 146–159. 10.1111/cmi.1221355. Maffatt J.H., Newton P., Newton H.J. Coxiella burnetii: turning hostility into a home. Cell. Microbiol., 2015, vol. 17, no. 5, pp. 621–631. doi: 10.1016/j.devcel.2006.05.01356. Machner M.P., Isberg R.R. Targeting of host Rab GTPase function by the intravacuolar pathogen Legionella pneumophila. Dev. Cell, 2006, vol. 11, no. 1, pp. 47–56. doi: 10.1016/j.devcel.2006.05.01357. Martinez E., Cantet F., Fava L., Norville I., Bonazzi M. Identification of OmpA, a Coxiella burnetii protein involved in host cell invasion, by multi-phenotypic high-content screening. PLOS Pathog., 2014, vol. 10, no. 3, e1004013. doi: 10.1371/journal.ppat.100401358. Maturana P., Graham J.G., Sharma U.M., Voth D.E. Refining the plasmid-encoded type IV secretion system substrate repertoire of Coxiella burnetii. J. Bacteriol., 2013, vol. 195, no. 14, pp. 3269–3276. doi: 10.1128/JB.00180-1359. Maurin M., Raoult D. Q fever. Clin. Microbiol. Rev., 1999, vol. 12, no. 4, pp. 518–553.60. McDonough J.A., Newton H.J., Klum S., Swiss R., Agaisse H., Roy C.R. Host pathways important for Coxiella burnetii infection revealed by genome-wide RNA interference screening. mBio, 2013, vol. 4, no. 1, e00606-12. doi: 10.1128/mBio.00606-1261. McPhee J.B., Lewenza S., Hancock R.E. Cationic antimicrobial peptides activate a two-component regulatory system, PmrAPmrB, that regulates resistance to polymyxin B and cationic antimicrobial peptides in Pseudomonas aeruginosa. Mol. Microbiol., 2003, vol. 50, no. 1, pp. 205–217. doi: 10.1046/j.1365-2958.2003.03673.x62. Meconi S., Capo C., Remacle-Bonnet M., Pommier G., Raoult D., Mege J.L. Activation of protein tyrosine kinases by Coxiella burnetii: role in actin cytoskeleton reorganization and bacterial phagocytosis. Infect. Immun., 2001, vol. 69, no. 4, pp. 2520–2526. doi: 10.1128/IAI.69.4.2520-2526.200163. Meconi S., Jacomo V., Boguet P., Raoult D., Mege J.L., Capo C. Coxiella burnetii induces reorganization of the actin cytoskeleton in human monocytes. Infect. Immun., 1998, vol. 66, no. 11, pp. 5527–5533.64. Mo Y.Y., Cianciotto N.P., Mallavia L.P. Molecular cloning of a Coxiella burnetii gene encoding a macrophage infectivity potentiator (Mip) analogue. Microbiology, 1995, vol. 141, no. 11, pp. 2861–2871. doi: 10.1099/13500872-141-11-286165. Morgan J.K., Luedtke B.E., Thompson H.A., Shaw E.I. Coxiella burnetii type IVB secretion system region I genes are expressed early during the infection of host cells. FEMS Microbiol. Lett., 2010, vol. 311, no. 11, pp. 61–69. doi: 10.1111/j.1574-6968.2010.02072.x66. Morgan J.K., Luedtke B.E., Shaw E.I. Polar localization of the Coxiella burnetii type IVB secretion system. FEMS Microbiol. Lett., 2010, vol. 305, no. 2, pp. 177–183. doi: 10.1111/j.1574-6968.2010.01926.x67. Nagai H., Kubori T. Type IVB secretion systems of Legionella and other Gram-negative bacteria. Front. Microbiol., 2011, vol. 2:136, eCollection 2011, doi: 10.3389/fmicb.2011.0013668. Newton H.J., Kohler L.J., McDonough J.A., Temoche-Diaz M., Crabill E., Hartland E.L., Roy C.R. A screen of Coxiella burnetii mutants reveals important roles for Dot/Icm effectors and host autophagy in vacuole biogenesis. PloS Pathog., 2014, vol. 10, no. 7, e1004286, doi: 10.1371/journal.ppat.100428669. Newton H.J., McDonough J.A., Roy C.R. Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocyticc maturation of the pathogen-occupied vacuole. PloS One, 2013, vol. 8, no. 1, e54566. doi: 10.1371/journal.pone.005456670. Omsland A., Beare P.A., Hill J., Cockrell D.C., Howe D., Hansen B., Samuel J.E., Hainzen R.A. Isolation from animal tissue and genetic transformation of Coxiella burnetii are facilitated by an improved axenic growth medium. Appl. Environ. Microbiol., 2011, vol. 77, no. 11, pp. 3720–3725. doi: 10.1128/AEM.02826-1071. Pan X., Luhrmann A., Satoh A., Laskowski-Arce M.A., Roy C.R. Ankyrin repeat proteins comprise a diverse family of bacterial type IV effectors. Science, 2008, vol. 320, no. 5883, pp. 1651–1654. doi: 10.1126/science.115816072. Peabody C.R., Chung Y.J., Yen M.R., Vidal-Ingigliardi D., Pubsley A.P., Saier M.H. JR. Type II protein secretion and its relationship to bacterial type IV pili and archaeal flagella. Microbiology, 2003, vol. 149, pt. 11, pp. 3051–3072. doi: 10.1099/mic.0.26364-073. Price C.T., Al-Quadan T., Santic M., Rosenshine I., Abu Kwaik Y. Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science, 2011, vol. 334, no. 6062, pp. 1553–1557. doi: 10.1126/science.121286874. Ren Q., Robertson S.J., Howe D., Barrows L.F., Heinzen R.A. Comparative DNA microarray analysis of host cell transcriptional responses to infection by Coxiella burnetii or Chlamydia trachomatis. Ann. NY Acad. Sci., 2003, vol. 990, pp. 701–713.75. Roman M.J., Coriz P.D., Baca O.G. A proposed model to explain persistent infection of host cells with Coxiella burnetii. J. Gen. Microbiol., 1986, vol. 132, no. 5, pp. 1415–1422.76. Roman M.J., Crissman H.A., Samsonoff W.A., Hechemy K.E., Baca O.G. Analysis of Coxiella burnetii isolates in cell culture and the expression of parasite-specific antigens on the host membrane surface. Acta Virol., 1991, vol. 35, no. 6, pp. 503–510.77. Romano P.S., Gutierrez M.G., Beron W., Rabinovitch M., Colombo M.A. The autophagic pathway is actively modulated by phase II Coxiella burnetii to efficiently replicate in the host cell. Cell. Microbiol., 2007, vol. 9, no. 4, pp. 891–909. doi: 10.1111/j.1462-5822.2006.00838.x78. Russell-Lodrigue K.E., Zhang G.Q., McMurray D.N., Samuel J.E. Clinical and pathologic changes in a guinea pig aerosol challenge model of acute Q fever. Infect. Immun., 2006, vol. 74, no. 11, pp. 6085–6091.79. Russell-Lodrigue K.E., Andoh M., Poels M.W., Shive H.R., Weeks B.R., Zhang G.Q., Tersteeg C., Fukushi H., Hirai K., McMurray D.N., Samuel J.E. Coxiella burnetii isolates cause genogroup-specific virulence in mouse and guinea pig models of acute Q fever. Infect. Immun., 2009, vol. 77, no. 12, pp. 5640–5650. doi: 10.1128/IAI.00851-0980. Samuel J.E., Frazier M.E., Mallavia L.P. Correlation of plasmid type and disease caused by Coxiella burnetii. Infect. Immun., 1985, vol. 49, no. 3, pp. 775–779.81. Seshadri R., Paulsen I.T., Eisen J.A., Read T.D., Nelson K.E., Nelson W.C., Ward N.L., Tettelin H., Davidsen T.M., Beanan M.J., Deboy R.T., Daugherty S.C., Brinkac L.M., Madupu R., Dodson R.J., Khouri H.M., Lee K.H., Carty H.A., Scanlan D., Heinzen R.A., Thompson H.A., Samuel J. E., Fraser C.M., Heidelberg J.F. Complete genome sequence of the Q-fever pathogen Coxiella burnetii. Proc. Natl. Acad. Sci. USA, 2003, vol. 100, no. 9, pp. 5455–5460.82. Sexton J.A., Vogel J.P. Type IVB secretion by intracellular pathogens. Traffic, 2002, vol. 3, no. 3, pp. 178–185.83. Shannon J.G., Howe D., Heinzen R.A. Virulent Coxiella burnetii does not activate human dendritic cells: role of lipopolysaccharide as a shielding molecule. Proc. Natl. Acad. Sci. USA, 2005, vol. 102, no. 24, pp. 8722–8727.84. Shen X., Banga S., Liu Y., Xu L., Gao P., Shamovsky I., Nudler E., Luo Z.Q. Targeting eEF1A by a Legionella pneumophila effector leads to inhibition of protein synthesis and induction of host stress response. Cell. Microbiol., 2009, vol. 11, no. 6, pp. 911–926. doi: 10.1111/j.1462-5822.2009.01301.x85. Siemsen D.W., Kirpotina L.N., Jutila M.A., Quinn M.T. Inhibition of the human neutrophil NADPH oxidase by Coxiella burnetii. Microbes Infect., 2009, vol. 11, no. 6–7, pp. 671–679. doi: 10.1016/j.micinf.2009.04.00586. Skultety L., Hajduch M., Floraz-Ramirez G., Miernyk J.A., Ciampor F., Toman R., Sekeyova Z. Proteomic comparison of virulent phase I and avirulent phase II of Coxiella burnetii, the causative agent of Q fever. J. Proteomics, 2011, vol. 74, no. 10, pp. 1971–1984. doi: 10.1016/j.jprot.2011.05.01787. Stead C.M., Omsland A., Beare P.A., Sandoz K.M., Heinzen R.A. Sec-mediated secretion by Coxiella burnetii. BMC Microbiol., 2013, vol. 13, p. 222. doi: 10.1186/1471-2180-13-22288. Stein A., Raoult D. Lack of pathotype specific genes in human Coxiella burnetii isolates. Microb. Pathol., 1993, vol. 15, no. 3, pp. 175–185.89. Telepnev M.V., Klimpel G.R., Haithcoat J., Knirel Y.A., Anisimov A.P., Motin V.L. Tetraacylated lipopolysaccharide of Yersinia pestis can inhibit multiple Toll-like receptor- mediated signaling pathways in human dendritic cells. J. Infect. Dis., 2009, vol. 200, no. 11, pp. 1694–1702. doi: 10.1086/64798690. Tigertt W.D., Benenson A.S., Gochenour W.S., Airborne Q fever. Bacteriol. Rev., 1961, vol. 25, pp. 285–293.91. Toman R., Garidel P., Andra J., Slaba K., Hussein A., Koch M.H., Brandenburg K. Physicochemical characterization of the endotoxins from Coxiella burnetii strain Priscilla in relation to their bioactivities. BMC Biochem., 2004, vol. 5:1. doi: 10.1186/1471-2091-5-192. Tse M.K., Cheung S.K., Ke Y.H., Lau C.C., Sze K.H., Yuen K.Y. Backbone and side-chain 1H, 13C and 15N assignments of the PPIase domain of macrophage infectivity potentiator (Mip) protein from Coxiella burnetii. Biomol. NMR Assign., 2014, vol. 8, no. 1, pp. 173–176. doi: 10.1007/s12104-013-9477-393. Tujulin E., Macellaro A., Lilliehook B., Norlander L. Effect of endocytosis inhibitors on Coxiella burnetii interaction with host cells. Acta Virol., 1998, vol. 42, no. 3, pp. 125–131.94. Yang J., Kiu X., Bhalla K., Kim C.N., Ibrado A.M., Cai J., Peng T.I., Jones D.P., Wang X. Prevention of apoptosis by Bcl2: release of cytochrome c from mitochondria blocked. Science, 1997, vol. 275, no. 5303, pp. 1129–1132. doi: 10.1126/science.275.5303.112995. Youle R.J., Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol., 2008, vol. 9, no. 1, pp. 47–59. doi: 10.1038/nrm230896. Vazquez C.L., Colombo M.I. Coxiella burnetii modulates Beclin 1 and Bcl2, preventing host cell apoptosis to generate a persistent bacterial infection. Cell Death Differ., 2010, vol. 17, no. 3, pp. 421–438. doi: 10.1038/cdd.2009.12997. Vila-del Sol V., Diaz-Munoz M.D., Fresno M. Requirement of tumor necrosis factor α and nuclear factor-κB in the induction by IFN-γ of inducible nitric oxide synthase in macrophages. J. Leukoc. Biol., 2007, vol. 81, no. 1, pp. 272–283. doi: 10.1189/jlb.090552998. Vincent C.D., Friedman J.R., Jeong K.C., Buford E.C., Miller J.L., Vogel J.P. Identification of the core transmembrane complex of the Legionella Dot/Icm type IV secretion system. Mol. Microbiol., 2006, vol. 62, no. 5, pp. 1278–1291.99. Vincent C.D., Friedman J.R., Jeong K.C., Sutherland M.C., Vogel J.P. Identification of the DotL coupling protein subcomplex of the Legionella Dot/Icm type IV secretion system. Mol. Microbiol., 2012, vol. 85, no. 2, pp. 378–391. doi: 10.1111/j.1365-2958.2012.08118.x100. Vishwanath S., Hackstadt T. Lipopolysaccharide phase variation determines the complement-mediated serum susceptibility of Coxiella burnetii. Infect. Immun., 1988, vol. 56, no. 1, pp. 40–44.101. Voth D.E., Howe D., Heinzen R.A. Coxiella burnetii inhibits apoptosis in human THP1 cells and monkey primary alveolar macrophages. Infect. Immun., 2007, vol. 75, no. 9, pp. 4263–4271. doi: 10.1128/IAI.00594-07102. Voth D.E., Heinzen R.A. Coxiella type IV secretion and cellular microbiology. Curr. Opin. Microbiol., 2009, vol. 12, no. 1, pp. 74–80. doi: 10.1016/j.mib.2008.11.005103. Voth D.E., Heinzen R.A. Sustained activation of Akt and Erk1/2 is required for Coxiella burnetii antiapoptotic activity. Infect. Immun., 2009, vol. 77, no. 1, pp. 205–213. doi: 10.1128/IAI.01124-08104. Voth D.E., Howe D., Beare P.A., Vogel J.P., Unsworth N., Samuel J.E., Heinzen R.A. The Coxiella burnetii ankyrin repeat domain-containing protein family is heterogeneous, with C-terminal truncations that influence Dot/Icm-mediated secretion. J. Bacteriol., 2009, vol. 191, no. 13, pp. 4232–4242. doi: 10.1128/JB.01656-08105. Voth D.E., Beare P.A., Howe D., Sharma U.M., Samoilis G., Cockrell D.C., Omsland A., Heinzen R.A. The Coxiella burnetii cryptic plasmid is enriched in genes encoding type IV secretion system substrates. J. Bacteriol., 2011, vol. 193, no. 7, pp. 1493–1503. doi: 10.1128/JB.01359-10106. Weber M.M., Cen C., Rowin K., Mertens K., Galvan G., Zhi H., Dealing C.M., Roman V.A., Bange S., Tan Y.Q., Luo Z.E., Samuel J. Identification of Coxiella burnetii type IV secretion substrates required for intracellular replication and Coxiellacontaining vacuole formation. J. Bacteriol., 2013, vol. 195, no. 17, pp. 3914–3924. doi: 10.1128/JB.00071-13107. Winchell C.G., Graham J.G., Kurten R.C., Voth D.E. Coxiella burnetii type IV secretion-dependent recruitment of macrofage autophagosomes. Infect. Immun., 2014, vol. 82, no. 6, pp. 2229–2238. doi: 10.1128/IAI.01236-13108. Zamboni D.S., McGrath S., Rabinovitch M., Roy C.R. Coxiella burnetii express type IV secretion system proteins that function similarly to components of the Legionella pneumophila Dot/Icm system. Mol. Microbiol., 2003, vol. 49, no. 4, pp. 965–976. doi: 10.1046/j.1365-2958.2003.03626.x109. Zamboni D.S., Rabinovitch M. Nitric oxide partially controls Coxiella burnetii phase II infection in mouse primary macrophages. Infect. Immun., 2003, vol. 71, no. 3, pp. 1225–1233. doi: 10.1128/IAI.71.3.1225-1233.2003110. Zamboni D.S., Campos M.A., Torrecilhas A.C., Kiss K., Samuel J.E., Golenbock D.T., Lauw F.N., Roy C.R., Almeida I.C., Gazinelli R.T. Stimulation of toll-like receptor 2 by Coxiella burnetii is required for macrophage production of pro-inflammatory cytokines and resistance to infection. J. Biol. Chem., 2004, vol. 279, no. 52, pp. 54405–54415. doi: 10.1074/jbc.M410340200111. Zechner E.L., Lang S., Schildbach J.F. Assembly and mechanisms of bacterial type IV secretion machines. Philos. Trans. R. Soc. Lond., B, Biol. Sci., 2012, vol. 367, no. 1592, pp. 1073–1087. doi: 10.1098/rstb.2011.0207112. Zhang Y., Zhang G., Hendrix L.R., Tesh V.L., Samuel J.E. Coxiella burnetii induces apoptosis during early stage infection via a caspase-independent pathway in human monocytic THP1 cells. PLoS ONE, 2012, vol. 7, no. 1, pp. e30841. doi: 10.1371/journal.pone.0030841113. Zusman T., Aloni G., Halperin E., Kotzer H., Degtyar E., Feldman M., Segal G. The response regulator PmrA is a major regulator of the icm/dot type IV secretion system in Legionella pneumophila and Coxiella burnetii. Mol. Microbiol., 2007, vol. 63, no. 5, pp. 1508–1523. doi: 10.1111/j.1365-2958.2007.05604.x