Perillyl alcohol exhibits in vitro inhibitory activity against Plasmodium falciparum and protects against experimental cerebral malaria

Cerebral malaria (CM) is a severe immunovasculopathy which presents high mortality rate (15–20%), despite the availability of artemisinin-based therapy. More effective immunomodulatory and/or antiparasitic therapies are urgently needed. Experimental Cerebral Malaria (ECM) in mice is used to elucidate aspects involved in this pathology since manifests many of the neurological features of CM. In the present study, we evaluated the potential mechanisms involved in the protection afforded by perillyl alcohol (POH) in mouse strains susceptible to CM caused by Plasmodium berghei ANKA (PbA) infection through intranasal preventive treatment. Additionally, to evaluate the interaction of POH with the cerebral endothelium using an in vitro model of human brain endothelial cells (HBEC). Pharmacokinetic approaches demonstrated constant and prolonged levels of POH in the plasma and brain after a single intranasal dose. Treatment with POH effectively prevented vascular dysfunction. Furthermore, treatment with POH reduced the endothelial cell permeability and PbA s in the brain and spleen. Finally, POH treatment decreased the accumulation of macrophages and T and B cells in the spleen and downregulated the expression of endothelial adhesion molecules (ICAM-1, VCAM-1, and CD36) in the brain. POH is a potent monoterpene that prevents cerebrovascular dysfunction in vivo and in vitro, decreases parasite sequestration, and modulates different processes related to the activation, permeability, and integrity of the blood brain barrier (BBB), thereby preventing cerebral oedema and inflammatory infiltrates.

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THEMIS Is Required for Pathogenesis of Cerebral Malaria and Protection against Pulmonary Tuberculosis

Infection and Immunity ◽

10.1128/iai.02586-14 ◽

2014 ◽

Vol 83 (2) ◽

pp. 759-768 ◽

Cited By ~ 9

Author(s):

Sabrina Torre ◽

Sebastien P. Faucher ◽

Nassima Fodil ◽

Silayuv E. Bongfen ◽

Joanne Berghout ◽

...

Keyword(s):

Pulmonary Tuberculosis ◽

Cerebral Malaria ◽

Functional Coupling ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Proinflammatory Responses ◽

Inflammatory Bowel ◽

Blood Brain Barrier Integrity

We identify anN-ethyl-N-nitrosourea (ENU)-induced I23N mutation in the THEMIS protein that causes protection against experimental cerebral malaria (ECM) caused by infection withPlasmodium bergheiANKA.ThemisI23Nhomozygous mice show reduced CD4+and CD8+T lymphocyte numbers. ECM resistance inP. bergheiANKA-infectedThemisI23Nmice is associated with decreased cerebral cellular infiltration, retention of blood-brain barrier integrity, and reduced proinflammatory cytokine production. THEMISI23Nprotein expression is absent from mutant mice, concurrent with the decreased THEMISI23Nstability observedin vitro. Biochemical studiesin vitroand functional complementationin vivoinThemisI23N/+:Lck−/+doubly heterozygous mice demonstrate that functional coupling of THEMIS to LCK tyrosine kinase is required for ECM pathogenesis. Damping of proinflammatory responses inThemisI23Nmice causes susceptibility to pulmonary tuberculosis. Thus, THEMIS is required for the development and ultimately the function of proinflammatory T cells.ThemisI23Nmice can be used to study the newly discovered association ofTHEMIS(6p22.33) with inflammatory bowel disease and multiple sclerosis.

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Plasmodium falciparum Line-Dependent Association ofIn VitroGrowth-Inhibitory Activity and Risk of Malaria

Infection and Immunity ◽

10.1128/iai.06190-11 ◽

2012 ◽

Vol 80 (5) ◽

pp. 1900-1908 ◽

Cited By ~ 11

Author(s):

Josea Rono ◽

Anna Färnert ◽

Daniel Olsson ◽

Faith Osier ◽

Ingegerd Rooth ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Inhibitory Activity ◽

Content Type ◽

Phenotypic Differences ◽

Erythrocyte Invasion ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Control Study

ABSTRACTPlasmodium falciparum's ability to invade erythrocytes is essential for its survival within the human host. Immune mechanisms that impair this ability are therefore expected to contribute to immunity against the parasite. Plasma of humans who are naturally exposed to malaria has been shown to have growth-inhibitory activity (GIA)in vitro. However, the importance of GIA in relation to protection from malaria has been unclear. In a case-control study nested within a longitudinally followed population in Tanzania, plasma samples collected at baseline from 171 individuals (55 cases and 116 age-matched controls) were assayed for GIA using threeP. falciparumlines (3D7, K1, and W2mef) chosen based on their erythrocyte invasion phenotypes. Distribution of GIA differed between the lines, with most samples inhibiting the growth of 3D7 and K1 and enhancing the growth of W2mef. GIA to 3D7 was associated with a reduced risk of malaria within 40 weeks of follow-up (odds ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.96;P= 0.04), whereas GIA to K1 and W2mef was not. These results show that GIA, as well as its association with protection from malaria, is dependent on theP. falciparumline and can be explained by differences in erythrocyte invasion phenotypes between parasite lines. Our study contributes knowledge on the biological importance of growth inhibition and the potential influence ofP. falciparumerythrocyte invasion phenotypic differences on its relationship to protective immunity against malaria.

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Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments

Infection and Immunity ◽

10.1128/iai.01035-16 ◽

2017 ◽

Vol 85 (11) ◽

Cited By ~ 5

Author(s):

Ana Villegas-Mendez ◽

Patrick Strangward ◽

Tovah N. Shaw ◽

Ivana Rajkovic ◽

Vinko Tosevski ◽

...

Keyword(s):

Endothelial Cells ◽

Cerebral Malaria ◽

Myeloid Cell ◽

Gamma Interferon ◽

Cell Populations ◽

Experimental Cerebral Malaria ◽

Cerebral Pathology ◽

Multiple Cell ◽

Ifn Γ

ABSTRACT Experimental cerebral malaria (ECM) is a gamma interferon (IFN-γ)-dependent syndrome. However, whether IFN-γ promotes ECM through direct and synergistic targeting of multiple cell populations or by acting primarily on a specific responsive cell type is currently unknown. Here, using a panel of cell- and compartment-specific IFN-γ receptor 2 (IFN-γR2)-deficient mice, we show that IFN-γ causes ECM by signaling within both the hematopoietic and nonhematopoietic compartments. Mechanistically, hematopoietic and nonhematopoietic compartment-specific IFN-γR signaling exerts additive effects in orchestrating intracerebral inflammation, leading to the development of ECM. Surprisingly, mice with specific deletion of IFN-γR2 expression on myeloid cells, T cells, or neurons were completely susceptible to terminal ECM. Utilizing a reductionist in vitro system, we show that synergistic IFN-γ and tumor necrosis factor (TNF) stimulation promotes strong activation of brain blood vessel endothelial cells. Combined, our data show that within the hematopoietic compartment, IFN-γ causes ECM by acting redundantly or by targeting non-T cell or non-myeloid cell populations. Within the nonhematopoietic compartment, brain endothelial cells, but not neurons, may be the major target of IFN-γ leading to ECM development. Collectively, our data provide information on how IFN-γ mediates the development of cerebral pathology during malaria infection.

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Artemisinin-independent inhibitory activity of Artemisia sp. infusions against different Plasmodium stages including relapse-causing hypnozoites

Life Science Alliance ◽

10.26508/lsa.202101237 ◽

2021 ◽

Vol 5 (3) ◽

pp. e202101237

Author(s):

Kutub Ashraf ◽

Shahin Tajeri ◽

Christophe-Sébastien Arnold ◽

Nadia Amanzougaghene ◽

Jean-François Franetich ◽

...

Keyword(s):

Drug Resistance ◽

Plasmodium Falciparum ◽

Inhibitory Activity ◽

Parasite Species ◽

Artemisia Annua ◽

Combination Therapies ◽

Lead Compounds ◽

Low Concentrations ◽

Inhibitory Activities

Artemisinin-based combination therapies (ACT) are the frontline treatments against malaria worldwide. Recently the use of traditional infusions from Artemisia annua (from which artemisinin is obtained) or Artemisia afra (lacking artemisinin) has been controversially advocated. Such unregulated plant-based remedies are strongly discouraged as they might constitute sub-optimal therapies and promote drug resistance. Here, we conducted the first comparative study of the anti-malarial effects of both plant infusions in vitro against the asexual erythrocytic stages of Plasmodium falciparum and the pre-erythrocytic (i.e., liver) stages of various Plasmodium species. Low concentrations of either infusion accounted for significant inhibitory activities across every parasite species and stage studied. We show that these antiplasmodial effects were essentially artemisinin-independent and were additionally monitored by observations of the parasite apicoplast and mitochondrion. In particular, the infusions significantly incapacitated sporozoites, and for Plasmodium vivax and P. cynomolgi, disrupted the hypnozoites. This provides the first indication that compounds other than 8-aminoquinolines could be effective antimalarials against relapsing parasites. These observations advocate for further screening to uncover urgently needed novel antimalarial lead compounds.

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Light microscopic detection of Plasmodium falciparum in vitro through Pf histidine rich protein 2 (HRP 2) gold conjugate labeling: Rapid diagnosis of cerebral malaria in humans

AFRICAN JOURNAL OF BIOTECHNOLOGY ◽

10.5897/ajb10.723 ◽

2014 ◽

Vol 13 (8) ◽

pp. 978-982

Author(s):

Olalekan Michael Ogundele ◽

Sabiu Saheed ◽

Adeshina Oloruntoba Adekeye ◽

Philip Adeyemi Adeniyi ◽

Oluwatosin Olalekan Ogedengbe ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Cerebral Malaria ◽

Rapid Diagnosis ◽

Microscopic Detection ◽

Gold Conjugate

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CD47 blockade reduces the pathologic features of experimental cerebral malaria and promotes survival of hosts with Plasmodium infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1907653118 ◽

2021 ◽

Vol 118 (11) ◽

pp. e1907653118

Author(s):

Laughing Bear Torrez Dulgeroff ◽

Miranda S. Oakley ◽

Michal C. Tal ◽

Ying Ying Yiu ◽

Joy Q. He ◽

...

Keyword(s):

Cerebral Malaria ◽

Therapeutic Benefit ◽

Plasmodium Yoelii ◽

Experimental Cerebral Malaria ◽

Clinical Syndromes ◽

Pathologic Features ◽

Tnf Α ◽

Infected Rbcs ◽

Circulating Levels

CD47 is an antiphagocytic “don’t eat me” signal that inhibits programmed cell removal of self. As red blood cells (RBCs) age they lose CD47 expression and become susceptible to programmed cell removal by macrophages. CD47−/− mice infected with Plasmodium yoelii, which exhibits an age-based preference for young RBCs, were previously demonstrated to be highly resistant to malaria infection. Our study sought to test the therapeutic benefit of CD47 blockade on ameliorating the clinical syndromes of experimental cerebral malaria (ECM), using the Plasmodium berghei ANKA (Pb-A) murine model. In vitro we tested the effect of anti-CD47 mAb on Plasmodium-infected RBC phagocytosis and found that anti-CD47 treatment significantly increased clearance of Plasmodium-infected RBCs. Infection of C57BL/6 mice with Pb-A is lethal and mice succumb to the clinical syndromes of CM between days 6 and 10 postinfection. Strikingly, treatment with anti-CD47 resulted in increased survival during the cerebral phase of Pb-A infection. Anti-CD47–treated mice had increased lymphocyte counts in the peripheral blood and increased circulating levels of IFN-γ, TNF-α, and IL-22. Despite increased circulating levels of inflammatory cytokines, anti-CD47–treated mice had reduced pathological features in the brain. Survival of ECM in anti-CD47–treated mice was correlated with reduced cellular accumulation in the cerebral vasculature, improved blood–brain barrier integrity, and reduced cytotoxic activity of infiltrating CD8+ T cells. These results demonstrate the therapeutic benefit of anti-CD47 to reduce morbidity in a lethal model of ECM, which may have implications for preventing mortality in young African children who are the highest casualties of CM.

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Terminalia albida treatment improves survival in experimental cerebral malaria through reactive oxygen species scavenging and anti-inflammatory properties

Malaria Journal ◽

10.1186/s12936-019-3071-9 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 5

Author(s):

Aissata Camara ◽

Mohamed Haddad ◽

Karine Reybier ◽

Mohamed Sahar Traoré ◽

Mamadou Aliou Baldé ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cerebral Malaria ◽

Post Infection ◽

Inflammatory Markers ◽

Antiplasmodial Activity ◽

Oxygen Species ◽

Experimental Cerebral Malaria ◽

Anti Inflammatory

Abstract Background The development of Plasmodium resistance to the last effective anti-malarial drugs necessitates the urgent development of new anti-malarial therapeutic strategies. To this end, plants are an important source of new molecules. The objective of this study was to evaluate the anti-malarial effects of Terminalia albida, a plant used in Guinean traditional medicine, as well as its anti-inflammatory and antioxidant properties, which may be useful in treating cases of severe malaria. Methods In vitro antiplasmodial activity was evaluated on a chloroquine-resistant strain of Plasmodium falciparum (K-1). In vivo efficacy of the plant extract was measured in the experimental cerebral malaria model based on Plasmodium berghei (strain ANKA) infection. Mice brains were harvested on Day 7–8 post-infection, and T cells recruitment to the brain, expression levels of pro- and anti-inflammatory markers were measured by flow cytometry, RT-qPCR and ELISA. Non-malarial in vitro models of inflammation and oxidative response were used to confirm Terminalia albida effects. Constituents of Terminalia albida extract were characterized by ultra‐high performance liquid chromatography coupled with high resolution mass spectrometry. Top ranked compounds were putatively identified using plant databases and in silico fragmentation patterns. Results In vitro antiplasmodial activity of Terminalia albida was confirmed with an IC50 of 1.5 μg/mL. In vivo, Terminalia albida treatment greatly increased survival rates in P. berghei-infected mice. Treated mice were all alive until Day 12, and the survival rate was 50% on Day 20. Terminalia albida treatment also significantly decreased parasitaemia by 100% on Day 4 and 89% on Day 7 post-infection. In vivo anti-malarial activity was related to anti-inflammatory properties, as Terminalia albida treatment decreased T lymphocyte recruitment and expression of pro-inflammatory markers in brains of treated mice. These properties were confirmed in vitro in the non-malarial model. In vitro, Terminalia albida also demonstrated a remarkable dose-dependent neutralization activity of reactive oxygen species. Twelve compounds were putatively identified in Terminalia albida stem bark. Among them, several molecules already identified may be responsible for the different biological activities observed, especially tannins and triterpenoids. Conclusion The traditional use of Terminalia albida in the treatment of malaria was validated through the combination of in vitro and in vivo studies.

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In vitro antimalarial activity and molecular modeling studies of novel artemisinin derivatives

RSC Advances ◽

10.1039/c5ra07697h ◽

2015 ◽

Vol 5 (59) ◽

pp. 47959-47974 ◽

Cited By ~ 10

Author(s):

Rashmi Gaur ◽

Harveer Singh Cheema ◽

Yogesh Kumar ◽

Suriya Pratap Singh ◽

Dharmendra K. Yadav ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Molecular Modeling ◽

Cerebral Malaria ◽

Antimalarial Activity ◽

Anopheles Mosquito ◽

Fatal Disease ◽

Artemisinin Derivatives ◽

Modeling Studies ◽

Molecular Modeling Studies

Cerebral malaria is a serious and sometimes fatal disease caused by aPlasmodium falciparumparasite that infects a female anopheles mosquito which feeds on humans.

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Plasmodium falciparum-infected erythrocyte receptor(s) for CD36 and thrombospondin are restricted to knobs on the erythrocyte surface.

Journal of Histochemistry & Cytochemistry ◽

10.1177/40.9.1380530 ◽

1992 ◽

Vol 40 (9) ◽

pp. 1419-1422 ◽

Cited By ~ 22

Author(s):

K Nakamura ◽

T Hasler ◽

K Morehead ◽

R J Howard ◽

M Aikawa

Keyword(s):

Endothelial Cells ◽

Plasmodium Falciparum ◽

Cerebral Malaria ◽

Vascular Occlusion ◽

Cerebral Microvessels ◽

Erythrocyte Surface ◽

Infected Rbcs ◽

First Time

Adherence of Plasmodium falciparum-infected RBCs (PRBC) to endothelial cells causes PRBC sequestration in cerebral microvessels and is considered to be a major contributor to the pathogenesis of cerebral malaria. Both CD36 and thrombospondin (TSP) are glycoproteins that mediate PRBC adherence to endothelial cells in vitro. Because they are both expressed on the surface of endothelial cells, they probably contribute to PRBC sequestration and vascular occlusion in vivo. By applying affinity labeling of receptor binding sites with purified ligands, we showed for the first time that both CD36 and TSP can bind independently to the PRBC surface and that the PRBC receptor(s) for CD36 and TSP are localized specifically to the electron-dense knob protrusions of the PRBC surface. These findings may help in efforts to develop a malaria vaccine to prevent cerebral malaria.

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