Expression of functional TLR4 confers proinflammatory responsiveness to Trypanosoma cruzi glycoinositolphospholipids and higher resistance to infection with T. cruzi.
TLRs function as pattern recognition receptors in mammals and play an essential role in the recognition of microbial components. We found that the injection of glycoinositolphospholipids (GIPLs) from Trypanosoma cruzi into the peritoneal cavity of mice induced neutrophil recruitment in a TLR4-dependent manner: the injection of GIPL in the TLR4-deficient strain of mice (C57BL/10ScCr) caused no inflammatory response. In contrast, in TLR2 knockout mice, neutrophil chemoattraction did not differ significantly from that seen in wild-type controls. GIPL-induced neutrophil attraction and MIP-2 production were also severely affected in TLR4-mutant C3H/HeJ mice. The role of TLR4 was confirmed in vitro by testing genetically engineered mutants derived from TLR2-deficient Chinese hamster ovary (CHO)-K1 fibroblasts that were transfected with CD14 (CHO/CD14). Wild-type CHO/CD14 cells express the hamster TLR4 molecule and the mutant line, in addition, expresses a nonfunctional form of MD-2. In comparison to wild-type cells, mutant CHO/CD14 cells failed to respond to GIPLs, indicating a necessity for a functional TLR4/MD-2 complex in GIPL-induced NF-kappaB activation. Finally, we found that TLR4-mutant mice were hypersusceptible to T. cruzi infection, as evidenced by a higher parasitemia and earlier mortality. These results demonstrate that natural resistance to T. cruzi is TLR4 dependent, most likely due to TLR4 recognition of their GIPLs.
Oliveira
Ana-Carolina
AC
Instituto de Microbiologia Prof. Paulo de Góes, Rio de Janeiro, Brazil.
Peixoto
Jaqueline R
JR
de Arruda
Luciana B
LB
Campos
Marco A
MA
Gazzinelli
Ricardo T
RT
Golenbock
Douglas T
DT
Akira
Shizuo
S
Previato
José O
JO
Mendonça-Previato
Lúcia
L
Nobrega
Alberto
A
Bellio
Maria
M
D000818:Animals; D016466:CHO Cells; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D006017:Glycolipids / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007274:Injections, Intraperitoneal; D016753:Interleukin-10 / Q000096:biosynthesis; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010743:Phospholipids / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014349:Trypanosoma cruzi / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D006017:Glycolipids; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010743:Phospholipids; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C115336:glycoinositolphospholipid, Trypanosoma; D016753:Interleukin-10