title: MyD88/IL-18-dependent pathways rather than TLRs control early parasitaemia in non-lethal Plasmodium yoelii infection.
abstract: Plasmodium falciparum GPI contributes to malaria pathology by inducing cytokine release. It has been shown to be recognized through TLR2 and to a lesser extent TLR4 in vitro. However, previous findings on the role of TLRs in parasite clearance or pathology in vivo are conflicting. Thus, we analyzed the impact of TLR-signalling on protection using the P. yoelii infection model. Deficiency of single TLRs as well as triple TLR2/4/9-deficiency had no impact on parasitaemia. In contrast, mice deficient for the adaptor protein MyD88 were more susceptible to P. yoelii infection in that they exhibited an increased parasitaemia in the early phase of the infection and a higher lethality. This phenotype was caused mainly by impaired IL-18 signalling since parasitaemia in IL-18-deficient mice was also increased at early time points during P. yoelii infection compared to wild-type control mice. However, no lethality was observed in IL-18-deficient mice. Since parasitaemia in IL-1R-deficient mice was also slightly increased during P. yoelii infection, impaired IL-1R signalling contributed to the increased susceptibility of MyD88-deficient mice to a lesser extent. These findings correlated with a reduced IFN-gamma production in MyD88- and IL-18-deficient mice, but not in TLR2/4/9-deficient mice. We conclude that mainly IL-18/MyD88-dependent signalling but not TLR2/4/9-signalling is important for early parasite control in our model.
authors.affiliation: University Medical Center Hamburg-Eppendorf, I. Department of Medicine, Section Tropical Medicine, Martinistrasse 52, 20246 Hamburg, Germany.
authors.forename: Jakob P
authors.initials: JP
authors.lastname: Cramer
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.forename: Faustin
authors.initials: F
authors.lastname: Kamena
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.forename: Marina A
authors.initials: MA
authors.lastname: Freudenberg
authors.forename: Gerd D
authors.initials: GD
authors.lastname: Burchard
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liu
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
authors.forename: Thomas
authors.initials: T
authors.lastname: Jacobs
mesh_terms: D000818:Animals; D005260:Female; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D018512:Parasitemia / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D010967:Plasmodium yoelii / Q000472:pathogenicity*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors