scholarly journals The Glycosylphosphatidylinositol Transamidase Complex Subunit PbGPI16 of Plasmodium berghei Is Important for Inducing Experimental Cerebral Malaria

2018 ◽  
Vol 86 (8) ◽  
Author(s):  
Qingyang Liu ◽  
Yan Zhao ◽  
Li Zheng ◽  
Xiaotong Zhu ◽  
Liwang Cui ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Surface Display ◽  
Surface Proteins ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
T Complex ◽  
Proinflammatory Responses ◽  
Major Factors ◽  
Gpi Transamidase

ABSTRACT In animal models of experimental cerebral malaria (ECM), the glycosylphosphatidylinositols (GPIs) and GPI anchors are the major factors that induce nuclear factor kappa B (NF-κB) activation and proinflammatory responses, which contribute to malaria pathogenesis. GPIs and GPI anchors are transported to the cell surface via a process called GPI transamidation, which involves the GPI transamidase (GPI-T) complex. In this study, we showed that GPI16, one of the GPI-T subunits, is highly conserved among Plasmodium species. Genetic knockout of pbgpi16 (Δpbgpi16) in the rodent malaria parasite Plasmodium berghei strain ANKA led to a significant reduction of the amounts of GPIs in the membranes of merozoites, as well as surface display of several GPI-anchored merozoite surface proteins. Compared with the wild-type parasites, Δpbgpi16 parasites in C57BL/6 mice caused much less NF-κB activation and elicited a substantially attenuated T helper type 1 response. As a result, Δpbgpi16 mutant-infected mice displayed much less severe brain pathology, and considerably fewer Δpbgpi16 mutant-infected mice died from ECM. This study corroborated the GPI toxin as a significant inducer of ECM and further suggested that vaccines against parasite GPIs may be a promising strategy to limit the severity of malaria.

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

2014 ◽  
Vol 83 (2) ◽  
pp. 759-768 ◽  
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.

scholarly journals Efficacy of Proveblue (Methylene Blue) in an Experimental Cerebral Malaria Murine Model

2013 ◽  
Vol 57 (7) ◽  
pp. 3412-3414 ◽  
Author(s):  
Jérome Dormoi ◽  
Sébastien Briolant ◽  
Camille Desgrouas ◽  
Bruno Pradines
Keyword(s):  
Methylene Blue ◽  
Cerebral Malaria ◽  
Murine Model ◽  
Plasmodium Berghei ◽  
Active Metabolite ◽  
Line Treatment ◽  
First Line ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
First Line Treatment

ABSTRACTAlthough 100% of untreated mice infected withPlasmodium bergheidied with specific signs of cerebral malaria and 100% of mice treated with 3 mg/kg dihydroartemisinin, the active metabolite of artesunate, which is used as the first-line treatment for severe malaria, also died but showed no specific signs of cerebral malaria, 78% of mice treated with 10 mg/kg Proveblue (methylene blue) and 78% of mice treated with a combination of 3 mg dihydroartemisinin and 10 mg/kg Proveblue survived and showed no specific signs of cerebral malaria or detectable parasites.

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

2011 ◽  
Vol 80 (3) ◽  
pp. 1274-1279 ◽  
Author(s):  
Julius Clemence R. Hafalla ◽  
Jan Burgold ◽  
Anca Dorhoi ◽  
Olaf Gross ◽  
Jürgen Ruland ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Signaling Pathway ◽  
Decisive Role ◽  
Infection Model ◽  
Activated T Cells ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Caspase Recruitment Domain ◽  
Proinflammatory Responses ◽  
Cell Arrest

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 domain-containing protein 9 (CARD9) signaling pathway in the development of experimental cerebral malaria (ECM) using the murinePlasmodium bergheiANKA infection model.CARD9expression was upregulated in the brains of infected wild-type (WT) mice, suggesting a potential role for this pathway in ECM pathogenesis. However,P. bergheiANKA-infectedCard9−/−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.

scholarly journals Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice

2015 ◽  
Vol 84 (2) ◽  
pp. 502-510 ◽  
Author(s):  
Jannike Blank ◽  
Jochen Behrends ◽  
Thomas Jacobs ◽  
Bianca E. Schneider
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Parasite Clearance ◽  
Human Infection ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Cell Responses ◽  
The Tropics

Cerebral malaria (CM) is the most severe complication of human infection withPlasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM isPlasmodium bergheiANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome ofPbANKA infection in mice previously infected withMycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodentPlasmodiumparasites in experimental coinfection models. We found that concomitantM. tuberculosisinfection did not change the clinical course ofPbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected withPbANKA. Our data suggest thatM. tuberculosiscoinfection is not able to change the outcome ofPbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected withM. tuberculosis.

scholarly journals Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

2015 ◽  
Vol 83 (7) ◽  
pp. 2771-2784 ◽  
Author(s):  
Sylvie Briquet ◽  
Nadou Lawson-Hogban ◽  
Bertrand Boisson ◽  
Miguel P. Soares ◽  
Roger Péronet ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Inflammatory Diseases ◽  
High Mobility ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Extracellular Milieu ◽  
Nuclear Factors ◽  
Immune Mediated ◽  
The Brain

Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that thePlasmodiumgenome encodes two genuine HMGB factors,PlasmodiumHMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized thatPlasmodiumHMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected withPlasmodium bergheiANKA and that in many aspects resembles human cerebral malaria elicited byP. falciparuminfection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected withP. bergheiANKA lacking thehmgb2gene (Δhmgb2ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM inpbhmgb2-deficient mice was restored by the administration of recombinantPbHMGB2. Protection from experimental cerebral malaria in Δhmgb2ANKA-infected mice was associated with reduced sequestration in the brain of CD4+and CD8+T cells, including CD8+granzyme B+and CD8+IFN-γ+cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-typeP. bergheiANKA-infected mice. In summary,PlasmodiumHMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.

scholarly journals Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

2014 ◽  
Vol 82 (3) ◽  
pp. 1343-1353 ◽  
Author(s):  
Erik W. Settles ◽  
Lindsey A. Moser ◽  
Tajie H. Harris ◽  
Laura J. Knoll
Keyword(s):  
Toxoplasma Gondii ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Serum Levels ◽  
Interleukin 12 ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
T Cell Infiltration ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTA chronic infection with the parasiteToxoplasma gondiihas previously been shown to protect mice against subsequent viral, bacterial, or protozoal infections. Here we have shown that a chronicT. gondiiinfection can preventPlasmodium bergheiANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. Treatment with solubleT. gondiiantigens (STAg) reduced parasite sequestration and T cell infiltration in the brains ofP. berghei-infected mice. Administration of STAg also preserved blood-brain barrier function, reduced ECM symptoms, and significantly decreased mortality. STAg treatment 24 h post-P. bergheiinfection led to a rapid increase in serum levels of interleukin 12 (IL-12) and gamma interferon (IFN-γ). By 5 days afterP. bergheiinfection, STAg-treated mice had reduced IFN-γ levels compared to those of mock-treated mice, suggesting that reductions in IFN-γ at the time of ECM onset protected against lethality. Using IL-10- and IL-12βR-deficient mice, we found that STAg-induced protection from ECM is IL-10 independent but IL-12 dependent. Treatment ofP. berghei-infected mice with recombinant IL-12 significantly decreased parasitemia and mortality. These data suggest that IL-12, either induced by STAg or injected as a recombinant protein, mediates protection from ECM-associated pathology potentially through early induction of IFN-γ and reduction in parasitemia. These results highlight the importance of early IL-12 induction in protection against ECM.

Establishment of a murine model of cerebral malaria in KunMing mice infected with Plasmodium berghei ANKA

Parasitology ◽  
2016 ◽  
Vol 143 (12) ◽  
pp. 1672-1680 ◽  
Author(s):  
YAN DING ◽  
WENYUE XU ◽  
TAOLI ZHOU ◽  
TAIPING LIU ◽  
HONG ZHENG ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Blood Cells ◽  
Mononuclear Cells ◽  
Clinical Signs ◽  
Necrosis Factor Alpha ◽  
Experimental Cerebral Malaria ◽  
Km Mice

SUMMARYMalaria remains one of the most devastating diseases. Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection resulting in high mortality and morbidity worldwide. Analysis of precise mechanisms of CM in humans is difficult for ethical reasons and animal models of CM have been employed to study malaria pathogenesis. Here, we describe a new experimental cerebral malaria (ECM) model with Plasmodium berghei ANKA infection in KunMing (KM) mice. KM mice developed ECM after blood-stage or sporozoites infection, and the development of ECM in KM mice has a dose-dependent relationship with sporozoites inoculums. Histopathological findings revealed important features associated with ECM, including accumulation of mononuclear cells and red blood cells in brain microvascular, and brain parenchymal haemorrhages. Blood–brain barrier (BBB) examination showed that BBB disruption was present in infected KM mice when displaying clinical signs of CM. In vivo bioluminescent imaging experiment indicated that parasitized red blood cells accumulated in most vital organs including heart, lung, spleen, kidney, liver and brain. The levels of inflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, interleukin (IL)-17, IL-12, IL-6 and IL-10 were all remarkably increased in KM mice infected with P. berghei ANKA. This study indicates that P. berghei ANKA infection in KM mice can be used as ECM model to extend further research on genetic, pharmacological and vaccine studies of CM.

Cloned Lines of Plasmodium berghei ANKA Differ in Their Abilities To Induce Experimental Cerebral Malaria

1998 ◽  
Vol 66 (9) ◽  
pp. 4093-4099 ◽  
Author(s):  
Véronique Amani ◽  
Mariama Idrissa Boubou ◽  
Sylviane Pied ◽  
Myriam Marussig ◽  
David Walliker ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Plasmodium Berghei Anka ◽  
Experimental Cerebral Malaria

scholarly journals T-lymphocytes response persists following Plasmodium berghei strain Anka infection resolution and may contribute to later experimental cerebral malaria outcomes

2019 ◽  
Vol 330 ◽  
pp. 5-11 ◽  
Author(s):  
Aline Silva de Miranda ◽  
Rodrigo Novaes Ferreira ◽  
Érica Leandro Marciano Vieira ◽  
Larissa Katharina Sabino Abreu ◽  
Fátima Brant ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Experimental Cerebral Malaria

scholarly journals High Parasite Burdens Cause Liver Damage in Mice following Plasmodium berghei ANKA Infection Independently of CD8+T Cell-Mediated Immune Pathology

2011 ◽  
Vol 79 (5) ◽  
pp. 1882-1888 ◽  
Author(s):  
Ashraful Haque ◽  
Shannon E. Best ◽  
Fiona H. Amante ◽  
Anne Ammerdorffer ◽  
Fabian de Labastida ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Damage ◽  
Plasmodium Berghei ◽  
Clinical Symptoms ◽  
Neurological Symptoms ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Immune Pathology ◽  
The Brain

ABSTRACTInfection of C57BL/6 mice withPlasmodium bergheiANKA induces a fatal neurological disease commonly referred to as experimental cerebral malaria. The onset of neurological symptoms and mortality depend on pathogenic CD8+T cells and elevated parasite burdens in the brain. Here we provide clear evidence of liver damage in this model, which precedes and is independent of the onset of neurological symptoms. Large numbers of parasite-specific CD8+T cells accumulated in the liver followingP. bergheiANKA infection. However, systemic depletion of these cells at various times during infection, while preventing neurological symptoms, failed to protect against liver damage or ameliorate it once established. In contrast, rapid, drug-mediated removal of parasites prevented hepatic injury if administered early and quickly resolved liver damage if administered after the onset of clinical symptoms. These data indicate that CD8+T cell-mediated immune pathology occurs in the brain but not the liver, while parasite-dependent pathology occurs in both organs duringP. bergheiANKA infection. Therefore, we show thatP. bergheiANKA infection of C57BL/6 mice is a multiorgan disease driven by the accumulation of parasites, which is also characterized by organ-specific CD8+T cell-mediated pathology.

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