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.

A Neuroprotective Effect of the Glutamate Receptor Antagonist MK801 on Long-Term Cognitive and Behavioral Outcomes Secondary to Experimental Cerebral Malaria

2016 ◽  
Vol 54 (9) ◽  
pp. 7063-7082 ◽  
Author(s):  
Aline Silva de Miranda ◽  
Fátima Brant ◽  
Luciene Bruno Vieira ◽  
Natália Pessoa Rocha ◽  
Érica Leandro Marciano Vieira ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Cerebral Malaria ◽  
Glutamate Receptor ◽  
Neuroprotective Effect ◽  
Behavioral Outcomes ◽  
Glutamate Receptor Antagonist ◽  
Experimental Cerebral 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 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 Reduction of Retrovirus-Induced Immunosuppression by In Vivo Modulation of T Cells during Acute Infection

2004 ◽  
Vol 78 (21) ◽  
pp. 11641-11647 ◽  
Author(s):  
Hong He ◽  
Ronald J. Messer ◽  
Shimon Sakaguchi ◽  
Guojun Yang ◽  
Shelly J. Robertson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Acute Infection ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Responses ◽  
Th1 Immune Responses ◽  
Necrosis Factor

ABSTRACT Chronic infection with Friend retrovirus is associated with suppressed antitumor immune responses. In the present study we investigated whether modulation of T-cell responses during acute infection would restore antitumor immunity in persistently infected mice. T-cell modulation was done by treatments with DTA-1 anti- glucocorticoid-induced tumor necrosis factor receptor monoclonal antibodies. The DTA-1 monoclonal antibody is nondepleting and delivers costimulatory signals that both enhance the activation of effector T cells and inhibit suppression by regulatory T cells. DTA-1 therapy produced faster Th1 immune responses, significant reductions in both acute virus loads and pathology and, most importantly, long-term improvement of CD8+ T-cell-mediated antitumor responses.

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 Severe COVID-19 and Sepsis: Immune Pathogenesis and Laboratory Markers

2021 ◽  
Vol 9 (1) ◽  
pp. 159
Author(s):  
Mai M. Zafer ◽  
Hadir A. El-Mahallawy ◽  
Hossam M. Ashour
Keyword(s):  
Immune Responses ◽  
Multiorgan Failure ◽  
Serum Levels ◽  
Lung Damage ◽  
The Novel ◽  
Inflammatory Reactions ◽  
Dynamic Events ◽  
Cytokines And Chemokines ◽  
Plasma Leakage ◽  
Novel Coronavirus

The ongoing outbreak of the novel coronavirus disease 2019 (COVID-19), induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has taken a significant toll on people and countries all over the world. The pathogenesis of COVID-19 has not been completely elucidated yet. This includes the interplay between inflammation and coagulation which needs further investigation. The massive production of proinflammatory cytokines and chemokines results in the so-called cytokine storm, leading to plasma leakage, vascular hyperpermeability, and disseminated vascular coagulation. This is usually accompanied by multiorgan failure. The extensive changes in the serum levels of cytokines are thought to play a crucial role in the COVID-19 pathogenesis. Additionally, the viral load and host inflammation factors are believed to have a significant role in host damage, particularly lung damage, from SARS-CoV-2. Interestingly, patients exhibit quantitative and qualitative differences in their immune responses to the virus, which can impact the clinical manifestation and outcomes of COVID-19. There needs to be a better understanding of the dynamic events that involve immune responses, inflammatory reactions, and viral replication in the context of the COVID-19 infection. Here, we discuss the main aspects of COVID-19 pathogenesis while supporting the hypothesis that inflammatory immune responses are involved in the progression of the disease to a more critical and fatal phase. We also explore the similarities and differences between severe COVID-19 and sepsis. A deeper understanding of the COVID-19 clinical picture as it relates to better-known conditions such as sepsis can provide useful clues for the management, prevention, and therapy of the disease.

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 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 Protein Kinase C θ Deficiency Increases Resistance of C57BL/6J Mice to Plasmodium berghei Infection-Induced Cerebral Malaria

2010 ◽  
Vol 78 (10) ◽  
pp. 4195-4205 ◽  
Author(s):  
Ariel Ohayon ◽  
Jacob Golenser ◽  
Rosa Sinay ◽  
Ami Tamir ◽  
Amnon Altman ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
Immune Responses ◽  
Cerebral Malaria ◽  
Plasmodium Berghei ◽  
Neurological Symptoms ◽  
Experimental Cerebral Malaria ◽  
Kinase C

ABSTRACT Protein kinase C θ (PKCθ) functions as a core component of the immunological synapse and serves as a key protein in the integrated T-cell antigen receptor (TCR)/CD28-induced signaling cascade leading to T-cell activation. However, the involvement of PKCθ in host-mediated immune responses to pathogens has not been thoroughly investigated. We tested the consequences of PKCθ ablation on the host response to infection by Plasmodium berghei ANKA (PbA). We found that both PKCθ+/+ and PKCθ−/− C57BL/6J mice are susceptible to infection with PbA. However, despite a similar parasite burden, PKCθ+/+ mice had an earlier onset of neurological signs, characteristics of experimental cerebral malaria (ECM), resulting in an earlier death. These mice suffered from an early and pronounced splenomegaly with a concomitant increase in the total number of CD4+ splenic T cells. In contrast, a large proportion of PbA-infected PKCθ−/− mice overcame the acute phase characterized by neurological symptoms and survived longer than PKCθ+/+ mice. The partial resistance of PKCθ−/− mice to ECM was associated with an impaired production of Th1-type cytokines, including gamma interferon and tumor necrosis factor alpha/lymphotoxin-α, which are known to exacerbate symptoms leading to ECM. In addition, PbA infection-induced LFA-1 expression in CD8+ T cells was suppressed in PKCθ-deficient T cells, suggesting a diminished ability to adhere to endothelial cells and sequester in brain microvasculature, which may explain the decrease in neurological symptoms. These data implicate PKCθ in CD4+ Th1+ and CD8+ T-cell-mediated immune responses during PbA infection that contribute to the development of ECM.

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