Caspase-1 Activation of Interleukin-1β (IL-1β) and IL-18 Is Dispensable for Induction of Experimental Cerebral Malaria

Kordes, Maximilian; Matuschewski, Kai; Hafalla, Julius Clemence R.

doi:10.1128/iai.05459-11

Cited by 60 publications

(67 citation statements)

References 51 publications

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“…3C). In agreement with published data (14), concentrations of IL-6, IL-10, IFN-␥, MCP-1, and TNF-␣ (Fig. 3D to H) were significantly increased during the course of infection in WT mice, and infected Card9 Ϫ/Ϫ mice had comparable levels of these cytokines.…”

Section: Resultssupporting

confidence: 80%

“…Consistent with previous findings (14), both sporozoiteinfected WT and Card9 Ϫ/Ϫ mice succumbed to infection with a mean survival of 7 days. These animals displayed neurological signs associated with ECM, such as ataxia, paralysis, convulsion, or coma (Fig.…”

Section: Resultssupporting

confidence: 80%

“…Early studies in this model have focused on the roles of the adaptor molecule myeloid differentiation factor 88 (MyD88), which signals downstream of most Toll-like receptors (TLRs) in ECM development. However, effects of MyD88 deficiency, or single or multiple deletions of TLRs, have yielded controversial results, ranging from full protection against ECM (5,10,14) to no protection at all (17,19). In addition, studies with the adaptor molecule Toll/interleukin 1 receptor (TIR) domain-containing adapter-inducing beta interferon (TRIF), which is downstream of TLR3 and TLR4, was found to be dispensable in ECM (5).…”

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confidence: 99%

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Experimental Cerebral Malaria Develops Independently of Caspase Recruitment Domain-Containing Protein 9 Signaling

et al. 2012

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The outcome of infection depends on multiple layers of immune regulation, with innate immunity playing a decisive role in shaping protection or pathogenic sequelae of acquired immunity. The contribution of pattern recognition receptors and adaptor molecules in immunity to malaria remains poorly understood. Here, we interrogate the role of the caspase recruitment domaincontaining protein 9 (CARD9) signaling pathway in the development of experimental cerebral malaria (ECM) using the murine Plasmodium berghei ANKA infection model. CARD9 expression was upregulated in the brains of infected wild-type (WT) mice, suggesting a potential role for this pathway in ECM pathogenesis. However, P. berghei ANKA-infected Card9 ؊/؊ mice succumbed to neurological signs and presented with disrupted blood-brain barriers similar to WT mice. Furthermore, consistent with the immunological features associated with ECM in WT mice, Card9 ؊/؊ mice revealed (i) elevated levels of proinflammatory responses, (ii) high frequencies of activated T cells, and (iii) CD8 ؉ T cell arrest in the cerebral microvasculature. We conclude that ECM develops independently of the CARD9 signaling pathway.

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Section: Resultssupporting

confidence: 80%

Section: Resultssupporting

confidence: 80%

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confidence: 99%

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Experimental Cerebral Malaria Develops Independently of Caspase Recruitment Domain-Containing Protein 9 Signaling

et al. 2012

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“…However, whether these TLRs shape the immune response during malaria infection in vivo is a matter of debate. For example, TLR2 deficiency was reported to confer protection from CM in at least two studies (19,36) but was found to have no effect in others (19,27,28). These ambiguous results suggest that more quantitative approaches may offer additional insights into the roles of individual TLRs in sensing infection.…”

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confidence: 97%

“…In addition, a MYD88-dependent but TLR9-independent pathway appears to contribute to immunopathology in the P. berghei ANKA model of CM. Although conflicting data exist (27), several studies agree that Myd88 Ϫ/Ϫ mice exhibit decreased production of proinflammatory cytokines and improved survival compared to wild-type mice during infection with P. berghei ANKA (19,28,35,36), whereas TLR9-deficient mice exhibit a milder defect in cytokine production than do Myd88 Ϫ/Ϫ mice (19,28) and may not be protected from CM to the same extent (discussed in reference 28, but see reference 19). Together, these data suggest that other MYD88-dependent innate sensors may cooperate with TLR9 in host recognition of Plasmodium infection.…”

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Toll-Like Receptor 7 Mediates Early Innate Immune Responses to Malaria

et al. 2013

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Innate immune recognition of malaria parasites is the critical first step in the development of the host response. At present, Tolllike receptor 9 (TLR9) is thought to play a central role in sensing malaria infection. However, we and others have observed that Tlr9 ؊/؊ mice, in contrast to mice deficient in the downstream adaptor, Myeloid differentiation primary response gene 88 (MYD88), exhibit few deficiencies in immune function during early infection with the malaria parasite Plasmodium chabaudi, implying that another MYD88-dependent receptor also contributes to the antimalarial response. Here we use candidate-based screening to identify TLR7 as a key sensor of early P. chabaudi infection. We show that TLR7 mediates a rapid systemic response to infection through induction of cytokines such as type I interferons (IFN-I), interleukin 12, and gamma interferon. TLR7 is also required for induction of IFN-I by other species and strains of Plasmodium, including an etiological agent of human disease, P. falciparum, suggesting that malaria parasites harbor a common pathogen-associated molecular pattern (PAMP) recognized by TLR7. In contrast to the nonredundant requirement for TLR7 in early immune activation, sensing through both TLR7 and TLR9 was required for proinflammatory cytokine production and immune cell activation during the peak of parasitemia. Our findings indicate that TLR7 plays a central role in early immune activation during malaria infection, whereas TLR7 and TLR9 contribute combinatorially to immune responses as infection progresses.

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Critical role of IL‐33 receptor ST2 in experimental cerebral malaria development

et al. 2015

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were not affected in the absence of functional ST2 pathway, the local expression of ICAM-1, CXCR3, and LT-α, crucial for ECM development, was strongly reduced, and this may explain the diminished pathogenic T-cell recruitment and resistance to ECM. Therefore, IL-33 is induced in PbA sporozoite infection, and the pathogenic T-cell responses with local microvascular pathology are dependent on IL-33/ST2 signaling, identifying IL-33 as a new actor in ECM development. Keywords:Experimental cerebral malaria r IL-33 r Plasmodium berghei ANKA r Sporozoite r ST2Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria is the most common parasitosis in the world, leading to around 650 000 deaths in 2012, especially African children [1]. Plasmodium falciparum is responsible for the major and oftenCorrespondence: Dr. Valérie F. J. Quesniaux e-mail: quesniaux@cnrs-orleans.fr fatal cerebral malaria complication [2]. The pathophysiology of cerebral malaria, which remains poorly understood, is associated with microvessel obstruction and excessive inflammation in the brain. Indeed, studies in humans and mice have shown that cerebral malaria correlates with the sequestration of RBCs, * These authors contributed equally to this work. The contribution of the innate response in ECM development has remained more elusive. Indeed, although MyD88-deficient mice show protection against ECM upon PbA sporozoite infection ([11] and our unpublished data), little contribution of the TLRs pathways was reported [12,13]. MyD88 adaptor is also used by receptors of the IL-1 family, but both IL-1β and IL-18 seem dispensable for induction of ECM [11]. MyD88 is further shared by more recently characterized members of the IL-1 family such as IL-33 and IL-36. We were interested in studying the implication of IL-33, a modulator of T H 2 responses, in ECM development since the T H 1/T H 2 balance has been shown to modulate ECM [10,14]. IL-33, essential in innate and epithelial immune response [15,16], activates T H 2 T-cell differentiation and release of T H 2 cytokines and chemokines. IL-33 is overexpressed in clinical or experimental visceral leishmaniasis and it suppresses T H 1 responses in mice infected with Leishmania donovani [17]. IL-33 levels are increased in the plasma of infants with severe malaria, as compared with infection-free controls [18]. In addition, IL-33 has been associated with some cerebral diseases. IL-33 is implicated in Toxoplasma gondii induced encephalitis in mice, and was shown to attenuate EAE by suppressing IL-17 and IFN-γ production [19,20]. IL-33 is expressed within CNS by brain endothelial cells and astrocytes, LPS upregulating IL-33 expression by astrocytes [21]. In view of IL-33 implication in CNS pathologies and its role in modulating the T H 2/T H 1 balance, we investigated the role of IL-33 pathway in ECM development.Here, ECM development in response to PbA infection was investigated in mice deficient for IL-33 receptor, ST2. We show that br...

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Caspase-1 Activation of Interleukin-1β (IL-1β) and IL-18 Is Dispensable for Induction of Experimental Cerebral Malaria

Cited by 60 publications

References 51 publications

Experimental Cerebral Malaria Develops Independently of Caspase Recruitment Domain-Containing Protein 9 Signaling

Experimental Cerebral Malaria Develops Independently of Caspase Recruitment Domain-Containing Protein 9 Signaling

Toll-Like Receptor 7 Mediates Early Innate Immune Responses to Malaria

Critical role of IL‐33 receptor ST2 in experimental cerebral malaria development

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