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MyD88/IL-18-dependent pathways rather than TLRs control early parasitaemia in non-lethal Plasmodium yoelii infection
Jakob P Cramer1, Bernd Lepenies, Faustin Kamena
1University Medical Center Hamburg-Eppendorf, I. Department of Medicine, Section Tropical Medicine, Martinistrasse 52, 20246 Hamburg, Germany.
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.
Insights
Toll-like receptor (TLR) signaling, particularly through MyD88 and IL-18, is crucial for controlling early Plasmodium yoelii infection and reducing malaria pathology. TLR2, TLR4, and TLR9 signaling do not significantly impact parasite control in this model.
Area of Science:
- Immunology
- Infectious Diseases
- Parasitology
Background:
- Plasmodium falciparum glycosylphosphatidylinositol (GPI) induces malaria pathology via cytokine release.
- In vitro studies suggest Toll-like receptor 2 (TLR2) and TLR4 recognize GPI, but in vivo roles remain unclear.
- Conflicting findings necessitate further investigation into TLR signaling's impact on malaria parasite clearance and pathology.
Purpose of the Study:
- To investigate the in vivo role of Toll-like receptor (TLR) signaling in malaria parasite control and pathology using the Plasmodium yoelii infection model.
- To determine the specific contribution of TLR2, TLR4, TLR9, and the adaptor protein MyD88 to host defense against P. yoelii.
- To elucidate the involvement of IL-18 and IL-1 receptor (IL-1R) signaling pathways in P. yoelii infection.
Main Methods:
- Analysis of Plasmodium yoelii infection in mice deficient for single TLRs (TLR2, TLR4, TLR9) and a triple TLR2/4/9-deficient mutant.
- Assessment of parasitemia and lethality in MyD88-deficient mice infected with P. yoelii.
- Evaluation of parasitemia and lethality in IL-18-deficient and IL-1R-deficient mice.
- Measurement of Interferon-gamma (IFN-gamma) production in deficient mouse models.
Main Results:
- Mice deficient in single TLRs or triple TLR2/4/9 showed no significant difference in parasitemia.
- MyD88-deficient mice exhibited increased early parasitemia and higher lethality during P. yoelii infection.
- IL-18-deficient mice displayed increased early parasitemia but no increased lethality, indicating a primary role for IL-18 signaling.
- Impaired IL-1R signaling contributed partially to the susceptibility of MyD88-deficient mice.
- Reduced IFN-gamma production was observed in MyD88- and IL-18-deficient mice, but not in TLR2/4/9-deficient mice.
Conclusions:
- MyD88-dependent signaling, primarily through IL-18, is critical for early parasite control and host defense in P. yoelii infection.
- TLR2, TLR4, and TLR9 signaling pathways are not essential for controlling P. yoelii parasitemia in this model.
- IL-18 plays a significant role in regulating early parasite burden and is a key mediator in the MyD88-dependent protective response against malaria.
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