Apresenta

1
Mutations in Toll predispose to Aspergillus
fumigatus infection
Lemaitre et al. Cell 1996 86 973-83

• Innate Immune Receptors
• for Protozoan Parasites
• Identify relevant innate immune receptors
• Define parasite targets for innate immune
  receptors
• Define their role on hostparasite interaction,
  and disease outcome
• Elaborate prophylactic/therapeutic interventions
  employing protozoan derived PAMPs .

2
The innate immune system senses the invasion of
pathogenic microorganisms through the Toll-like
receptors (TLRs), which recognize specific
molecular patterns that are present in microbial
components.
Beutler, Ann. Rev. Immunol., 2006
Beutler, Ann. Rev. Immunol., 2006
3
(No Transcript)
4
(No Transcript)
5
Complete blockade of TNF-a and nitric oxide
synthesis by macrophages from TLR2 KO, TLR6 KO
and CD14 KO exposed to tGPI-mucins but not to
live trypomastigotes
6
TLR4 mediates NF-kB-dependent cellular activation
and pro-inflammatory activity upon exposure to
purified ceramide containing GIPL.
GIPL
Functional expression of TLR4 confers
proinflammatory responsiveness to Trypanosoma
cruzi GIPLs and higher resistance to infection
Oliveira A.C. et. al., J. Immunol. 173 (2004)
7
Lack of TLR2, TLR4 and CD14 does not affect host
resistance to acute infection with Trypanosoma
cruzi
8
(No Transcript)
9
Stimulatory oligonucleotides derived from T.
cruzi genome
10
(No Transcript)
11
TLR9 expression on dendritic cells is essential
for optimal IFN-g production and host resistance
acute infection with Trypanosoma cruzi
12
3d mice with combined deficiency on
TLR3/TLR7/TLR9 are highly susceptible to
infection with Trypanosoma cruzi
13
UNC93B1 and MyD88 are important elements for the
optimal CD8 responses during early stage of
infection with Trypanosoma cruzi
14
Clone CL-14 de Trypanosoma cruzi

• Origem Cepa infectante CL

• Base Molecular deficiência expressão da gp82

• Parasitemia e Mortalidade negativos

• Resposta protetora desafio com CL ou Y

15
Expression of the tumor antigen NY-ESO-1 by the
highly attenuated CL-14 strain of T. cruzi
16
CL-14 strain of T. cruzi expressing NY-ESO-1
induces strong humoral and cellular specific
immune responses and protects mice against tumor
development
CL-14 NY-ESO-1
17
T. cruzi derived CpG, but not GIPLs, pontentiates
humoral and cellular immune responses specific
for NY-ESO-1 and protects mice against tumor
development
CL-14 NY-ESO-1
18

• Conclusions
• Trypanosoma cruzi derived GPI anchors and DNA
  (unmethylated CpG motifs) act as TLR agonists.
• 2) Nucleotide sensing TLRs appear to be critical
  ones for eliciting protective immune responses
  during T. cruzi infection.
• 3) Optimal CD4 T as well as CD8 T cell
  responses elicited by T. cruzi are dependent on
  both MyD88 and UNC93B1 activities.
• 4) CL-14 strain induces a strong T-cell mediated
  immune response and protection against a
  melanoma cell line (B16) expressing the tumor
  antigen NY-ESO-1.

19
Acknowledgements
IMPAR - CPqRR-FIOCRUZ/UFMG Bruno Galvão Caroline
F. Junqueira Catherine Ropert Flávia
Rodrigues Helton Santiago Marco A. S. Campos
Eneida P. Valente .
University of Massachusetts - USA Braulia
Caetano Douglas T. Golenbock Eicke Latz Mariane
Melo Peggy Parroche Cheri Sirois
Ludwig Institute for Cancer Research - USA Andrew
Simpson Jonhatan Skipper Loyd Old Gerd Ritter
Inst. Ciencias Biologicas UFMG Daniella
Bartholomeu Jacqueline Alvarez-Leite Santuza M.
R. Teixeira Egler Chiari
National Institutes of Health - USA Andre
Bafica Romina Goldszmid Alan Sher
Inst. Ciencias Biomedicas UFRJ Jose Oswaldo
Previato Lucia Mendonça-Previato Maria Bellio
Osaka University Japan Scripps Res. Inst.
USA Shizuo Akira Bruce
Beutler
UNIFESP Maurício M. Rodrigues