#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity


Autoři: Heather L. Mercer aff001;  Lindsay M. Snyder aff001;  Claire M. Doherty aff001;  Barbara A. Fox aff002;  David J. Bzik aff002;  Eric Y. Denkers aff001
Působiště autorů: Center for Evolutionary and Theoretical Immunology and Department of Biology, University of New Mexico, Albuquerque, New Mexico, United States of America aff001;  Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America aff002
Vyšlo v časopise: Toxoplasma gondii dense granule protein GRA24 drives MyD88-independent p38 MAPK activation, IL-12 production and induction of protective immunity. PLoS Pathog 16(5): e32767. doi:10.1371/journal.ppat.1008572
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008572

Souhrn

The apicomplexan Toxoplasma gondii induces strong protective immunity dependent upon recognition by Toll-like receptors (TLR)11 and 12 operating in conjunction with MyD88 in the murine host. However, TLR11 and 12 proteins are not present in humans, inspiring us to investigate MyD88-independent pathways of resistance. Using bicistronic IL-12-YFP reporter mice on MyD88+/+ and MyD88-/- genetic backgrounds, we show that CD11c+MHCII+F4/80- dendritic cells, F4/80+ macrophages, and Ly6G+ neutrophils were the dominant cellular sources of IL-12 in both wild type and MyD88 deficient mice after parasite challenge. Parasite dense granule protein GRA24 induces p38 MAPK activation and subsequent IL-12 production in host macrophages. We show that Toxoplasma triggers an early and late p38 MAPK phosphorylation response in MyD88+/+ and MyD88-/- bone marrow-derived macrophages. Using the uracil auxotrophic Type I T. gondii strain cps1-1, we demonstrate that the late response does not require active parasite proliferation, but strictly depends upon GRA24. By i. p. inoculation with cps1-1 and cps1-1:Δgra24, we identified unique subsets of chemokines and cytokines that were up and downregulated by GRA24. Finally, we demonstrate that cps1-1 triggers a strong host-protective GRA24-dependent Th1 response in the absence of MyD88. Our data identify GRA24 as a major mediator of p38 MAPK activation, IL-12 induction and protective immunity that operates independently of the TLR/MyD88 cascade.

Klíčová slova:

Cytokines – Enzyme-linked immunoassays – Parasitic diseases – Toll-like receptors – Toxoplasma – Toxoplasma gondii – Tachyzoites – Uracils


Zdroje

1. Robert-Gangneux F, Darde ML (2012) Epidemiology of and diagnostic strategies for toxoplasmosis. Clin Microbiol Rev 25: 264–296. doi: 10.1128/CMR.05013-11 22491772

2. Dubey JP (2013) The history and life-cycle of Toxoplasma gondii. In: Weiss LM, Kim K, editors. Toxoplasma gondii The model apicomplexan: Perspective and methods. 2nd ed. San Diego: Academic Press. pp. 1–17.

3. McLeod RM, van Tubbergen C, Montoya JG, Petersen E (2013) Human Toxoplasma infection. In: Weiss LM, Kim K, editors. Toxoplasma gondii The Model Apicomplexan: Perspectives and Methods. 2nd ed. San Diego: Academic Press. pp. 100–159.

4. Pfaff AW, Liesenfeld O, Candolfi E (2007) Congenital toxoplasmosis. In: Ajioka JW, Soldati D, editors. Toxoplasma molecular and cellular biology. Norfolk: Horizon Bioscience. pp. 93–110.

5. Denkers EY, Gazzinelli RT (1998) Regulation and function of T-cell-mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev 11: 569–588. 9767056

6. Dupont CD, Christian DA, Hunter CA (2012) Immune response and immunopathology during toxoplasmosis. Semin Immunopathol 34: 793–813. doi: 10.1007/s00281-012-0339-3 22955326

7. Yarovinsky F (2014) Innate immunity to Toxoplasma gondii infection. Nat Rev Immunol 14: 109–121. doi: 10.1038/nri3598 24457485

8. Cohen SB, Denkers EY (2015) Impact of Toxoplasma gondii on Dendritic Cell Subset Function in the Intestinal Mucosa. J Immunol 195: 2754–2762. doi: 10.4049/jimmunol.1501137 26283477

9. Mashayekhi M, Sandau MM, Dunay IR, Frickel EM, Khan A, Goldszmid RS, Sher A, Ploegh HL, Murphy TL, Sibley LD, Murphy KM (2011) CD8alpha(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites. Immunity 35: 249–259. S1074-7613(11)00313-X [pii] doi: 10.1016/j.immuni.2011.08.008 21867928

10. Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, Germain RN, Sher A (1997) In vivo microbial stimulation induces rapid CD40L-independent production of IL-12 by dendritic cells and their re-distribution to T cell areas. J Exp Med 186: 1819–1829. doi: 10.1084/jem.186.11.1819 9382881

11. Yap G, Pesin M, Sher A (2000) IL-12 is required for the maintenance of IFN-g production in T cells mediating chronic resistance to the intracellular pathogen, Toxoplasma gondii. J Immunol 165: 628–631. doi: 10.4049/jimmunol.165.2.628 10878333

12. Degrandi D, Kravets E, Konermann C, Beuter-Gunia C, Klumpers V, Lahme S, Wischmann E, Mausberg AK, Beer-Hammer S, Pfeffer K (2013) Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication. Proc Natl Acad Sci U S A 110: 294–299. doi: 10.1073/pnas.1205635110 23248289

13. Haldar AK, Saka HA, Piro AS, Dunn JD, Henry SC, Taylor GA, Frickel EM, Valdivia RH, Coers J (2013) IRG and GBP host resistance factors target aberrant, "non-self" vacuoles characterized by the missing of "self" IRGM proteins. PLoS Pathog 9: e1003414. doi: 10.1371/journal.ppat.1003414 23785284

14. Martens S, Parvanova I, Zerrahn J, Griffiths G, Schell G, Reichmann G, Howard JC (2005) Disruption of Toxoplasma gondii Parasitophorous Vacuoles by the Mouse p47-Resistance GTPases. PLoS Pathog 1: e24. doi: 10.1371/journal.ppat.0010024 16304607

15. Yamamoto M, Okuyama M, Ma JS, Kimura T, Kamiyama N, Saiga H, Ohshima J, Sasai M, Kayama H, Okamoto T, Huang DC, Soldati-Favre D, Horie K, Takeda J, Takeda K (2012) A Cluster of Interferon-gamma-Inducible p65 GTPases Plays a Critical Role in Host Defense against Toxoplasma gondii. Immunity. doi: 10.1016/j.immuni.2012.06.009 22795875

16. Zhao YO, Khaminets A, Hunn JP, Howard JC (2009) Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNgamma-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death. PLoS Pathog 5: e1000288. doi: 10.1371/journal.ppat.1000288 19197351

17. Scanga CA, Aliberti J, Jankovic D, Tilloy F, Bennouna S, Denkers EY, Medzhitov R, Sher A (2002) Cutting edge: MyD88 is required for resistance to Toxoplasma gondii infection and regulates parasite-induced IL-12 production by dendritic cells. J Immunol 168: 5997–6001. doi: 10.4049/jimmunol.168.12.5997 12055206

18. Gazzinelli RT, Denkers EY (2006) Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat Rev Immunol 6: 895–906. doi: 10.1038/nri1978 17110955

19. Hou B, Benson A, Kuzmich L, DeFranco AL, Yarovinsky F (2011) Critical coordination of innate immune defense against Toxoplasma gondii by dendritic cells responding via their Toll-like receptors. Proc Natl Acad Sci U S A 108: 278–283. 1011549108 [pii] doi: 10.1073/pnas.1011549108 21173242

20. Bliss SK, Butcher BA, Denkers EY (2000) Rapid recruitment of neutrophils with prestored IL-12 during microbial infection. J Immunol 165: 4515–4521. doi: 10.4049/jimmunol.165.8.4515 11035091

21. Cohen SB, Maurer KJ, Egan CE, Oghumu S, Satoskar AR, Denkers EY (2013) CXCR3-dependent CD4(+) T cells are required to activate inflammatory monocytes for defense against intestinal infection. PLoS Pathog 9: e1003706. doi: 10.1371/journal.ppat.1003706 24130498

22. Pifer R, Benson A, Sturge CR, Yarovinsky F (2011) UNC93B1 is essential for TLR11 activation and IL-12 dependent host resistance to Toxoplasma Gondii. J Biol Chem 286: 3307–3314. doi: 10.1074/jbc.M110.171025 21097503

23. Yarovinsky F, Kanzler H, Hieny S, Coffman RL, Sher A (2006) Toll-like receptor recognition regulates immunodominance in an antimicrobial CD4+ T cell response. Immunity 25: 655–664. doi: 10.1016/j.immuni.2006.07.015 17000122

24. Andrade WA, Souza MD, Ramos-Martinez E, Nagpal K, Dutra MS, Melo MB, Bartholomeu DC, Ghosh S, Golenbock DT, Gazzinelli RT (2013) Combined Action of Nucleic Acid-Sensing Toll-like Receptors and TLR11/TLR12 Heterodimers Imparts Resistance to Toxoplasma gondii in Mice. Cell Host Microbe 13: 42–53. doi: 10.1016/j.chom.2012.12.003 23290966

25. Raetz M, Kibardin A, Sturge CR, Pifer R, Li H, Burstein E, Ozato K, Larin S, Yarovinsky F (2013) Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin. J Immunol 191: 4818–4827. doi: 10.4049/jimmunol.1301301 24078692

26. Yarovinsky F, Zhang D, Anderson JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A (2005) TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 308: 1626–1629. doi: 10.1126/science.1109893 15860593

27. Plattner F, Yarovinsky F, Romero S, Didry D, Carlier MF, Sher A, Soldati-Favre D (2008) Toxoplasma profilin is essential for host cell invasion and TLR dependent induction of interleukin-12. Cell Host and Microbe 14: 77–87.

28. Debierre-Grockiego F, Campos MA, Azzouz N, Schmidt J, Bieker U, Resende MG, Mansur DS, Weingart R, Schmidt RR, Golenbock DT, Gazzinelli RT, Schwarz RT (2007) Activation of TLR2 and TLR4 by glycosylphosphatidylinositols derived from Toxoplasma gondii. J Immunol 179: 1129–1137. doi: 10.4049/jimmunol.179.2.1129 17617606

29. Mun H-S, Aosai F, Norose K, Chen M, Piao L-X, Takeuchi O, Akira S, Ishikura H, Yano A (2003) TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection. Internat Parasitol 15: 1081–1087.

30. Gazzinelli RT, Mendonca-Neto R, Lilue J, Howard J, Sher A (2014) Innate resistance against Toxoplasma gondii: an evolutionary tale of mice, cats, and men. Cell Host Microbe 15: 132–138. doi: 10.1016/j.chom.2014.01.004 24528860

31. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Arostegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yague J, Anton J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Marodi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A, Casanova JL (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691–696. doi: 10.1126/science.1158298 18669862

32. von Bernuth H, Picard C, Puel A, Casanova JL (2012) Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur J Immunol 42: 3126–3135. doi: 10.1002/eji.201242683 23255009

33. Sukhumavasi W, Egan CE, Warren AL, Taylor GA, Fox BA, Bzik DJ, Denkers EY (2008) TLR adaptor MyD88 is essential for pathogen control during oral toxoplasma gondii infection but not adaptive immunity induced by a vaccine strain of the parasite. J Immunol 181: 3464–3473. doi: 10.4049/jimmunol.181.5.3464 18714019

34. Kim L, Del Rio L, Butcher BA, Mogensen TH, Paludan S, Flavell RA, Denkers EY (2005) p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection. J Immunol 174: 4178–4184. doi: 10.4049/jimmunol.174.7.4178 15778378

35. Braun L, Brenier-Pinchart MP, Yogavel M, Curt-Varesano A, Curt-Bertini RL, Hussain T, Kieffer-Jaquinod S, Coute Y, Pelloux H, Tardieux I, Sharma A, Belrhali H, Bougdour A, Hakimi MA (2013) A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation. J Exp Med 210: 2071–2086. doi: 10.1084/jem.20130103 24043761

36. Pellegrini E, Palencia A, Braun L, Kapp U, Bougdour A, Belrhali H, Bowler MW, Hakimi MA (2017) Structural Basis for the Subversion of MAP Kinase Signaling by an Intrinsically Disordered Parasite Secreted Agonist. Structure 25: 16–26. doi: 10.1016/j.str.2016.10.011 27889209

37. Robben PM, Mordue DG, Truscott SM, Takeda K, Akira S, Sibley LD (2004) Production of IL-12 by macrophages infected with Toxoplasma gondii depends on the parasite genotype. J Immunol 172: 3686–3694. doi: 10.4049/jimmunol.172.6.3686 15004172

38. DeLaney AA, Berry CT, Christian DA, Hart A, Bjanes E, Wynosky-Dolfi MA, Li X, Tummers B, Udalova IA, Chen YH, Hershberg U, Freedman BD, Hunter CA, Brodsky IE (2019) Caspase-8 promotes c-Rel-dependent inflammatory cytokine expression and resistance against Toxoplasma gondii. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1820529116 31147458

39. Reinhardt RL, Hong S, Kang SJ, Wang ZE, Locksley RM (2006) Visualization of IL-12/23p40 in vivo reveals immunostimulatory dendritic cell migrants that promote Th1 differentiation. J Immunol 177: 1618–1627. doi: 10.4049/jimmunol.177.3.1618 16849470

40. Fox BA, Bzik DJ (2010) Avirulent uracil auxotrophs based on disruption of orotidine-5'-monophosphate decarboxylase elicit protective immunity to Toxoplasma gondii. Infect Immun 78: 3744–3752. doi: 10.1128/IAI.00287-10 20605980

41. Fox BA, Sanders KL, Rommereim LM, Guevara RB, Bzik DJ (2016) Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity. PLoS Genet 12: e1006189. doi: 10.1371/journal.pgen.1006189 27447180

42. Butcher BA, Fox BA, Rommereim LM, Kim SG, Maurer KJ, Yarovinsky F, Herbert DR, Bzik DJ, Denkers EY (2011) Toxoplasma gondii rhoptry kinase ROP16 activates STAT3 and STAT6 resulting in cytokine inhibition and arginase-1-dependent growth control. PLoS Pathog 7: e1002236. doi: 10.1371/journal.ppat.1002236 21931552

43. Butcher BA, Kim L, Panopoulos A, Watowich SS, Murray PJ, Denkers EY (2005) Cutting Edge: IL-10-independent STAT3 activation by Toxoplasma gondii mediates suppression of IL-12 and TNF-a in host macrophages. J Immunol 174: 3148–3152. doi: 10.4049/jimmunol.174.6.3148 15749841

44. Kim L, Denkers EY (2006) Toxoplasma gondii triggers Gi-dependent phosphatidylinositol 3-kinase signaling required for inhibition of host cell apoptosis. J Cell Sci 119: 2119–2126. doi: 10.1242/jcs.02934 16638808

45. Cuenda A, Alessi DR (2000) Use of kinase inhibitors to dissect signaling pathways. Methods Mol Biol 99: 161–175. doi: 10.1385/1-59259-054-3:161 10909084

46. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A (1994) Parasite-induced IL-12 stimulates early IFN-g synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol 153: 2533–2543. 7915739

47. Bougdour A, Durandau E, Brenier-Pinchart MP, Ortet P, Barakat M, Kieffer S, Curt-Varesano A, Curt-Bertini RL, Bastien O, Coute Y, Pelloux H, Hakimi MA (2013) Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression. Cell Host Microbe 13: 489–500. doi: 10.1016/j.chom.2013.03.002 23601110

48. Bougdour A, Tardieux I, Hakimi MA (2014) Toxoplasma exports dense granule proteins beyond the vacuole to the host cell nucleus and rewires the host genome expression. Cell Microbiol 16: 334–343. doi: 10.1111/cmi.12255 24373221

49. Mota CM, Oliveira AC, Davoli-Ferreira M, Silva MV, Santiago FM, Nadipuram SM, Vashisht AA, Wohlschlegel JA, Bradley PJ, Silva JS, Mineo JR, Mineo TW (2016) Neospora caninum Activates p38 MAPK as an Evasion Mechanism against Innate Immunity. Front Microbiol 7: 1456. doi: 10.3389/fmicb.2016.01456 27679624

50. Hakimi MA, Bougdour A (2015) Toxoplasma's ways of manipulating the host transcriptome via secreted effectors. Curr Opin Microbiol 26: 24–31. doi: 10.1016/j.mib.2015.04.003 25912924

51. Coffey MJ, Sleebs BE, Uboldi AD, Garnham A, Franco M, Marino ND, Panas MW, Ferguson DJ, Enciso M, O'Neill MT, Lopaticki S, Stewart RJ, Dewson G, Smyth GK, Smith BJ, Masters SL, Boothroyd JC, Boddey JA, Tonkin CJ (2015) An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell. Elife 4. doi: 10.7554/eLife.10809 26576949

52. Curt-Varesano A, Braun L, Ranquet C, Hakimi MA, Bougdour A (2016) The aspartyl protease TgASP5 mediates the export of the Toxoplasma GRA16 and GRA24 effectors into host cells. Cell Microbiol 18: 151–167. doi: 10.1111/cmi.12498 26270241

53. Franco M, Panas MW, Marino ND, Lee MC, Buchholz KR, Kelly FD, Bednarski JJ, Sleckman BP, Pourmand N, Boothroyd JC (2016) A Novel Secreted Protein, MYR1, Is Central to Toxoplasma's Manipulation of Host Cells. MBio 7: e02231–02215. doi: 10.1128/mBio.02231-15 26838724

54. Baba M, Batanova T, Kitoh K, Takashima Y (2017) Adhesion of Toxoplasma gondii tachyzoite-infected vehicle leukocytes to capillary endothelial cells triggers timely parasite egression. Sci Rep 7: 5675. doi: 10.1038/s41598-017-05956-z 28720868

55. Portillo JC, Muniz-Feliciano L, Lopez Corcino Y, Lee SJ, Van Grol J, Parsons SJ, Schiemman WP, Subauste CS (2017) Toxoplasma gondii induces FAK-Src-STAT3 signaling during infection of host cells that prevents parasite targeting by autophagy. PLoS Pathog 13: e1006671. doi: 10.1371/journal.ppat.1006671 29036202

56. Tosh KW, Mittereder L, Bonne-Annee S, Hieny S, Nutman TB, Singer SM, Sher A, Jankovic D (2016) The IL-12 Response of Primary Human Dendritic Cells and Monocytes to Toxoplasma gondii Is Stimulated by Phagocytosis of Live Parasites Rather Than Host Cell Invasion. J Immunol 196: 345–356. doi: 10.4049/jimmunol.1501558 26597011

57. Lopez-Yglesias AH, Camanzo E, Martin AT, Araujo AM, Yarovinsky F (2019) TLR11-independent inflammasome activation is critical for CD4+ T cell-derived IFN-gamma production and host resistance to Toxoplasma gondii. PLoS Pathog 15: e1007872. doi: 10.1371/journal.ppat.1007872 31194844

58. Sturge CR, Benson A, Raetz M, Wilhelm CL, Mirpuri J, Vitetta ES, Yarovinsky F (2013) TLR-independent neutrophil-derived IFN-gamma is important for host resistance to intracellular pathogens. Proc Natl Acad Sci U S A 110: 10711–10716. doi: 10.1073/pnas.1307868110 23754402

59. Rosowski EE, Lu D, Julien L, Rodda L, Gaiser RA, Jensen KD, Saeij JP (2011) Strain-specific activation of the NF-kappaB pathway by GRA15, a novel Toxoplasma gondii dense granule protein. J Exp Med 208: 195–212. doi: 10.1084/jem.20100717 21199955

60. Hakimi MA, Olias P, Sibley LD (2017) Toxoplasma Effectors Targeting Host Signaling and Transcription. Clin Microbiol Rev 30: 615–645. doi: 10.1128/CMR.00005-17 28404792

61. Ma JS, Sasai M, Ohshima J, Lee Y, Bando H, Takeda K, Yamamoto M (2014) Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6. J Exp Med 211: 2013–2032. doi: 10.1084/jem.20131272 25225460

62. Gay G, Braun L, Brenier-Pinchart MP, Vollaire J, Josserand V, Bertini RL, Varesano A, Touquet B, De Bock PJ, Coute Y, Tardieux I, Bougdour A, Hakimi MA (2016) Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-gamma-mediated host defenses. J Exp Med. doi: 10.1084/jem.20160340 27503074

63. Olias P, Etheridge RD, Zhang Y, Holtzman MJ, Sibley LD (2016) Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-gamma-Dependent Gene Expression. Cell Host Microbe 20: 72–82. doi: 10.1016/j.chom.2016.06.006 27414498

64. Saeij JP, Coller S, Boyle JP, Jerome ME, White MW, Boothroyd JC (2007) Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445: 324–327. doi: 10.1038/nature05395 17183270

65. Jensen KD, Wang Y, Wojno ED, Shastri AJ, Hu K, Cornel L, Boedec E, Ong YC, Chien YH, Hunter CA, Boothroyd JC, Saeij JP (2011) Toxoplasma polymorphic effectors determine macrophage polarization and intestinal inflammation. Cell Host Microbe 9: 472–483. doi: 10.1016/j.chom.2011.04.015 21669396

66. Sangare LO, Olafsson EB, Wang Y, Yang N, Julien L, Camejo A, Pesavento P, Sidik SM, Lourido S, Barragan A, Saeij JPJ (2019) In Vivo CRISPR Screen Identifies TgWIP as a Toxoplasma Modulator of Dendritic Cell Migration. Cell Host Microbe 26: 478–492 e478. doi: 10.1016/j.chom.2019.09.008 31600500

67. Gazzinelli RT, Hieny S, Wynn T, Wolf S, Sher A (1993) IL-12 is required for the T-cell independent induction of IFN-g by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci USA 90: 6115–6119. doi: 10.1073/pnas.90.13.6115 8100999


Článek vyšel v časopise

PLOS Pathogens


2020 Číslo 5
Nejčtenější tento týden
Nejčtenější v tomto čísle
Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Přihlášení
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

#ADS_BOTTOM_SCRIPTS#