Turkiye Klinikleri Journal of Medical Sciences

.: REVIEW
ESX-1, ESX-3 ve ESX-5 Salgı Sistemleri ve Mycobacterium Tuberculosis
ESX-1, ESX-3 and ESX-5 Secretory Systems and Mycobacterium Tuberculosis
Gülşah TOLLUa
aMersin Üniversitesi Teknik Bilimler Meslek Yüksekokulu, Veterinerlik Bölümü, Mersin, TÜRKİYE
Turkiye Klinikleri J Med Sci. 2020;40(3):375-81
doi: 10.5336/medsci.2020-74818
Article Language: TR
Full Text
ÖZET
 Tüberküloz (TB) ile mücadele, günümüz global halk sağlığı önceliklerinden biridir. Mycobacterium tuberculosis (Mtb) en önemli bakteriyel patojenlerden biridir; bu patojen dünya nüfusunun neredeyse %30'unu enfekte ederek, birçok kişinin ölümüne neden olmaktadır. Mtb basilleri büyüme, sağkalım ve virülansta, membranlardan bakteri yüzeyine ve çevreye kompleks hücre duvarı boyunca bir dizi protein efekti ihraç eden eşsiz salgı sistemleri kullanırlar. Patojenik Mtb'nin 5 paralog ESX salgılama sistemi vardır; bunlar ESX-1 ile ESX-5 arasındadır. ESX salgılama sistemleri diğer birçok aktinobakteriyel, grampozitif bakteride bulunur ve son zamanlarda tip VII salgılama sistemleri [type VII secrection system (T7SS)] olarak adlandırılmaları önerilmiştir. T7SS tarafından, konakçı hücrelere salgılanan proteinler Mtb ile ilişkili virülansta aracı bir rol oynar; bu durum, bu sistemi gelecekteki ilaç ve aşı gelişimi için aday yapar. Bununla birlikte, T7SS'ye dâhil olan bileşenlerin birçoğu tanımlanmış olsa da hem iç hem de dış mikobakteriyel zarlar boyunca translokasyon mekanizması büyük ölçüde açıklanamamıştır. Yapılan tüm çalışmalar incelendiğinde, ESX sistemlerinin mikobakterilerde protein sekresyonunun lokalizasyonunu yöneten, daha önce görülmemiş mekanizmalar oldukları öngörülmektedir. T7SS'nin temel rolünü anlamak, acilen ihtiyaç duyulan yeni potansiyel terapötik hedefleri ve tüberkülozu tedavi etmek için yeni müdahale stratejileri geliştirilmesini sağlayabilir.

Anahtar Kelimeler: ESX-1; ESX-3; ESX-5; tüberküloz; tip VII salgı sistemi
ABSTRACT
 Combating tuberculosis (TB) is one of the current global public health priorities. Mycobacterium tuberculosis (Mtb) is one of the most important bacterial pathogens; this pathogen infects almost 30% of the world's population, causing the death of many. Mtb bacilli use unique secretion systems that export a range of protein effects across the complex cell wall, from membranes to the bacterial surface and the environment, in growth, survival and virulence. The pathogenic Mtb has 5 paralogous ESX secretion systems, which range from ESX1 to ESX-5. ESX secretory systems are found in many other actinobacteria, gram-positive bacteria and have recently been referred to as type VII secretion systems (T7SS). Proteins secreted by T7SS into host cells play a mediating role in Mtb-related virulence, making this system a candidate for future drug and vaccine development.. However, although many of the components included in T7SS have been identified, the mechanism of translocation across both internal and external mycobacterial membranes has not been largely explained. When all studies are examined, it is seen that ESX systems are unprecedented mechanisms that govern the localization of protein secretion in mycobacteria. Understanding the basic role of T7SS can lead to the development of new potential therapeutic targets and new intervention strategies to treat tuberculosis.

Keywords: ESX-1; ESX-3; ESX-5; tuberculosis; type VII secretion system
REFERENCES:
  1. WHO. Global Tuberculosis Report 2019. p.297. [Crossref]  [PubMed]  [PMC] 
  2. Gengenbacher M, Kaufmann SH. Mycobacterium tuberculosis: success through dormancy. FEMS Microbiol Rev. 2012;36(3):514-532. [Crossref]  [PubMed]  [PMC] 
  3. Sani M, Houben ENG, Geurtsen J, Pierson J, de Punder K, van Zon M, et al. Direct visualization by cryo-EM of the mycobacterial capsular layer: a labile structure containing ESX-1-secreted proteins. PLoS Pathog. 2010;6(3);e1000794. [Crossref]  [PubMed]  [PMC] 
  4. Abdallah AM, van Pittius NCG, Champion PAD, Cox J, Luirink J, Vandenbroucke-Grauls CMJE, et al. Type VII secretion--mycobacteria show the way. Nat Rev Microbiol. 2007;5(11):883-91. [Crossref]  [PubMed] 
  5. Houben ENG, Bestebroer J, Ummels R, Wilson L, Piersma SR, Jiménez CR, et al. Composition of the type VII secretion system membrane complex. Mol Microbiol. 2012;86(2):472-84. [Crossref]  [PubMed] 
  6. Stanley SA, Raghavan S, Hwang WW, Cox JS. Acute infection and macrophage subversion by mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A. 2003;100(22):13001-6. [Crossref]  [PubMed]  [PMC] 
  7. Ates LS, Ummels R, Commandeur S, Van de Weerd R, Sparrius M, Weerdenburg E, Alber M, et al. Essential role of the ESX-5 secretion system in outer membrane permeability of pathogenic mycobacteria. PLOS Genet. 2015;11:1005190. [Crossref]  [PubMed]  [PMC] 
  8. Stoop EJM, Bitter W, van der Sar AM. Tuberculosis bacilli rely on a type VII army for pathogenicity. Trends Microbiol. 2012;20(10):477-84. [Crossref]  [PubMed] 
  9. Van Pittius NCG, Gamieldien J, Hide W, Brown GD, Siezen RJ, Beyers AD. The ESAT-6 gene cluster of mycobacterium tuberculosis and other high G+C gram-positive bacteria. Genom Biol. 2001;2(10):RESEARCH0044. [Crossref]  [PubMed]  [PMC] 
  10. Jagielski T, Ignatowska H, Bakuła Z, Dziewit Ł, Napiórkowska A, Augustynowicz-Kopeć E, et al. Screening for streptomycin resistance-conferring mutations in mycobacterium tuberculosis clinical isolates from Poland. PLoS One. 2014;9(6):e100078. [Crossref]  [PubMed]  [PMC] 
  11. Gygli SM, Borrell S, Trauner A, Gagneux S. Antimicrobial resistance in mycobacterium tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiol Rev. 2017;41(3):354-73. [Crossref]  [PubMed] 
  12. WHO. Global Tuberculosis Report, 2017. p.147.
  13. Chapman HJ, Lauzardo M. Advances in diagnosis and treatment of latent tuberculosis infection. J Am Board Fam Med. 2014;27(5):704-12. [Crossref]  [PubMed] 
  14. Loudon RG, Bumgarner LR, Lacy J, Coffman GK. Aerial transmission of mycobacteria. Am Rev Respir Dis. 1969;100(2):165-71.
  15. Stead WW. Pathogenesis of a first episode of chronic pulmonary tuberculosis in man: recrudescence of residuals of the primary infection or exogenous reinfection? Am Rev Respir Dis. 1967;95(5):729-45.
  16. Merrell DS, Falkow S. Frontal and stealth attack strategies in microbial pathogenesis. Nature. 2004;430(6996):250-6. [Crossref]  [PubMed] 
  17. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003;163(9):1009-21. [Crossref]  [PubMed] 
  18. Jackson M. The mycobacterial cell envelope-lipids. Cold Spring Harb Perspect Med. 2014;4(10):a021105. [Crossref]  [PubMed]  [PMC] 
  19. Chiaradia L, Lefebvre C, Parra J, Marcoux J, Burlet-Schiltz O, Etienne G, et al. Dissecting the mycobacterial cell envelope and defining the composition of the native mycomembrane. Sci Rep. 2017;7(1):12807. [Crossref]  [PubMed]  [PMC] 
  20. Costa TR, Felisberto-Rodrigues C, Meir A, Prevost MS, Redzej A, Trokter M, et al. Secretion systems in gram-negative bacteria: structural and mechanistic insights. Nat Rev Microbiol. 2015;13(6):343-59. [Crossref]  [PubMed] 
  21. Orgeur M, Brosch R. Evolution of virulence in the mycobacterium tuberculosis complex. Curr Opin Microbiol. 2018;41:68-75. [Crossref]  [PubMed] 
  22. Abdallah AM, Bestebroer J, Savage NDL, Punder K, van Zon M, Wilson L, et al. Mikobakteriyel sekresyon sistemleri ESX-1 ve ESX-5, konakçı hücre ölümü ve inflamatuar aktivasyonda farklı roller oynar. J Immunol. 2011;187:4744-53. [Crossref]  [PubMed] 
  23. Bitter W, Houben ENG, Bottai D, Brodin P, Brown EJ, Cox JS, et al. Systematic genetic nomenclature for type VII secretion systems. PLoS Pathog. 2009;5(10):e1000507. [Crossref]  [PubMed]  [PMC] 
  24. Pallen MJ. The ESAT-6/WXG100 superfamily -- and a new gram-positive secretion system? Trends Microbiol. 2002;10(5):209-12. [Crossref] 
  25. Burts ML, Williams WA, DeBord K, Missiakas DM. EsxA and EsxB are secreted by an ESAT-6-like system that is required for the pathogenesis of staphylococcus aureus infections. Proc Natl Acad Sci U S A. 2005;102(4):1169-1174. [Crossref]  [PubMed]  [PMC] 
  26. Ummels R, Abdallah AM, Kuiper V, Aâjoud A, Sparrius M, Naeem R, et al. Identification of a novel conjugative plasmid in mycobacteria that requires both type IV and type VII secretion. mBio. 2014;5(5):e01744-14. [Crossref]  [PubMed]  [PMC] 
  27. Newton-Foot M, Warren RM, Sampson SL, van Helden PD, van Pittius NCG. The plasmid-mediated evolution of the mycobacterial ESX (Type VII) secretion systems. BMC Evol Biol. 2016;16:62. [Crossref]  [PubMed]  [PMC] 
  28. Simeone R, Sayes F, Song O, Gröschel MI, Brodin P, Brosch R, et al. Cytosolic access of mycobacterium tuberculosis: critical impact of phagosomal acidification control and demonstration of occurrence in vivo. PLoS Pathog. 2015;11(2):e1004650. [Crossref]  [PubMed]  [PMC] 
  29. Tufariello JM, Chapman JR, Kerantzas CA, Wong KW, Vilchèze C, Jones CM, et al. Separable roles for mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence. Proc Natl Acad Sci U S A. 2016;113(3):E348-57. [Crossref]  [PubMed]  [PMC] 
  30. Van Winden VJC, Damen MPM, Ummels R, Bitter W, Houben ENG. Protease domain and transmembrane domain of the type VII secretion mycosin protease determine system-specific functioning in mycobacteria. J Biol Chem. 2019;294(13):4806-4814. [Crossref]  [PubMed]  [PMC] 
  31. Fortune SM, Jaeger A, Sarracino DA, Chase MR, Sassetti CM, Sherman DR, et al. Mutually dependent secretion of proteins required for mycobacterial virulence. Proc Natl Acad Sci U S A. 2005;102(30):10676-81. [Crossref]  [PubMed]  [PMC] 
  32. Maciag A, Dainese E, Rodriguez GM, Milano A, Provvedi R, Pasca MR, et al. Global analysis of the mycobacterium tuberculosis Zur (FurB) regulon. J Bacteriol. 2007;189(3):730-40. [Crossref]  [PubMed]  [PMC] 
  33. Carlsson F, Joshi SA, Rangell L, Brown EJ. Polar localization of virulence-related Esx-1 secretion in mycobacteria. PLoS Pathog. 2009;5(1):e1000285. [Crossref]  [PubMed]  [PMC] 
  34. Garces K, Atmakuri K, Chase MR, Woodworth BS, Krastins B, Rothchild AC, et al. EspA acts as a critical mediator of ESX1- dependent virulence in mycobacterium tuberculosis by affecting bacterial cell wall integrity. PLoS Pathog. 2010;6(6):e1000957. [Crossref]  [PubMed]  [PMC] 
  35. Majlessi L, Brodin P, Brosch R, Rojas MJ, Khun H, Huerre M, et al. Influence of ESAT-6 secretion system 1 (RD1) of mycobacterium tuberculosis on the interaction between mycobacteria and the host immune system. J. Immunol. 2005;174(6):3570-9. [Crossref]  [PubMed] 
  36. Pym AS, Brodin P, Brosch R, Huerre M, Cole ST. Loss RD1 contributed to the attenuation of the live tuberculosis vaccines mycobacterium bovis BCG and mycobacterium microti. Mol Microbiol. 2002;46:709-17. [Crossref]  [PubMed] 
  37. Houben D, Demangel C, Van Ingen J, Perez J, Baldeón L, Abdallah AM, et al. ESX-1 mediated translocation to the cytosol controls virulence of mycobacteria. Cell Microbiol. 2012;14(8):1287-98. [Crossref]  [PubMed] 
  38. Simeone R, Bobard A, Lippmann J, Bitter W, Majlessi L, Brosch R, et al. Phagosomal rupture by mycobacterium tuberculosis results in toxicity and host cell death. PLoS Pathog. 2012;8(2):1002507. [Crossref]  [PubMed]  [PMC] 
  39. Van der Woude AD, Mahendran KR, Ummels R, Piersma SR, Pham TV, Jiménez CR, et al. Differential detergent extraction of mycobacterium marinum cell envelope proteins identifies an extensively modified threonine-rich outer membrane protein with channel activity. J Bacteriol. 2013;195(9):2050-9. [Crossref]  [PubMed]  [PMC] 
  40. Coburn B, Sekirov I, Finlay BB. Type III secretion systems and disease. Clin Microbiol Rev. 2007;20(4):535-59. [Crossref]  [PubMed]  [PMC] 
  41. Backert S, Meyer TF. Type IV secretion systems and their effectors in bacterial pathogenesis. Curr Opin Microbiol. 2006;9(2):207-17. [Crossref]  [PubMed] 
  42. Judd PK, Kumar RB, Das A. Spatial location and requirements for the assembly of the agrobacterium tumefaciens type IV secretion apparatus. Proc Natl Acad Sci U S A. 2005;102(32):11498-503. [Crossref]  [PubMed]  [PMC] 
  43. Jaumouillé V, Francetic O, Sansonetti PJ, Van Nhieu GT. Cytoplasmic targeting of IpaC to the bacterial pole directs polar type III secretion in shigella. EMBO J. 2008;27(2):447-57. [Crossref]  [PubMed]  [PMC] 
  44. Pandey R, Russo R, Ghanny S, Huang X, Helmann J, Rodriguez GM. MntR(Rv2788): a transcriptional regulator that controls manganese homeostasis in mycobacterium tuberculosis. Mol Microbiol. 2015;98(6):1168-83. [Crossref]  [PubMed]  [PMC] 
  45. Siegrist MS, Unnikrishnan M, McConnell MJ, Borowsky M, Cheng TY, Siddiqi N, et al. Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition. Proc Natl Acad U S A. 2009;106(44):18792-7. [Crossref]  [PubMed]  [PMC] 
  46. Serafini A, Boldrin F, Palù G, Manganelli R. Characterization of a mycobacterium tuberculosis ESX-3 conditional mutant: essentiality and rescue by iron and zinc. J Bacteriol. 2009;191(20):6340-4. [Crossref]  [PubMed]  [PMC] 
  47. Serafini A, Pisu D, Palù G, Rodriguez GM, Manganelli R. The ESX-3 secretion system is necessary for iron and zinc homeostasis in mycobacterium tuberculosis. PLoS One. 2013;14(8): e78351. [Crossref]  [PubMed]  [PMC] 
  48. Siegrist MS, Steigedal M, Ahmad R, Mehra A, Dragset MS, Schuster BM, et al. Mycobacterial Esx-3 requires multiple components for iron acquisition. mBio. 2014;5(3)e01073-14. [Crossref]  [PubMed]  [PMC] 
  49. Stinear TP, Seemann T, Harrison PF, Jenkin GA, Davies JK, Johnson PDR, et al. Insights from the complete genome sequence of mycobacterium marinum on the evolution of mycobacterium tuberculosis. Genome Res. 2008;18(5):729-41. [Crossref]  [PubMed]  [PMC] 
  50. Sassetti CM, Rubin EJ. Enfeksiyon sırasında mikobakteriyel sağkalım için genetik gereksi-nimler Proc. Natl. Acad. Sci. ABD. 2003; 100:12989-94. [Crossref]  [PubMed]  [PMC] 
  51. Sweeney KA, Dao DN, Goldberg MF, Hsu T, Venkataswamy MM, Henao-Tamayo M, et al. A recombinant mycobacterium smegmatis induces potent bactericidal immunity against mycobacterium tuberculosis. Nat Med. 2011;17(10):1261-8. [Crossref]  [PubMed]  [PMC] 
  52. Ilghari D, Lightbody KL, Veverka V, Waters LC, Muskett FW, Renshaw PS, et al. Solution structure of the mycobacterium tuberculosis EsxG?EsxH complex: functional implications and comparisons with other M. tuberculosis Esx family complexes. J Biol Chem. 2011;286(34):29993-30002. [Crossref]  [PubMed]  [PMC] 
  53. Houben EN, Korotkov KV, Bitter W. Take five-type VII secretion systems of mycobacteria. Biochim Biophys Acta. 2014;843(8):1707-16. [Crossref]  [PubMed] 
  54. Ohol YM, Goetz DH, Chan K, Shiloh MU, Craik CS, Cox JS. Mycobacterium tuberculosis MycP1 protease plays a dual role in regulation of ESX-1 secretion and virulence. Cell Host Microbe. 2010;7(3):210-20. [Crossref]  [PubMed]  [PMC] 
  55. Griffin JE, Gawronski JD, DeJesus MA, Ioerger TR, Akerley BJ, Sassetti CM. High-resolution phenotypic profiling defines genes essential for mycobacterial growth and cholesterol catabolism. PLoS Pathog. 2011;7(9):e1002251. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

.: Process List

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com