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 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 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 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 Suppression of CD4+Effector Responses by Naturally Occurring CD4+CD25+Foxp3+Regulatory T Cells Contributes to Experimental Cerebral Malaria

2015 ◽  
Vol 84 (1) ◽  
pp. 329-338 ◽  
Author(s):  
Anne-Laurence Blanc ◽  
Tarun Keswani ◽  
Olivier Gorgette ◽  
Antonio Bandeira ◽  
Bernard Malissen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cerebral Malaria ◽  
T Cell Response ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Naturally Occurring ◽  
Cell Enrichment

The role of naturally occurring CD4+CD25+Foxp3+regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4+T cells in an attenuated model ofPlasmodium bergheiANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6)P. bergheiANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4+T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4+T cell response toP. bergheiANKA infectionin vivoin both CM-susceptible (B6) and CM-resistant (B6-CD4−/−) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional duringP. bergheiANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.

scholarly journals Functional Roles for C5a and C5aR but Not C5L2 in the Pathogenesis of Human and Experimental Cerebral Malaria

2013 ◽  
Vol 82 (1) ◽  
pp. 371-379 ◽  
Author(s):  
Hani Kim ◽  
Laura K. Erdman ◽  
Ziyue Lu ◽  
Lena Serghides ◽  
Kathleen Zhong ◽  
...  
Keyword(s):  
Immune Response ◽  
Cerebral Malaria ◽  
Case Control ◽  
Brain Parenchyma ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Functional Roles ◽  
Angiopoietin 2 ◽  
Endothelial Integrity

ABSTRACTThe host immune response plays an important role in the onset and progression of cerebral malaria (CM). The complement system is an essential component of the innate immune response to malaria, and its activation generates the anaphylatoxin C5a. To test the hypothesis that C5a signaling contributes to the pathogenesis of CM, we investigated a causal role for the C5a receptors C5aR and C5L2 in a mouse model of experimental CM (ECM) induced byPlasmodium bergheiANKA infection, and using a case-control design, we examined levels of C5a in plasma samples from Ugandan children presenting with CM or uncomplicated malaria (UM). In the ECM model,C5aR−/−mice displayed significantly improved survival compared to their wild-type (WT) counterparts (P= 0.004), whereasC5L2−/−mice showed no difference in survival from WT mice. Improved survival inC5aR−/−mice was associated with reduced levels of the proinflammatory cytokines tumor necrosis factor (TNF) and gamma interferon (IFN-γ) and the chemokine, monocyte chemoattractant protein 1 (MCP-1) (CCL2). Furthermore, endothelial integrity was enhanced, as demonstrated by increased levels of angiopoietin-1, decreased levels of angiopoietin-2 and soluble ICAM-1, and decreased Evans blue extravasation into brain parenchyma. In the case-control study, the median levels of C5a at presentation were significantly higher in children with CM versus those in children with UM (43.7 versus 22.4 ng/ml;P< 0.001). These findings demonstrate that C5a is dysregulated in human CM and contributes to the pathogenesis of ECM via C5aR-dependent inflammation and endothelial dysfunction.

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

2011 ◽  
Vol 79 (9) ◽  
pp. 3633-3641 ◽  
Author(s):  
Maximilian Kordes ◽  
Kai Matuschewski ◽  
Julius Clemence R. Hafalla
Keyword(s):  
Cerebral Malaria ◽  
Blood Stage ◽  
Interleukin 1Β ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Effector Cells ◽  
Caspase 1 ◽  
Disease Outcomes ◽  
Absolute Dependence ◽  
Toll Like Receptor 2

ABSTRACTMalaria infection is initiated by sporozoite invasion of hepatocytes and asexual reproduction of liver stages, processes that are regarded to be “clinically and diagnostically silent.” Merozoites, which egress from hepatocytes, infect erythrocytes in periodic cycles and induce disease. How the host innate immune system contributes to disease outcomes and to the induction of effector cells during malaria remains unclear. Likewise, how the initial liver stages may shape responses to blood-stage parasites is unknown. Here, using both sporozoite- and blood-stage-induced infections with the rodent malaria parasitePlasmodium bergheiANKA, we show that the MyD88 and Toll-like receptor 2/4 (TLR2/4) pathways play critical roles in the development of experimental cerebral malaria (ECM). Strikingly, an absolute dependence on MyD88 and TLR2/4 was observed when infections were initiated with sporozoites. In addition, we show that caspase-1 activation of interleukin-1β (IL-1β) and IL-18, which is associated with the inflammasome pathway, does not contribute toP. bergheiANKA-induced immunopathology. Consistent with these data, prophylactic cover with the IL-1β antagonist anakinra did not reduce the incidence of ECM. Therefore, we propose that protection against ECM due to loss of TLR signaling functions is caused by effector mechanisms other than IL-1β activation.

scholarly journals Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e103295 ◽  
Author(s):  
Johan Normark ◽  
Maria Nelson ◽  
Patrik Engström ◽  
Marie Andersson ◽  
Rafael Björk ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cerebral Malaria ◽  
Infection Model ◽  
Experimental Cerebral Malaria ◽  
Host Immune Responses

scholarly journals IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8+T Cells in Experimental Cerebral Malaria

2015 ◽  
Vol 83 (4) ◽  
pp. 1406-1417 ◽  
Author(s):  
Jintao Guo ◽  
James A. McQuillan ◽  
Belinda Yau ◽  
Gregory S. Tullo ◽  
Carole A. Long ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Type I ◽  
Experimental Cerebral Malaria ◽  
Content Type ◽  
Cytokines And Chemokines ◽  
Specific Effector ◽  
Ifn Γ

Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection withPlasmodiumspecies. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used thePlasmodium bergheiANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA forIrgm1andIrgm3was found in the brains and spleens of infected mice at times of peak IFN-γ production.Irgm3−/−but notIrgm1−/−mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+T cells within the brain. Although antigen-specific proliferation of transferred CD8+T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred intoIrgm3−/−recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens ofIrgm3−/−mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology inIrgm3−/−mice occurs due to impaired generation of CD8+effector function. This defect is nonintrinsic to CD8+T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.

scholarly journals Reduction of Experimental Cerebral Malaria and Its Related Proinflammatory Responses by the Novel Liposome-Basedβ-Methasone Nanodrug

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Jintao Guo ◽  
Judith H. Waknine-Grinberg ◽  
Andrew J. Mitchell ◽  
Yechezkel Barenholz ◽  
Jacob Golenser
Keyword(s):  
Immune Responses ◽  
Cerebral Malaria ◽  
Time Window ◽  
The Novel ◽  
Experimental Cerebral Malaria ◽  
Cytokines And Chemokines ◽  
Proinflammatory Responses ◽  
Th1 And Th2 Responses ◽  
Th1 Immune Responses

Cerebral malaria (CM) is a severe complication of and a leading cause of death due toPlasmodium falciparuminfection. CM is likely the result of interrelated events, including mechanical obstruction due to parasite sequestration in the microvasculature, and upregulation of Th1 immune responses. In parallel, blood-brain-barrier (BBB) breakdown and damage or death of microglia, astrocytes, and neurons occurs. We found that a novel formulation of a liposome-encapsulated glucocorticosteroid,β-methasone hemisuccinate (nSSL-BMS), prevents experimental cerebral malaria (ECM) in a murine model and creates a survival time-window, enabling administration of an antiplasmodial drug before severe anemia develops. nSSL-BMS treatment leads to lower levels of cerebral inflammation, expressed by altered levels of corresponding cytokines and chemokines. The results indicate the role of integrated immune responses in ECM induction and show that the new steroidal nanodrug nSSL-BMS reverses the balance between the Th1 and Th2 responses in malaria-infected mice so that the proinflammatory processes leading to ECM are prevented. Overall, because of the immunopathological nature of CM, combined immunomodulator/antiplasmodial treatment should be considered for prevention/treatment of human CM and long-term cognitive damage.

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