#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni, Vidi, Vici!!


Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the “code of conduct” of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.


Vyšlo v časopise: Manipulation of Costimulatory Molecules by Intracellular Pathogens: Veni, Vidi, Vici!!. PLoS Pathog 8(6): e32767. doi:10.1371/journal.ppat.1002676
Kategorie: Review
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002676

Souhrn

Some of the most successful pathogens of human, such as Mycobacterium tuberculosis (Mtb), HIV, and Leishmania donovani not only establish chronic infections but also remain a grave global threat. These pathogens have developed innovative strategies to evade immune responses such as antigenic shift and drift, interference with antigen processing/presentation, subversion of phagocytosis, induction of immune regulatory pathways, and manipulation of the costimulatory molecules. Costimulatory molecules expressed on the surface of various cells play a decisive role in the initiation and sustenance of immunity. Exploitation of the “code of conduct” of costimulation pathways provides evolutionary incentive to the pathogens and thereby abates the functioning of the immune system. Here we review how Mtb, HIV, Leishmania sp., and other pathogens manipulate costimulatory molecules to establish chronic infection. Impairment by pathogens in the signaling events delivered by costimulatory molecules may be responsible for defective T-cell responses; consequently organisms grow unhindered in the host cells. This review summarizes the convergent devices that pathogens employ to tune and tame the immune system using costimulatory molecules. Studying host-pathogen interaction in context with costimulatory signals may unveil the molecular mechanism that will help in understanding the survival/death of the pathogens. We emphasize that the very same pathways can potentially be exploited to develop immunotherapeutic strategies to eliminate intracellular pathogens.


Zdroje

1. FinlayBBMcFaddenG 2006 Anti-immunology: evasion of the host immune system by bacterial and viral pathogens. Cell 124 767 782

2. CurtsingerJMMescherMF 2010 Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 22 333 340

3. JenkinsMK 1994 The ups and downs of T cell costimulation. Immunity 1 443 446

4. SuvasSSinghVSahdevSVohraHAgrewalaJN 2002 Distinct role of CD80 and CD86 in the regulation of the activation of B cell and B cell lymphoma. J Biol Chem 277 7766 7775

5. GowthamanUChodisettiSBAgrewalaJN 2010 T cell help to B cells in germinal centers: putting the jigsaw together. Int Rev Immunol 29 403 420

6. CellaMScheideggerDPalmer-LehmannKLanePLanzavecchiaA 1996 Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T-T help via APC activation. J Exp Med 184 747 752

7. OrabonaCGrohmannUBelladonnaMLFallarinoFVaccaC 2004 CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nat Immunol 5 1134 1142

8. BanchereauJBazanFBlanchardDBriereFGalizziJP 1994 The CD40 antigen and its ligand. Annu Rev Immunol 12 881 922

9. De KeersmaeckerBHeirmanCCorthalsJEmpsenCvan GrunsvenLA 2011 The combination of 4-1BBL and CD40L strongly enhances the capacity of dendritic cells to stimulate HIV-specific T cell responses. J Leukoc Biol 89 989 999

10. WalunasTLLenschowDJBakkerCYLinsleyPSFreemanGJ 1994 CTLA-4 can function as a negative regulator of T cell activation. Immunity 1 405 413

11. KeirMEButteMJFreemanGJSharpeAH 2008 PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26 677 704

12. KrutzikSRSielingPAModlinRL 2001 The role of Toll-like receptors in host defense against microbial infection. Curr Opin Immunol 13 104 108

13. CooperAM 2009 Cell-mediated immune responses in tuberculosis. Annu Rev Immunol 27 393 422

14. BoiseLHMinnAJNoelPJJuneCHAccavittiMA 1995 CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL. Immunity 3 87 98

15. GrewalISFlavellRA 1996 The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 153 85 106

16. SchreiberHAHulsebergPDLeeJPrechlJBartaP 2010 Dendritic cells in chronic mycobacterial granulomas restrict local anti-bacterial T cell response in a murine model. PLoS One 5 e11453 doi:10.1371/journal.pone.0011453

17. BonatoVLMedeirosAILimaVMDiasARFacciolitiLH 2001 Downmodulation of CD18 and CD86 on macrophages and VLA-4 on lymphocytes in experimental tuberculosis. Scand J Immunol 54 564 573

18. PecoraNDFultonSARebaSMDrageMGSimmonsDP 2009 Mycobacterium bovis BCG decreases MHC-II expression in vivo on murine lung macrophages and dendritic cells during aerosol infection. Cell Immunol 254 94 104

19. HendersonRAWatkinsSCFlynnJL 1997 Activation of human dendritic cells following infection with Mycobacterium tuberculosis. J Immunol 159 635 643

20. SahaBDasGVohraHGangulyNKMishraGC 1994 Macrophage-T cell interaction in experimental mycobacterial infection. Selective regulation of co-stimulatory molecules on Mycobacterium-infected macrophages and its implication in the suppression of cell-mediated immune response. Eur J Immunol 24 2618 2624

21. AgrewalaJNKumarBVohraH 1998 Potential role of B7-1 and CD28 molecules in immunosuppression in leprosy. Clin Exp Immunol 111 56 63

22. FuseSZhangWUsherwoodEJ 2008 Control of memory CD8+ T cell differentiation by CD80/CD86-CD28 costimulation and restoration by IL-2 during the recall response. J Immunol 180 1148 1157

23. BhattKUzelacAMathurSMcBrideAPotianJ 2009 B7 costimulation is critical for host control of chronic Mycobacterium tuberculosis infection. J Immunol 182 3793 3800

24. HeroldKCLuJRulifsonIVezysVTaubD 1997 Regulation of C-C chemokine production by murine T cells by CD28/B7 costimulation. J Immunol 159 4150 4153

25. AriasMAJaramilloGLopezYPMejiaNMejiaC 2007 Mycobacterium tuberculosis antigens specifically modulate CCR2 and MCP-1/CCL2 on lymphoid cells from human pulmonary hilar lymph nodes. J Immunol 179 8381 8391

26. Kan-SuttonCJagannathCHunterRLJr 2009 Trehalose 6,6′-dimycolate on the surface of Mycobacterium tuberculosis modulates surface marker expression for antigen presentation and costimulation in murine macrophages. Microbes Infect 11 40 48

27. SinghBSinghGTrajkovicVSharmaP 2003 Intracellular expression of Mycobacterium tuberculosis-specific 10-kDa antigen down-regulates macrophage B7.1 expression and nitric oxide release. Clin Exp Immunol 134 70 77

28. GrewalISBorrowPPamerEGOldstoneMBFlavellRA 1997 The CD40-CD154 system in anti-infective host defense. Curr Opin Immunol 9 491 497

29. YamauchiPSBleharskiJRUyemuraKKimJSielingPA 2000 A role for CD40-CD40 ligand interactions in the generation of type 1 cytokine responses in human leprosy. J Immunol 165 1506 1512

30. MurrayRASiddiquiMRMendilloMKrahenbuhlJKaplanG 2007 Mycobacterium leprae inhibits dendritic cell activation and maturation. J Immunol 178 338 344

31. SamtenBThomasEKGongJBarnesPF 2000 Depressed CD40 ligand expression contributes to reduced gamma interferon production in human tuberculosis. Infect Immun 68 3002 3006

32. Campos-NetoAOvendalePBementTKoppiTAFanslowWC 1998 CD40 ligand is not essential for the development of cell-mediated immunity and resistance to Mycobacterium tuberculosis. J Immunol 160 2037 2041

33. LazarevicVMyersAJScangaCAFlynnJL 2003 CD40, but not CD40L, is required for the optimal priming of T cells and control of aerosol M. tuberculosis infection. Immunity 19 823 835

34. StewartGRSnewinVAWalzlGHussellTTormayP 2001 Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection. Nat Med 7 732 737

35. SakaiSKawamuraIOkazakiTTsuchiyaKUchiyamaR 2010 PD-1-PD-L1 pathway impairs T(h)1 immune response in the late stage of infection with Mycobacterium bovis bacillus Calmette-Guerin. Int Immunol 22 915 925

36. JuradoJOAlvarezIBPasquinelliVMartinezGJQuirogaMF 2008 Programmed death (PD)-1:PD-ligand 1/PD-ligand 2 pathway inhibits T cell effector functions during human tuberculosis. J Immunol 181 116 125

37. AlvarezIBPasquinelliVJuradoJOAbbateEMusellaRM 2010 Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J Infect Dis 202 524 532

38. Lazar-MolnarEChenBSweeneyKAWangEJLiuW 2010 Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci U S A 107 13402 13407

39. BarberDLMayer-BarberKDFengCGSharpeAHSherA 2010 CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 186 1598 1607

40. HanekomWAMendilloMMancaCHaslettPASiddiquiMR 2003 Mycobacterium tuberculosis inhibits maturation of human monocyte-derived dendritic cells in vitro. J Infect Dis 188 257 266

41. ShortmanKHeathWR 2001 Immunity or tolerance? That is the question for dendritic cells. Nat Immunol 2 988 989

42. LevingsMKSangregorioRRoncaroloMG 2001 Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 193 1295 1302

43. AndersonKMCzinnSJRedlineRWBlanchardTG 2006 Induction of CTLA-4-mediated anergy contributes to persistent colonization in the murine model of gastric Helicobacter pylori infection. J Immunol 176 5306 5313

44. YaoTMecsasJHealyJIFalkowSChienY 1999 Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, yopH. J Exp Med 190 1343 1350

45. PryjmaJBaranJErnstMWoloszynMFladHD 1994 Altered antigen-presenting capacity of human monocytes after phagocytosis of bacteria. Infect Immun 62 1961 1967

46. WyantTLTannerMKSzteinMB 1999 Potent immunoregulatory effects of Salmonella typhi flagella on antigenic stimulation of human peripheral blood mononuclear cells. Infect Immun 67 1338 1346

47. DasSSuarezGBeswickEJSierraJCGrahamDY 2006 Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol 176 3000 3009

48. BeswickEJPinchukIVDasSPowellDWReyesVE 2007 Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect Immun 75 4334 4341

49. SkinnerJAReissingerAShenHYukMH 2004 Bordetella type III secretion and adenylate cyclase toxin synergize to drive dendritic cells into a semimature state. J Immunol 173 1934 1940

50. RossPJLavelleECMillsKHBoydAP 2004 Adenylate cyclase toxin from Bordetella pertussis synergizes with lipopolysaccharide to promote innate interleukin-10 production and enhances the induction of Th2 and regulatory T cells. Infect Immun 72 1568 1579

51. EverettHMcFaddenG 1999 Apoptosis: an innate immune response to virus infection. Trends Microbiol 7 160 165

52. PriceDAKlenermanPBoothBLPhillipsRESewellAK 1999 Cytotoxic T lymphocytes, chemokines and antiviral immunity. Immunol Today 20 212 216

53. World Health Organization 2010 Global health observatory (GHO). Available: http://www.who.int/gho/hiv/en/index.html Accessed 5 June 2012

54. DavisCBDikicIUnutmazDHillCMArthosJ 1997 Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5. J Exp Med 186 1793 1798

55. GeijtenbeekTBvan KooykY 2003 DC-SIGN: a novel HIV receptor on DCs that mediates HIV-1 transmission. Curr Top Microbiol Immunol 276 31 54

56. DouekDCBrenchleyJMBettsMRAmbrozakDRHillBJ 2002 HIV preferentially infects HIV-specific CD4+ T cells. Nature 417 95 98

57. Rowland-JonesS 1999 HIV infection: where have all the T cells gone? Lancet 354 5 7

58. KornbluthRS 2002 An expanding role for CD40L and other tumor necrosis factor superfamily ligands in HIV infection. J Hematother Stem Cell Res 11 787 801

59. Smed-SorensenALoreKWalther-JallowLAnderssonJSpetzAL 2004 HIV-1-infected dendritic cells up-regulate cell surface markers but fail to produce IL-12 p70 in response to CD40 ligand stimulation. Blood 104 2810 2817

60. KornbluthRS 2000 The emerging role of CD40 ligand in HIV infection. J Leukoc Biol 68 373 382

61. QiaoXHeBChiuAKnowlesDMChadburnA 2006 Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 7 302 310

62. CagigiANilssonAPensierosoSChiodiF 2010 Dysfunctional B-cell responses during HIV-1 infection: implication for influenza vaccination and highly active antiretroviral therapy. Lancet Infect Dis 10 499 503

63. De MilitoANilssonATitanjiKThorstenssonRReizensteinE 2004 Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection. Blood 103 2180 2186

64. BoudetFLecoeurHGougeonML 1996 Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection. J Immunol 156 2282 2293

65. GehriRHahnSRothenMSteuerwaldMNueschR 1996 The Fas receptor in HIV infection: expression on peripheral blood lymphocytes and role in the depletion of T cells. Aids 10 9 16

66. DolfiDVDuttaguptaPABoesteanuACMuellerYMOliaiCH 2011 Dendritic cells and CD28 costimulation are required to sustain virus-specific CD8+ T cell responses during the effector phase in vivo. J Immunol 186 4599 4608

67. ChaudhryADasSRHussainAMayorSGeorgeA 2005 The Nef protein of HIV-1 induces loss of cell surface costimulatory molecules CD80 and CD86 in APCs. J Immunol 175 4566 4574

68. VenkatachariNJMajumderBAyyavooV 2007 Human immunodeficiency virus (HIV) type 1 Vpr induces differential regulation of T cell costimulatory molecules: direct effect of Vpr on T cell activation and immune function. Virology 358 347 356

69. De KeersmaeckerBThielemansKAertsJL 2011 Fighting with the enemy's weapons? the role of costimulatory molecules in HIV. Curr Mol Med 11 172 196

70. Servet-DelpratCVidalainPOBausingerHManieSLe DeistF 2000 Measles virus induces abnormal differentiation of CD40 ligand-activated human dendritic cells. J Immunol 164 1753 1760

71. SalioMCellaMSuterMLanzavecchiaA 1999 Inhibition of dendritic cell maturation by herpes simplex virus. Eur J Immunol 29 3245 3253

72. Auffermann-GretzingerSKeeffeEBLevyS 2001 Impaired dendritic cell maturation in patients with chronic, but not resolved, hepatitis C virus infection. Blood 97 3171 3176

73. CoscoyLGanemD 2001 A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation. J Clin Invest 107 1599 1606

74. WherryEJ 2011 T cell exhaustion. Nat Immunol 12 492 499

75. DayCLKaufmannDEKiepielaPBrownJAMoodleyES 2006 PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443 350 354

76. PetrovasCCasazzaJPBrenchleyJMPriceDAGostickE 2006 PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203 2281 2292

77. ChikumaSTerawakiSHayashiTNabeshimaRYoshidaT 2009 PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol 182 6682 6689

78. TrabattoniDSaresellaMBiasinMBoassoAPiacentiniL 2003 B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. Blood 101 2514 2520

79. ChenLZhangZChenWZhangZLiY 2007 B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J Immunol 178 6634 6641

80. HallBFJoinerKA 1991 Strategies of obligate intracellular parasites for evading host defences. Immunol Today 12 A22 27

81. KayePMRogersNJCurryAJScottJC 1994 Deficient expression of co-stimulatory molecules on Leishmania-infected macrophages. Eur J Immunol 24 2850 2854

82. FischerHGDorflerRSchadeBHaddingU 1999 Differential CD86/B7-2 expression and cytokine secretion induced by Toxoplasma gondii in macrophages from resistant or susceptible BALB H-2 congenic mice. Int Immunol 11 341 349

83. CampbellKAOvendalePJKennedyMKFanslowWCReedSG 1996 CD40 ligand is required for protective cell-mediated immunity to Leishmania major. Immunity 4 283 289

84. MartinSAgarwalRMurugaiyanGSahaB 2010 CD40 expression levels modulate regulatory T cells in Leishmania donovani infection. J Immunol 185 551 559

85. MukherjeePChauhanVS 2008 Plasmodium falciparum-free merozoites and infected RBCs distinctly affect soluble CD40 ligand-mediated maturation of immature monocyte-derived dendritic cells. J Leukoc Biol 84 244 254

86. QinHWilsonCALeeSJZhaoXBenvenisteEN 2005 LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia. Blood 106 3114 3122

87. TerawakiSChikumaSShibayamaSHayashiTYoshidaT 2011 IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 186 2772 2779

88. LimWGeeKMishraSKumarA 2005 Regulation of B7.1 costimulatory molecule is mediated by the IFN regulatory factor-7 through the activation of JNK in lipopolysaccharide-stimulated human monocytic cells. J Immunol 175 5690 5700

89. JaiswalAIDubeyCSwainSLCroftM 1996 Regulation of CD40 ligand expression on naive CD4 T cells: a role for TCR but not co-stimulatory signals. Int Immunol 8 275 285

90. LenschowDJWalunasTLBluestoneJA 1996 CD28/B7 system of T cell costimulation. Annu Rev Immunol 14 233 258

91. RubADeyRJadhavMKamatRChakkaramakkilS 2009 Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function. Nat Immunol 10 273 280

92. DingLLinsleyPSHuangLYGermainRNShevachEM 1993 IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol 151 1224 1234

93. GeijtenbeekTBVan VlietSJKoppelEASanchez-HernandezMVandenbroucke-GraulsCM 2003 Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 197 7 17

94. PathakSKBasuSBasuKKBanerjeeAPathakS 2007 Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages. Nat Immunol 8 610 618

95. MeierABagchiASidhuHKAlterGSuscovichTJ 2008 Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS 22 655 658

96. MuthumaniKShedlockDJChooDKFagonePKawalekarOU 2010 HIV-mediated phosphatidylinositol 3-kinase/serine-threonine kinase activation in APCs leads to programmed death-1 ligand upregulation and suppression of HIV-specific CD8 T cells. J Immunol 187 2932 2943

97. ChaudhryADasSRJameelSGeorgeABalV 2007 A two-pronged mechanism for HIV-1 Nef-mediated endocytosis of immune costimulatory molecules CD80 and CD86. Cell Host Microbe 1 37 49

98. SwigutTShohdyNSkowronskiJ 2001 Mechanism for down-regulation of CD28 by Nef. Embo J 20 1593 1604

99. MahonRNRojasREFultonSAFrankoJLHardingCV 2009 Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling. Infect Immun 77 4574 4583

100. ChirmuleNMcCloskeyTWHuRKalyanaramanVSPahwaS 1995 HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71). J Immunol 155 917 924

101. ManninenARenkemaGHSakselaK 2000 Synergistic activation of NFAT by HIV-1 nef and the Ras/MAPK pathway. J Biol Chem 275 16513 16517

102. YaoZQKingEPraytherDYinDMoormanJ 2007 T cell dysfunction by hepatitis C virus core protein involves PD-1/PDL-1 signaling. Viral Immunol 20 276 287

103. LeonardJPFriedbergJWYounesAFisherDGordonLI 2007 A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with rituximab for relapsed or refractory, follicular lymphoma. Ann Oncol 18 1216 1223

104. AgrawalALingappaJLepplaSHAgrawalSJabbarA 2003 Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin. Nature 424 329 334

105. ChouPJNewtonCAPerkinsIFriedmanHKleinTW 2008 Suppression of dendritic cell activation by anthrax lethal toxin and edema toxin depends on multiple factors including cell source, stimulus used, and function tested. DNA Cell Biol 27 637 648

106. MitchellPGermainCFioriPLKhamriWFosterGR 2007 Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development. Infect Immun 75 810 819

107. SahaBDasGVohraHGangulyNKMishraGC 1995 Macrophage-T cell interaction in experimental visceral leishmaniasis: failure to express costimulatory molecules on Leishmania-infected macrophages and its implication in the suppression of cell-mediated immunity. Eur J Immunol 25 2492 2498

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2012 Číslo 6
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#