TLR-Dependent Induction of IFN-beta Mediates Host Defense against Trypanosoma cruzi

Koga R, Hamano S, Kuwata H, Atarashi K, Ogawa M, Hisaeda H, Yamamoto M, Akira S, Himeno K, Matsumoto M, Takeda K
Source: J Immunol
Publication Date: (2006)
Issue: 177(10): 7059-66
Research Area:
Immunotherapy / Hematology
Cells used in publication:
Macrophage, mouse
Species: mouse
Tissue Origin: bone marrow
Macrophage, mouse - C57BL/6
Species: mouse
Tissue Origin: bone marrow
Macrophage, mouse - BALB/c
Species: mouse
Tissue Origin: bone marrow
Nucleofectorâ„¢ I/II/2b
Host resistance to the intracellular protozoan parasite Trypanosoma cruzi depends on IFN-gamma production by T cells and NK cells. However, the involvement of innate immunity in host resistance to T. cruzi remains unclear. In the present study, we investigated host defense against T. cruzi by focusing on innate immunity. Macrophages and dendritic cells (DCs) from MyD88(-/-)TRIF(-/-) mice, in which TLR-dependent activation of innate immunity was abolished, were defective in the clearance of T. cruzi and showed impaired induction of IFN-beta during T. cruzi infection. Neutralization of IFN-beta in MyD88(-/-) macrophages led to enhanced T. cruzi growth. Cells from MyD88(-/-)IFNAR1(-/-) mice also showed impaired T. cruzi clearance. Furthermore, both MyD88(-/-)TRIF(-/-) and MyD88(-/-)IFNAR1(-/-) mice were highly susceptible to in vivo T. cruzi infection, highlighting the involvement of innate immune responses in T. cruzi infection. We further analyzed the molecular mechanisms for the IFN-beta-mediated antitrypanosomal innate immune responses. MyD88(-/-)TRIF(-/-) and MyD88(-/-)IFNAR1(-/-) macrophages and DCs exhibited defective induction of the GTPase IFN-inducible p47 (IRG47) after T. cruzi infection. RNA interference-mediated reduction of IRG47 expression in MyD88(-/-) macrophages resulted in increased intracellular growth of T. cruzi. These findings suggest that TLR-dependent expression of IFN-beta is involved in resistance to T. cruzi infection through the induction of IRG47.