Dataset Information

Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.

ABSTRACT: Cerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1? production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1? release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33-NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.

SUBMITTER: Strangward P

PROVIDER: S-EPMC6048513 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.

Strangward Patrick P Haley Michael J MJ Albornoz Manuel G MG Barrington Jack J Shaw Tovah T Dookie Rebecca R Zeef Leo L Baker Syed M SM Winter Emma E Tzeng Te-Chen TC Golenbock Douglas T DT Cruickshank Sheena M SM Allan Stuart M SM Craig Alister A Liew Foo Y FY Brough David D Couper Kevin N KN

Proceedings of the National Academy of Sciences of the United States of America 20180628 28

Cerebral malaria (CM) is a serious neurological complication caused by <i>Plasmodium falciparum</i> infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics ana ...[more]

PMID: 29954866

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Project description:BackgroundHuman cerebral malaria (HCM) is a life-threatening complication caused by Plasmodium falciparum infection that continues to be a major global health problem despite optimal anti-malarial treatment. In the experimental model of cerebral malaria (ECM) by Plasmodium berghei ANKA, bolus administration of nimodipine at high doses together with artemether, increases survival of mice with ECM. However, the dose and administration route used is associated with cardiovascular side effects such as hypotension and bradycardia in humans and mice, which could preclude its potential use as adjunctive treatment in HCM.MethodsIn the present study, alternative delivery systems for nimodipine during late-stage ECM in association with artesunate were searched to define optimal protocols to achieve maximum efficacy in increasing survival in rescue therapy while causing the least cardiac side effects. The baseline electrocardiogram (ECG) and arterial pressure characteristics of uninfected control animals and of mice with ECM and its response upon rescue treatment with artesunate associated or not with nimodipine is also analysed.ResultsNimodipine, given at 0.5 mg/kg/day via a slow and continuous delivery system by osmotic pumps, increases survival of mice with ECM when used as adjunctive treatment to artesunate. Mice with ECM showed hypotension and ECG changes, including bradycardia and increases in PR, QRS, QTc and ST interval duration. ECM mice also show increased QTc dispersion, heart rate variability (HRV), RMSSD, low frequency (LF) and high frequency (HF) bands of the power spectrum. Both sympathetic and parasympathetic inputs to the heart were increased, but there was a predominance of sympathetic tone as demonstrated by an increased LF/HF ratio. Nimodipine potentiated bradycardia when given by bolus injection, but not when via osmotic pumps. In addition, nimodipine shortened PR duration and improved HRV, RMSSD, LF and HF powers in mice with ECM. In addition, nimodipine did not increased hypotension or decreased the speed of arterial pressure recovery when used in rescue therapy with artesunate.ConclusionsThese data show that slow and continuous delivery of lower doses of nimodipine improves survival of mice with ECM in rescue therapy with artesunate while showing a safer profile in terms of cardiovascular effects.

Dataset Information

Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.

Publications

Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria.

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