Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

Hisaeda, Hajime; Tetsutani, Kohhei; Imai, Takashi; Moriya, Chikako; Tu, Liping; Hamano, Shinjiro; Duan, Xuefeng; Chou, Bin; Ishida, Hidekazu; Aramaki, Akiko; Shen, Jianying; Ishii, Ken J.; Coban, Cevayir; Akira, Shizuo; Takeda, Kiyoshi; Yasutomo, Koji; Torii, Motomi; Himeno, Kunisuke

doi:10.4049/jimmunol.180.4.2496

Cited by 87 publications

(83 citation statements)

References 57 publications

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“…TLR9 may also affect signaling to dendritic cells and thus affect activation of T regulatory cells (Tregs), as has been recently demonstrated in a murine model. 52 A recent study showed that individuals infected with malaria have upregulation of TLR-9 and increased IFN-γ, and that TLR-9 knockout mice have significantly reduced levels of IFN-γ in response to Plasmodium chabaudi infection as compared with wild-type mice, 53 supporting the importance of TLR-9 in IFN-γ production in malaria infection. Further studies are required to determine the specific effects of these SNP genotypes on TLR9 signaling.…”

Section: Discussionmentioning

confidence: 99%

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

Sam-Agudu

Greene

Opoka

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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Abstract. Toll-like receptor (TLR) polymorphisms have been associated with disease severity in malaria infection, but mechanisms for this association have not been characterized. The TLR2, 4, and 9 single nucleotide polymorphism (SNP) frequencies and serum interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) levels were assessed in Ugandan children with cerebral malaria (CM, N = 65) and uncomplicated malaria (UM, N = 52). The TLR9 C allele at −1237 and G allele at 1174 were strongly linked, and among children with CM, those with the C allele at −1237 or the G allele at 1174 had higher levels of IFN-γ than those without these alleles ( P = 0.03 and 0.008, respectively). The TLR9 SNPs were not associated with altered IFN-γ levels in children with UM or altered TNF-α levels in either group. We present the first human data that TLR SNPs are associated with altered cytokine production in parasitic infection.

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Section: Discussionmentioning

confidence: 99%

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

Sam-Agudu

Greene

Opoka

et al. 2010

The American Journal of Tropical Medicine and Hygiene

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“…Although we did not address how DCs recognize such cells, Toll-like receptor (TLR) signals appear to be important for induction of IL-23 [35,36]. It would be interesting to investigate whether the strain/species dependency of IL-23-mediated disease protection is attributable to quantitative and/or qualitative differences in TLR ligands, something we have previously suggested accounts for the difference in TLR9 ligands between an avirulent and virulent strain of P. yoelii [20].…”

Section: Discussionmentioning

confidence: 99%

“…Our previous findings that activation of Treg is required for immune evasion during malaria [19,20] suggest that Treg suppression might be an important factor for IL-23-mediated protection. However, this appears unlikely because we found that activation of Treg was similar in both p19KO and WT mice following infection with PbNK (as assessed by the proportion of CD25 + foxp3 + cells in CD4 + cells, and by the degree of suppression of T-cell proliferation after TCR signaling (Supporting Information Fig.…”

Section: Protective Roles For Il-23 During Infection With Pbnkmentioning

confidence: 99%

“…Our previous findings that activation of Treg is required for immune evasion during malaria [19,20] (as assessed by the proportion of CD25 + foxp3 + cells in CD4 + cells, and by the degree of suppression of T-cell proliferation after TCR signaling (Supporting Information Fig. 1)).…”

Section: Protective Roles For Il-23 During Infection With Pbnkmentioning

confidence: 99%

“…Although we did not address how DCs recognize such cells, Toll-like receptor (TLR) signals appear to be important for induction of 36]. It would be interesting to investigate whether the strain/species dependency of IL-23-mediated disease protection is attributable to quantitative and/or qualitative differences in TLR ligands, something we have previously suggested accounts for the difference in TLR9 ligands between an avirulent and virulent strain of P. yoelii [20].From a pathological perspective, it is quite possible that IL-23 causes pathogenesis in malaria for the following reasons. First, the related cytokine, IL-12, contributes more toward disease pathology, liver injury specifically, than disease protection in mice infected with PbNK [17,18].…”

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IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

et al. 2013

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Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. Keywords: IL-17 · IL-23 · Macrophage · Malaria · Plasmodium bergheiAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria, caused by protozoan parasites of the genus Plasmodium, is still one of the most life-threatening infectious diseases. Two hundred million people are infected annually with malaria paraCorrespondence: Dr. Hajime Hisaeda e-mail: hisa@med.gunma-u.ac.jp sites while about a million people are believed to die every year from the disease [1]. Despite the urgent need for effective vaccines against malaria, progress on vaccine development has been disappointing [2]. A major obstacle for vaccine development is that the immune responses crucial for eradication of malaria * These authors contributed equally to this work. parasites are not fully understood. Another concern is that infection with Plasmodium falciparum, which causes the most severe form of the disease in young children and pregnant women, can lead to pathological inflammation resulting in severe complications, such as cerebral malaria. Thus, to succeed in developing an effective vaccine against malaria, it is crucial that the mechanisms underlying protective immunity as well as those that drive pathogenic responses are better understood.IL-23 is a proinflammatory cytokine that belongs to IL-12 cytokine family. It is a heterodimeric molecule composed of p40 and p19 subunits [3]. The proinflammatory activities of IL-23 are responsible for the onset not only of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [4,5], but also infection-induced pathological consequences of infection with the pathogens causing Lyme disease and ...

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Introduction to Protozoan Infections

Guiliano¹,

Lamb²

2012

Immunity to Parasitic Infection

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Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells

Cited by 87 publications

References 57 publications

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

TLR9 Polymorphisms Are Associated with Altered IFN-γ Levels in Children with Cerebral Malaria

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

Introduction to Protozoan Infections

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