Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88.
Studies performed in vitro suggest that activation of Toll-like receptors (TLRs) by parasite-derived molecules may initiate inflammatory responses and host innate defense mechanisms against Trypanosoma cruzi. Here, we evaluated the impact of TLR2 and myeloid differentiation factor 88 (MyD88) deficiencies in host resistance to infection with T. cruzi. Our results show that macrophages derived from TLR2 (-/-) and MyD88(-/-) mice are less responsive to GPI-mucin derived from T. cruzi trypomastigotes and parasites. In contrast, the same cells from TLR2(-/-) still produce TNF-alpha, IL-12, and reactive nitrogen intermediates (RNI) upon exposure to live T. cruzi trypomastigotes. Consistently, we show that TLR2(-/-) mice mount a robust proinflammatory cytokine response as well as RNI production during the acute phase of infection with T. cruzi parasites. Further, deletion of the functional TLR2 gene had no major impact on parasitemia nor on mortality. In contrast, the MyD88(-/-) mice had a diminished cytokine response and RNI production upon acute infection with T. cruzi. More importantly, we show that MyD88(-/-) mice are more susceptible to infection with T. cruzi as indicated by the higher parasitemia and accelerated mortality, as compared with the wild-type mice. Together, our results indicate that T. cruzi parasites elicit an alternative inflammatory pathway independent of TLR2. This pathway is partially dependent on MyD88 and necessary for mounting optimal inflammatory and RNI responses that control T. cruzi replication during the early stages of infection.
Campos
Marco A
MA
Department of Biochemistry and Immunology, Instituto de Ciências Biológicas, and School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Closel
Meire
M
Valente
Eneida P
EP
Cardoso
Jarbas E
JE
Akira
Shizuo
S
Alvarez-Leite
Jacqueline I
JI
Ropert
Catherine
C
Gazzinelli
Ricardo T
RT
D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D026361:Reactive Nitrogen Species / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014349:Trypanosoma cruzi / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D026361:Reactive Nitrogen Species; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma