Impaired Innate Immunity in Mice but Preserved CD8 T Cell Responses against in -, -, - or -Deficient Mice
The murine model of T. cruzi infection has provided compelling evidence that development of host resistance against intracellular protozoans critically depends on the activation of members of the Toll-like receptor (TLR) family via the MyD88 adaptor molecule. However, the possibility that TLR/MyD88 signaling pathways also control the induction of immunoprotective CD8+ T cell-mediated effector functions has not been investigated to date. We addressed this question by measuring the frequencies of IFN-γ secreting CD8+ T cells specific for H-2Kb-restricted immunodominant peptides as well as the in vivo Ag-specific cytotoxic response in infected animals that are deficient either in TLR2, TLR4, TLR9 or MyD88 signaling pathways. Strikingly, we found that T. cruzi-infected Tlr2−/−, Tlr4−/−, Tlr9−/− or Myd88−/− mice generated both specific cytotoxic responses and IFN-γ secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-γ+CD4+ cells was diminished in infected Myd88−/− mice. We also analyzed the efficiency of TLR4-driven immune responses against T. cruzi using TLR4-deficient mice on the C57BL genetic background (B6 and B10). Our studies demonstrated that TLR4 signaling is required for optimal production of IFN-γ, TNF-α and nitric oxide (NO) in the spleen of infected animals and, as a consequence, Tlr4−/− mice display higher parasitemia levels. Collectively, our results indicate that TLR4, as well as previously shown for TLR2, TLR9 and MyD88, contributes to the innate immune response and, consequently, resistance in the acute phase of infection, although each of these pathways is not individually essential for the generation of class I-restricted responses against T. cruzi.
Vyšlo v časopise:
Impaired Innate Immunity in Mice but Preserved CD8 T Cell Responses against in -, -, - or -Deficient Mice. PLoS Pathog 6(4): e32767. doi:10.1371/journal.ppat.1000870
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1000870
Souhrn
The murine model of T. cruzi infection has provided compelling evidence that development of host resistance against intracellular protozoans critically depends on the activation of members of the Toll-like receptor (TLR) family via the MyD88 adaptor molecule. However, the possibility that TLR/MyD88 signaling pathways also control the induction of immunoprotective CD8+ T cell-mediated effector functions has not been investigated to date. We addressed this question by measuring the frequencies of IFN-γ secreting CD8+ T cells specific for H-2Kb-restricted immunodominant peptides as well as the in vivo Ag-specific cytotoxic response in infected animals that are deficient either in TLR2, TLR4, TLR9 or MyD88 signaling pathways. Strikingly, we found that T. cruzi-infected Tlr2−/−, Tlr4−/−, Tlr9−/− or Myd88−/− mice generated both specific cytotoxic responses and IFN-γ secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-γ+CD4+ cells was diminished in infected Myd88−/− mice. We also analyzed the efficiency of TLR4-driven immune responses against T. cruzi using TLR4-deficient mice on the C57BL genetic background (B6 and B10). Our studies demonstrated that TLR4 signaling is required for optimal production of IFN-γ, TNF-α and nitric oxide (NO) in the spleen of infected animals and, as a consequence, Tlr4−/− mice display higher parasitemia levels. Collectively, our results indicate that TLR4, as well as previously shown for TLR2, TLR9 and MyD88, contributes to the innate immune response and, consequently, resistance in the acute phase of infection, although each of these pathways is not individually essential for the generation of class I-restricted responses against T. cruzi.
Zdroje
1. DutraWO
GollobKJ
2008 Current concepts in immunoregulation and pathology of human Chagas disease. Curr Opin Infect Dis 21 287 292
2. IwasakiA
MedzhitovR
2004 Toll-like receptor control of the adaptive immune responses. Nat Immunol 5 987 995
3. CamposMA
AlmeidaIC
TakeuchiO
AkiraS
ValenteEP
2001 Activation of Toll-like receptor-2 by glycosylphosphatidylinositol anchors from a protozoan parasite. J Immunol 167 416 423
4. OuaissiA
GuilvardE
DelnesteY
CaronG
MagistrelliG
2002 The Trypanosoma cruzi Tc52-released protein induces human dendritic cell maturation, signals via Toll-like receptor 2, and confers protection against lethal infection. J Immunol 168 6366 6374
5. OliveiraA-C
PeixotoRJ
ArrudaLB
CamposMA
GazzinelliRT
2004 Expression of functional TLR4 confers pro-inflammatory responsiveness to Trypanosoma cruzi glycoinositolphospholipids and higher resistance to infection with T. cruzi. J Immunol 173 5688 5696
6. BaficaA
SantiagoHC
GoldszmidR
RopertC
GazzinelliRT
2006 Cutting edge: TLR9 and TLR2 signaling together account for MyD88-dependent control of parasitemia in Trypanosoma cruzi infection. J Immunol 177 3515 3519
7. CamposMA
CloselM
ValenteEP
CardosoJE
AkiraS
2004 Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J Immunol 172 1711 1718
8. KogaR
HamanoS
KuwataH
AtarashiK
OgawaM
2006 TLR-dependent induction of IFN-β mediates host defense against Trypanosoma cruzi. J Immunol 177 7059 7066
9. PoltorakA
HeX
SmirnovaI
LiuMY
Van HuffelC
1998 Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282 2085 2088
10. TakeuchiO
HoshinoK
KawaiT
SanjoH
TakadaH
1999 Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11 443 451
11. LatzE
VisintinA
LienE
FitzgeraldKA
MonksBG
2002 Lipopolysaccharide rapidly traffics to and from the Golgi apparatus with the toll-like receptor 4-MD-2-CD14 complex in a process that is distinct from the initiation of signal transduction. J Biol Chem 277 47834 47843
12. TanakaY
KiyotakiC
TanowitzH
BloomBR
1982 Reconstitution of a variant macrophage cell line defective in oxygen metabolism with a H2O2-generating system. Proc Natl Acad Sci U S A 79 2584 2588
13. LocksleyRM
KlebanoffSJ
1983 Oxygen-dependent microbicidal systems of phagocytes and host defense against intracellular protozoa. J Cell Biochem 22 173 185
14. Munoz-FernandezMA
FernandezMA
FresnoM
1992 Synergism between tumor necrosis factor-alpha and interferon-gamma on macrophage activation for the killing of intracellular Trypanosoma cruzi through a nitric oxide-dependent mechanism. Eur J Immunol 22 301 307
15. VespaGN
CunhaFQ
SilvaJS
1994 Nitric oxide is involved in control of Trypanosoma cruzi-induced parasitemia and directly kills the parasite in vitro. Infect Immun 62 5177 5182
16. BalcerczykA
SowaK
BartoszG
2007 Metal chelators react also with reactive oxygen and nitrogen species. Biochem Biophys Res Commun 352 522 525
17. MartinsGA
VieiraLQ
CunhaFQ
SilvaJS
1999 Gamma interferon modulates CD95 (Fas) and CD95 ligand (Fas-L) expression and nitric oxide-induced apoptosis during the acute phase of Trypanosoma cruzi infection: a possible role in immune response control. Infect Immun 67 3864 3871
18. GazzinelliRT
OswaldIP
HienyS
JamesSL
SherA
1992 The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. Eur J Immunol 22 2501 2506
19. MartinD
TarletonR
2004 Generation, specificity, and function of CD8+ T cells in Trypanosoma cruzi infection. Immunol Rev 201 304 317
20. LowHP
SantosMA
WizelB
TarletonRL
1998 Amastigote surface proteins of Trypanosoma cruzi are targets for CD8+ CTL. J Immunol 160 1817 1823
21. MartinDL
WeatherlyDB
LaucellaSA
CabinianMA
CrimMT
2006 CD8+ T-Cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes. PLoS Pathog 2 e77 doi:10.1371/journal.ppat.0020077
22. TzelepisF
de AlencarBC
PenidoML
GazzinelliRT
PersechiniPM
2006 Distinct kinetics of effector CD8+ cytotoxic T cells after infection with Trypanosoma cruzi in naive or vaccinated mice. Infect Immun 74 2477 2481
23. MedeirosMM
PeixotoJR
OliveiraAC
Cardilo-ReisL
KoatzVL
2007 Toll-like receptor 4 (TLR4)-dependent proinflammatory and immunomodulatory properties of the glycoinositolphospholipid (GIPL) from Trypanosoma cruzi. J Leukoc Biol 82 488 496
24. TardieuxI
WebsterP
RaveslootJ
BoronW
LunnJA
1992 Lysosome recruitment and fusion are early events required for trypanosome invasion of mammalian cells. Cell 71 1117 1130
25. BurleighBA
2005 Host cell signaling and Trypanosoma cruzi invasion: do all roads lead to lysosomes? Sci STKE 2005 pe36
26. WoolseyAM
SunwooL
PetersenCA
BrachmannSM
CantleyLC
2003 Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation. J Cell Sci 116 3611 3622
27. UnderhillDM
GantnerB
2004 Integration of Toll-like receptor and phagocytic signaling for tailored immunity. Microbes Infect 6 1368 1373
28. Maganto-GarciaE
PunzonC
TerhorstC
FresnoM
2008 Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in macrophages. Traffic 9 1299 1315
29. BlanderJM
MedzhitovR
2004 Regulation of phagosome maturation by signals from toll-like receptors. Science 304 1014 1018
30. DenicolaA
RubboH
RodriguezD
RadiR
1993 Peroxynitrite-mediated cytotoxicity to Trypanosoma cruzi. Arch Biochem Biophys 304 279 286
31. AlvarezMN
PiacenzaL
IrigoinF
PeluffoG
RadiR
2004 Macrophage-derived peroxynitrite diffusion and toxicity to Trypanosoma cruzi. Arch Biochem Biophys 432 222 232
32. HolscherC
KohlerG
MullerU
MossmannH
SchaubGA
1998 Defective nitric oxide effector functions lead to extreme susceptibility of Trypanosoma cruzi-infected mice deficient in gamma interferon receptor or inducible nitric oxide synthase. Infect Immun 66 1208 1215
33. SaeftelM
FleischerB
HoeraufA
2001 Stage-dependent role of nitric oxide in control of Trypanosoma cruzi infection. Infect Immun 69 2252 2259
34. WrightsmanR
KrassnerS
WatsonJ
1982 Genetic control of responses to Trypanosoma cruzi in mice: multiple genes influencing parasitemia and survival. Infect Immun 36 637 644
35. TrischmannTM
BloomBR
1982 Genetics of murine resistance to Trypanosoma cruzi. Infect Immun 35 546 551
36. AlibertiJC
SoutoJT
MarinoAP
Lannes-VieiraJ
TeixeiraMM
2001 Modulation of chemokine production and inflammatory responses in interferon-gamma- and tumor necrosis factor-R1-deficient mice during Trypanosoma cruzi infection. Am J Pathol 158 1433 1440
37. KayamaH
KogaR
AtarashiK
OkuyamaM
KimuraT
2009 NFATc1 mediates Toll-like receptor-independent innate immune responses during Trypanosoma cruzi infection. PLoS Pathog 5 e1000514 doi:10.1371/journal.ppat.1000514
38. MachadoAV
CardosoJE
ClaserC
RodriguesMM
GazzinelliRT
2006 Long-term protective immunity induced against Trypanosoma cruzi infection after vaccination with recombinant adenoviruses encoding amastigote surface protein-2 and trans-sialidase. Hum Gene Ther 17 898 908
39. TzelepisF
PersechiniPM
RodriguesMM
2007 Modulation of CD4+ T cell-dependent specific cytotoxic CD8+ T cells differentiation and proliferation by the timing of increase in the pathogen load. PLoS ONE 2 e393 doi:10.1371/journal.pone.0000393
40. SilvaGK
GutierrezFRS
GuedesPMM
HortaCV
CunhaLD
2009 Cutting Edge: Nucleotide-Binding Oligomerization Domain 1-Dependent Responses Account for Murine Resistance against Trypanosoma cruzi Infection. J Immunol jimmunol.0902254
41. MonteiroAC
SchmitzV
MorrotA
de ArrudaLB
NagajyothiF
2007 Bradykinin B2 Receptors of dendritic cells, acting as sensors of kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses. PLoS Pathog 3 e185 doi:10.1371/journal.ppat.0030185
42. GallucciS
LolkemaM
MatzingerP
1999 Natural adjuvants: endogenous activators of dendritic cells. Nat Med 5 1249 1255
43. LuftT
PangKC
ThomasE
HertzogP
HartDN
1998 Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol 161 1947 1953
44. CurtsingerJM
ValenzuelaJO
AgarwalP
LinsD
MescherMF
2005 Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 174 4465 4469
45. LangPA
Cervantes-BarraganL
VerschoorA
NavariniAA
RecherM
2009 Hematopoietic cell-derived interferon controls viral replication and virus-induced disease. Blood 113 1045 1052
46. CostaVM
TorresKC
MendoncaRZ
GresserI
GollobKJ
2006 Type I IFNs stimulate nitric oxide production and resistance to Trypanosoma cruzi infection. J Immunol 177 3193 3200
47. EganCE
SukhumavasiW
ButcherBA
DenkersEY
2009 Functional aspects of Toll-like receptor/MyD88 signalling during protozoan infection: focus on Toxoplasma gondii. Clin Exp Immunol 156 17 24
48. SukhumavasiW
EganCE
WarrenAL
TaylorGA
FoxBA
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
49. BolzDD
SundsbakRS
MaY
AkiraS
KirschningCJ
2004 MyD88 plays a unique role in host defense but not arthritis development in Lyme disease. J Immunol 173 2003 2010
50. von BernuthH
PicardC
JinZ
PanklaR
XiaoH
2008 Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321 691 696
51. WaySS
KollmannTR
HajjarAM
WilsonCB
2003 Cutting edge: protective cell-mediated immunity to Listeria monocytogenes in the absence of myeloid differentiation factor 88. J Immunol 171 533 537
52. ShiS
NathanC
SchnappingerD
DrenkowJ
FuortesM
2003 MyD88 Primes Macrophages for Full-Scale Activation by Interferon-{gamma} yet Mediates Few Responses to Mycobacterium tuberculosis. J Exp Med 198 987 997
53. TarletonRL
GrusbyMJ
PostanM
GlimcherLH
1996 Trypanosoma cruzi infection in MHC-deficient mice: further evidence for the role of both class I- and class II-restricted T cells in immune resistance and disease. Int Immunol 8 13 22
54. KumarS
TarletonRL
1998 The relative contribution of antibody production and CD8+ T cell function to immune control of Trypanosoma cruzi. Parasite Immunol 20 207 216
55. PasareC
MedzhitovR
2005 Control of B-cell responses by Toll-like receptors. Nature 438 364 368
56. GavinAL
HoebeK
DuongB
OtaT
MartinC
2006 Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314 1936 1938
57. BrowneEP
LittmanDR
2009 Myd88 is required for an antibody response to retroviral infection. PLoS Pathog 5 e1000298 doi:10.1371/journal.ppat.1000870
58. HeerAK
ShamshievA
DondaA
UematsuS
AkiraS
2007 TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. J Immunol 178 2182 2191
59. GuayHM
AndreyevaTA
GarceaRL
WelshRM
Szomolanyi-TsudaE
2007 MyD88 is required for the formation of long-term humoral immunity to virus infection. J Immunol 178 5124 5131
60. NakanishiY
LuB
GerardC
IwasakiA
2009 CD8+ T lymphocyte mobilization to virus-infected tissue requires CD4+ T-cell help. Nature 462 510 513
61. Pereira da SilvaLH
NussenzweigV
1953 Sobre uma cepa de Trypanosoma cruzi altamente virulenta para o camundongo branco. Fol Clin Biol 20 191
62. GreenLC
WagnerDA
GlogowskiJ
SkipperPL
WishnokJS
1982 Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 126 131 138
63. de AlencarBC
AraujoAF
PenidoML
GazzinelliRT
RodriguesMM
2007 Cross-priming of long lived protective CD8+ T cells against Trypanosoma cruzi infection: importance of a TLR9 agonist and CD4+ T cells. Vaccine 25 6018 6027
64. MartinDL
TarletonRL
2005 Antigen-Specific T Cells Maintain an Effector Memory Phenotype during Persistent Trypanosoma cruzi Infection. J Immunol 174 1594 1601
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2010 Číslo 4
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- The Effect of Vaccination on the Evolution and Population Dynamics of Avian Paramyxovirus-1
- Reconstitution of SARS-Coronavirus mRNA Cap Methylation
- Deficiencies in Jasmonate-Mediated Plant Defense Reveal Quantitative Variation in Pathogenesis
- A Timescale for Evolution, Population Expansion, and Spatial Spread of an Emerging Clone of Methicillin-Resistant