• Plasmodium
• CCL5
• Malaria
• RANTES
• Systematic review

• Chemokine CCL5/blood
• Humans
• Malaria, Vivax/blood
• Malaria, Vivax/immunology
• Plasmodium vivax/physiology
• Malaria, Falciparum/parasitology
• Plasmodium falciparum

• Anemia
• Cytokines
• Disease severity
• Immunopathogenesis
• Plasmodium vivax
• Thrombocytopenia

• inflammation
• malaria

• Humans
• Plasmodium falciparum/metabolism
• Monocytes/metabolism
• Interleukin-6/metabolism
• Cytokines/metabolism
• Malaria, Falciparum
• Malaria/metabolism
• Epigenesis, Genetic

• National Health and Medical Research Council

• Humans
• Genetic Predisposition to Disease
• Genotype
• Plasmodium falciparum/genetics
• Polymorphism, Single Nucleotide
• Tumor Necrosis Factor-alpha/genetics

• Thailand Science Research and Fundamental Fund
• National Research Council of Thailand
• Thammasat University
• Thammasat University Research Fund under Thammasat University Research Scholar

• Asia
• Cytokines
• Host Genetics
• Malaria
• MicroRNAs

• cerebral malaria
• cerebrospinal fluid (CSF)
• tumor necrosis factor-alpha (TNF-α)

• Humans
• Child
• Tumor Necrosis Factor-alpha/cerebrospinal fluid
• Malaria, Cerebral/diagnosis
• Malaria, Cerebral/cerebrospinal fluid
• Prospective Studies
• Cross-Sectional Studies
• ROC Curve

• TCF7L2 gene
• TNF-α
• cytokine
• hypothesis
• inflammation
• malaria
• malaria-endemic population
• type 2 diabetes (T2D)

• Animals
• Mice
• Antigen Presentation
• Parasites
• Endothelial Cells/pathology
• CD8-Positive T-Lymphocytes
• Brain
• Malaria, Cerebral
• Signal Transduction
• Immunity, Innate
• Endothelium/pathology
• Interferon Type I

• Benin
• Cerebral malaria
• Children
• Cytokine
• Immunologic marker
• NeuroCM
• Plasma
• Urine

• biomarkers
• cerebral malaria
• diagnosis
• plasmodium falciparum
• therapeutic avenues

• Humans
• Malaria, Cerebral/diagnosis
• Plasmodium falciparum
• Malaria, Falciparum/diagnosis
• Malaria, Falciparum/parasitology
• Microvessels
• Brain Diseases

• U19 AI089676 NIAID NIH HHS
• MR/S009450/1 Medical Research Council
• R21 AI142472 NIAID NIH HHS
• Science and Engineering Research Board
• Medical Research Council
• National Institute of Allergy and Infectious Diseases

• Acute disseminated encephalomyelitis
• COVID-19 pandemic
• Capillary leak
• Cerebral edema
• Cerebral malaria
• Cytoadherence
• Delayed cerebellar ataxia
• Falciparum malaria
• Guillain-Barré syndrome
• Malaria
• Neurological complications of malaria
• Post-malaria neurological syndrome
• Severe malaria
• Vivax malaria

• Adult
• Brain Edema
• COVID-19
• Child
• Cytokines
• Humans
• Hypoxia
• Malaria, Cerebral/complications
• Malaria, Cerebral/parasitology
• Malaria, Falciparum/complications
• Malaria, Falciparum/parasitology
• Pandemics
• Plasmodium falciparum/physiology
• Posterior Leukoencephalopathy Syndrome

• Plasmodium
• adaptation
• combination therapy
• cytokines
• immunomodulatory
• inflammation
• swertiamarin

Specific adhesion (sequestration) of Plasmodium falciparum parasite-infected erythrocytes (IEs) in deep vascular beds can cause severe complications resulting in death. This review describes our work on the discovery, characterization, and optimization of novel inhibitors that specifically prevent adhesion of IEs to the host vasculature during severe malaria, especially its placental and cerebral forms. The main idea of using anti-adhesion drugs in severe malaria is to release sequestered parasites (or prevent additional sequestration) as quickly as possible. This may significantly improve the outcomes for patients with severe malaria by decreasing local and systemic inflammation associated with the disease and reestablishing the microvascular blood flow. To identify anti-malarial adhesion-inhibiting molecules, we have developed a high-throughput (HT) screening approach and found a number of promising leads that can be further developed into anti-adhesion drugs providing an efficient adjunct therapy against severe forms of malaria.

• Animals
• Drug Discovery
• Erythrocytes
• Female
• Humans
• Malaria, Falciparum/drug therapy
• Malaria, Falciparum/parasitology
• Malaria, Falciparum/prevention & control
• Parasites
• Placenta
• Plasmodium falciparum
• Pregnancy

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses to Plasmodium parasites. Here we use a newly developed transgenic Plasmodium berghei ANKA (PbA_Ama1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates that Ifnar1^-/- mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8⁺ T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protected Ifnar1^-/- mice and wild type mice suffering from ECM. Importantly, CD8⁺ T cells were increased in the spleens of ECM-protected Ifnar1^-/- mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8⁺ T cell infiltration into the brain and increased ECM induction in PbA_Ama1OVA-infected Ifnar1^-/- mice. However, eosinophil-depletion did not reduce the CD8⁺ T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8⁺ T cell migration and proliferation during PbA_Ama1OVA-infection in Ifnar1^-/- mice and thereby are contributing to the protection from ECM.

• CCL5
• CD8 T cells
• IFNAR1
• NK cells
• Plasmodium berghei
• eosinophils
• experimental cerebral malaria (ECM)
• malaria

Annona muricata and Khaya grandifoliola are ethnomedicinally used for the treatment of malaria and have been experimentally shown to have an anti-plasmodial effect, but the mechanisms involved are not fully understood. This study investigated the effect of the ethanol extracts of their leaves on parasitemia, radical scavenging and cytokines in Plasmodium berghei ANKA-infected BALB/c mice.

BALB/c mice were infected with P. berghei and treated with chloroquine, A. muricata or K. grandifoliola extract for 4 days. The percentage of parasitemia and the level of cytokine expression were determined after treatment. Trace element, phytochemical and nitric oxide (NO) scavenging activity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging properties assays were done to study the antioxidant effects of AN and KG in vitro.

P. berghei consistently increased parasitemia in BALB/c mice. The tested doses (100-, 200-, and 400 mg/kg) of A. muricata and K. grandifoliola attenuated the P. berghei-induced elevation of parasitemia and cytokines (TNF-α, IL-5, and IL-6) in vivo during the experimental period, though not as much as chloroquine. Moreover, both extracts scavenged the DPPH and NO radicals, though A. muricata had more anti-oxidant effect than K. grandifoliola in-vitro.

The ethanol extracts of A. muricata and K. grandifoliola reduce parasitemia in P. berghei-treated mice BALB/c by scavenging free radicals and reducing cytokines, though the extracts were not as effective as chloroquine.

• Annona muricata
• BALB/c mice
• Khaya grandifoliola
• Plasmodium berghei
• cerebral malaria
• cytokine inhibition

• Anti-malarial-based liposomes
• In vitro and in vivo anti-malarial activity
• Liposomal malaria antigens
• Malaria
• Targeting delivery

• Antimalarials/therapeutic use
• Humans
• Liposomes/therapeutic use
• Malaria/prevention & control

• P. falciparum
• combinatorial chemistry
• drug discovery
• mixture-based libraries
• severe and cerebral malaria
• small molecule inhibitors
• solid-phase synthesis
• thiazoles

• Antimalarials/chemistry
• Antimalarials/pharmacology
• Erythrocytes/metabolism
• Erythrocytes/parasitology
• Erythrocytes/pathology
• Humans
• Intercellular Adhesion Molecule-1/metabolism
• Malaria, Falciparum/drug therapy
• Malaria, Falciparum/metabolism
• Malaria, Falciparum/pathology
• Plasmodium falciparum/metabolism
• Small Molecule Libraries/chemistry
• Small Molecule Libraries/pharmacology

• R21 AI137721 NIAID NIH HHS

• Anti-inflammatory
• Blood-brain barrier
• MLIF
• Malaria
• Neuroinflammation
• Neuroprotection

• Plasmodium berghei
• T cell
• YOP1
• cerebral malaria
• immune response

Pro- and anti-inflammatory cytokines are important mediators of immunity and are associated with malaria disease outcomes. However, their role in the establishment of asymptomatic infections, which may precede the development of clinical symptoms, is not as well-understood.

We determined the association of pro and anti-inflammatory cytokines and other immune effector molecules with the development of asymptomatic malaria. We measured and compared the plasma levels of pro-inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukin (IL)-6, IL-12p70, IL-17A, and granzyme B, the anti-inflammatory cytokine IL-4 and the regulatory cytokine IL-10 from children with asymptomatic malaria infections (either microscopic or submicroscopic) and uninfected controls using Luminex.

We show that individuals with microscopic asymptomatic malaria had significantly increased levels of TNF-α and IL-6 compared to uninfected controls. Children with either microscopic or submicroscopic asymptomatic malaria exhibited higher levels of IFN-γ, IL-17A, and IL-4 compared to uninfected controls. The levels of most of the pro and anti-inflammatory cytokines were comparable between children with microscopic and submicroscopic infections. The ratio of IFN-γ/IL-10, TNF-α/IL-10, IL-6/IL-10 as well as IFN-γ/IL-4 and IL-6/IL-4 did not differ significantly between the groups. Additionally, using a principal component analysis, the cytokines measured could not distinguish amongst the three study populations. This may imply that neither microscopic nor submicroscopic asymptomatic infections were polarized toward a pro-inflammatory or anti-inflammatory response.

The data show that asymptomatic malaria infections result in increased plasma levels of both pro and anti-inflammatory cytokines relative to uninfected persons. The balance between pro- and anti-inflammatory cytokines are, however, largely maintained and this may in part, explain the lack of clinical symptoms. This is consistent with the generally accepted observation that clinical symptoms develop as a result of immunopathology involving dysregulation of inflammatory mediator balance in favor of pro-inflammatory mediators.

• Plasmodium
• anti-inflammatory cytokines
• asymptomatic malaria
• microscopic
• pro-inflammatory cytokines
• submicroscopic

• Blood brain barrier
• Cerebral malaria
• Heterogeneity
• Inflammation
• Neurologic sequelae

In the past 20 years, patients with rheumatoid arthritis (RA), Crohn's disease (CD), and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFα inhibitors. With 5 approved anti-TNFα biologics on the market and soon available biosimilars, patients have more treatment options and have benefited from understanding the biology of TNFα. Nevertheless, many unmet needs remain for people living with TNFα-related diseases, namely some side effects and tolerance of current anti-TNFα biologics and resistance to therapies. Furthermore, common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFα therapies at early onset of symptoms. Development of new TNFα inhibitors focusing on TNFR1 specific inhibitors, preferably small molecules that can be delivered orally, is much needed.

• Antibodies
• Receptors
• Small molecule inhibitors
• TNFR1
• TNFα

• Adjunctive therapy
• Apoptosis
• BBB integrity
• Cerebral malaria
• Inflammation
• Oxidative stress

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine associated with autoimmune and infectious diseases. Importance of TNF-α in P. falciparum malaria and systemic lupus erythematosus (SLE) have been demonstrated. However, association of functional promoter variants with SLE and malaria is lacking in malaria endemic population. A total of 204 female SLE patients and 224 age and sex matched healthy controls were enrolled in the study. Three hundred fourteen P. falciparum infected patients with different clinical phenotypes were included. TNF-α polymorphisms (G-238A & G-308A) were genotyped by PCR-RFLP. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutants and minor alleles of TNF-α (G-238A and G-308A) polymorphisms were significantly higher in SLE patients compared to healthy controls and associated with development of lupus nephritis. In addition, both promoter variants were associated with severe P. falciparum malaria. SLE patients demonstrated higher levels of plasma TNF-α compared to healthy controls. TNF-α (G-238A and G-308A) variants were associated with higher plasma TNF-α. In conclusion, TNF-α (G-238A & G-308A) variants are associated with higher plasma TNF-α levels in SLE patients residing in malaria endemic areas and could be a contributing factor in the development of SLE and susceptibility to severe P. falciparum malaria.

Malaria is a disease with diverse symptoms depending on host immune status and pathogenicity of Plasmodium parasites. The continuous parasite growth within a host suggests mechanisms of immune evasion by the parasite and/or immune inhibition in response to infection. To identify pathways commonly inhibited after malaria infection, we infected C57BL/6 mice with four Plasmodium yoelii strains causing different disease phenotypes and 24 progeny of a genetic cross. mRNAs from mouse spleens day 1 and/or day 4 post infection (p.i.) were hybridized to a mouse microarray to identify activated or inhibited pathways, upstream regulators, and host genes playing an important role in malaria infection. Strong interferon responses were observed after infection with the N67 strain, whereas initial inhibition and later activation of hematopoietic pathways were found after infection with 17XNL parasite, showing unique responses to individual parasite strains. Inhibitions of pathways such as Th1 activation, dendritic cell (DC) maturation, and NFAT immune regulation were observed in mice infected with all the parasite strains day 4 p.i., suggesting universally inhibited immune pathways. As a proof of principle, treatment of N67-infected mice with antibodies against T cell receptors OX40 or CD28 to activate the inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine.

• Immunometabolomics
• Malaria
• Metabolism
• Metabolites
• Metabolomics

• Animals
• Biomarkers/metabolism
• Disease Progression
• Erythrocytes/metabolism
• Erythrocytes/parasitology
• Host-Parasite Interactions/physiology
• Humans
• Malaria/metabolism
• Malaria/parasitology
• Metabolic Networks and Pathways/physiology
• Metabolomics/methods
• Vertebrates/metabolism
• Vertebrates/parasitology

Alterations in the mechanical properties of erythrocytes occurring in inflammatory and hematologic disorders such as sickle cell disease (SCD) and malaria often lead to increased endothelial permeability, haemolysis, and microvascular obstruction. However, the associations among these pathological phenomena remain unknown. Here, we report a perfusable, endothelialized microvasculature-on-a-chip featuring an interpenetrating-polymer-network hydrogel that recapitulates the stiffness of blood-vessel intima, basement membrane self-deposition and self-healing endothelial barrier function for longer than 1 month. The microsystem enables the real-time visualization, with high spatiotemporal resolution, of microvascular obstruction and endothelial permeability under physiological flow conditions. We found how extracellular heme, a hemolytic byproduct, induces delayed but reversible endothelial permeability in a dose-dependent manner, and demonstrate that endothelial interactions with SCD or malaria-infected erythrocytes cause reversible microchannel occlusion and increased in situ endothelial permeability. The microvasculature-on-a-chip enables mechanistic insight into the endothelial barrier dysfunction associated with SCD, malaria and other inflammatory and haematological diseases.

Despite a global effort to develop an effective vaccine, malaria is still a significant health problem. Much of the pathology of malaria is immune mediated. This suggests that host immune responses have to be finely regulated. The innate immune system initiates and sets the threshold of the acquired immune response and determines the outcome of the disease. Yet, our knowledge of the regulation of innate immune responses during malaria is limited. Theoretically, inadequate activation of the innate immune system could result in unrestrained parasite growth. Conversely, hyperactivation of the innate immune system, is likely to cause excessive production of proinflammatory cytokines and severe pathology. Toll-like receptors (TLRs) have emerged as essential receptors which detect signature molecules and shape the complex host response during malaria infection. This review will highlight the mechanisms by which Plasmodium components are recognized by innate immune receptors with particular emphasis on TLRs. A thorough understanding of the complex roles of TLRs in malaria may allow the delineation of pathological versus protective host responses and enhance the efficacy of anti-malarial treatments and vaccines.

• Pattern recognition receptors
• TLRs
• host-pathogen interaction
• innate immunity
• malaria
• malaria immunity

• Host–pathogen interaction
• human
• parasitic helminth
• parasitic protozoan

Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection responsible for thousands of deaths in children in sub-Saharan Africa. CM pathogenesis remains incompletely understood but a number of effectors have been proposed, including plasma microparticles (MP). MP numbers are increased in CM patients’ circulation and, in the mouse model, they can be localised within inflamed vessels, suggesting their involvement in vascular damage. In the present work we define, for the first time, the protein cargo of MP during experimental cerebral malaria (ECM) with the overarching hypothesis that this characterisation could help understand CM pathogenesis. Using qualitative and quantitative high-throughput proteomics we compared MP proteins from non-infected and P. berghei ANKA-infected mice. More than 360 proteins were identified, 60 of which were differentially abundant, as determined by quantitative comparison using TMT^TM isobaric labelling. Network analyses showed that ECM MP carry proteins implicated in molecular mechanisms relevant to CM pathogenesis, including endothelial activation. Among these proteins, the strict association of carbonic anhydrase I and S100A8 with ECM was verified by western blot on MP from DBA/1 and C57BL/6 mice. These results demonstrate that MP protein cargo represents a novel ECM pathogenic trait to consider in the understanding of CM pathogenesis.

The majority of chickens in sub-Saharan Africa are indigenous ecotypes, well adapted to the local environment and raised in scavenging production systems. Although they are generally resilient to disease challenge, routine vaccination and biosecurity measures are rarely applied and infectious diseases remain a major cause of mortality and reduced productivity. Management and genetic improvement programmes are hampered by lack of routine data recording. Selective breeding based on genomic technologies may provide the means to enhance sustainability. In this study, we investigated the genetic architecture of antibody response to four major infectious diseases [infectious bursal disease (IBDV), Marek’s disease (MDV), fowl typhoid (SG), fowl cholera (PM)] and resistance to Eimeria and cestode parasitism, along with two production traits [body weight and body condition score (BCS)] in two distinct indigenous Ethiopian chicken ecotypes. We conducted variance component analyses, genome-wide association studies, and pathway and selective sweep analyses.

The large majority of birds was found to have antibody titres for all pathogens and were infected with both parasites, suggesting almost universal exposure. We derived significant moderate to high heritabilities for IBDV, MDV and PM antibody titres, cestodes infestation, body weight and BCS. We identified single nucleotide polymorphisms (SNPs) with genome-wide significance for each trait. Based on these associations, we identified for each trait, pathways, networks and functional gene clusters that include plausible candidate genes. Selective sweep analyses revealed a locus on chromosome 18 associated with viral antibody titres and resistance to Eimeria parasitism that is within a positive selection signal. We found no significant genetic correlations between production, immune and disease traits, implying that selection for altered antibody response and/or disease resistance will not affect production.

We confirmed the presence of genetic variability and identified SNPs significantly associated with immune, disease and production traits in indigenous village chickens. Results underpin the feasibility of concomitant genetic improvement for enhanced antibody response, resistance to parasitism and productivity within and across indigenous chicken ecotypes.

The online version of this article (doi:10.1186/s12711-016-0252-7) contains supplementary material, which is available to authorized users.

Cerebral malaria is still a deleterious health problem in tropical countries. The wide spread of malarial drug resistance and the lack of an effective vaccine are obstacles for disease management and prevention. Parasite and human genetic factors play important roles in malaria susceptibility and disease severity. The malaria parasite exerted a potent selective signature on the human genome, which is apparent in the genetic polymorphism landscape of genes related to pathogenesis. Currently, much genomic data and a novel body of knowledge, including the identification of microRNAs, are being increasingly accumulated for the development of laboratory testing cassettes for cerebral malaria prevention. Therefore, understanding of the underlying complex molecular basis of cerebral malaria is important for the design of strategy for cerebral malaria treatment and control.

• Cerebral malaria
• Genetics
• MicroRNA
• Pathogenesis

Central diabetes insipidus is an uncommon feature of malaria. A previously healthy 72-year-old man presented with fever, rigors, and altered mental status after a recent trip to Liberia, a country known for endemic falciparum malaria. Investigations confirmed plasmodium falciparum parasitemia. Within one week after admission, the serum sodium rose to 166 mEq/L and the urine output increased to 7 liters/day. Other labs were notable for a high serum osmolality, low urine osmolality, and low urine specific gravity. The hypernatremia did not respond to hypotonic fluids. Diabetes insipidus was suspected and parenteral desmopressin was started with a prompt decrease in urinary output and improvement in mental status. Additional testing showed normal anterior pituitary hormones. The desmopressin was eventually tapered off with complete resolution of symptoms. Central diabetes insipidus occurred likely as a result of obstruction of the neurohypophyseal microvasculature. Other endocrinopathies that have been reported with malaria include hyponatremia, adrenal insufficiency, hypothyroidism, hypocalcemia, hypophosphatemia, hyper-, and hypoglycemia, but none manifested in our patient. Though diabetes insipidus is a rare complication of malaria, clinicians need to be aware of this manifestation, as failure to do so may lead to fatality particularly if the patient is dehydrated.

• Meta-analysis
• P. falciparum malaria
• Polymorphism
• TIRAP
• TNF-α

• Cerebral malaria
• Lipids
• Metabolomics
• NMR
• OPLS-DA
• Prediction

• Brain
• Cytokines
• Malaria
• Obesity
• Systemic inflammation

Tumour necrosis factor (TNF) is central to the immune response to Plasmodium infection. Its plasma concentration is influenced by allele variants in the promoter region of TNF. The study’s objectives were to assess TNF allele variants (TNF₋₁₀₃₁, TNF₋₃₀₈): (1) modulation of malaria rates in young Tanzanian children; (2) modulation of the severity of malaria as indicated by haemoglobin concentrations at the time of presentation with febrile episodes; and (3) the association between Plasmodium infection and haemoglobin concentration in symptomless parasite carriers.

Data from a placebo-controlled trial in which 612 Tanzanian children aged 6–60 months with height-for-age z-score in the range −3 SD to 1.5 SD was utilised. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. An episode of malaria was predefined as current Plasmodium infection with an inflammatory response (axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L) in children reported sick. Linkage disequilibrium (LD) pattern assessment as well as haplotype analysis was conducted using HAPLOVIEW. Cox regression models used in the primary analysis accounted for multiple episodes per child.

Genotyping of 94.9% (581/612) children for TNF₋₁₀₃₁ (TNF₋₁₀₃₁T>C); allele frequency was 0.39. Corresponding values for rs1800629 (TNF₋₃₀₈G>A) were 95.4% (584/612) and 0.17. Compared to the wild type genotype (TT), malaria rates were increased in the TNF₋₁₀₃₁CC genotype (hazard ratio, HR [95% CI]: 1.41 [1.01‒1.97] and 1.31 [0.97‒1.76] for crude analysis and adjusting for pre-specified baseline factors, respectively) but decreased in those with the TNF₋₃₀₈AA genotype (corresponding HR: 0.13 [0.02‒0.63] and 0.16 [0.04‒0.67]). These associations were weaker when analysing first episodes of malaria (P value −0.59 and 0.38, respectively). No evidence that allele variants of TNF₋₁₀₃₁ and TNF₋₃₀₈ affected haemoglobin concentration at first episode of malaria, or that they modified the association between Plasmodium infection and haemoglobin concentrations at baseline was observed.

In this cohort of Tanzanian children, the TNF₋₁₀₃₁CC genotype was associated with increased rates of malarial episodes, whereas the TNF₋₃₀₈AA genotype was associated with decreased rates.

• Adoptive Transfer
• Animals
• Coculture Techniques
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Immunity, Innate
• Interleukin-33/immunology
• Macrophages/immunology
• Malaria, Cerebral/immunology
• Mice
• Mice, Inbred C57BL
• Plasmodium berghei/immunology
• Real-Time Polymerase Chain Reaction
• T-Lymphocytes, Regulatory/immunology
• Th2 Cells/immunology

• Wellcome Trust
• G0900487 Medical Research Council
• G9818261 Medical Research Council

• Artemisinin derivatives
• Haemozoin
• Malaria
• Metalloproteinase-9
• NF-κB
• Tumour necrosis factor alpha

Malaria, caused by Plasmodium sp. parasites, is a leading cause of global morbidity and mortality. Cerebral malaria, characterized by neurological symptoms, is a life-threatening complication of malaria affecting over 500,000 young children in Africa every year. Because of the prevalence and severity of cerebral malaria, a better understanding of the underlying molecular mechanisms of its pathology is desirable and could inform future development of therapeutics. This study sought to clarify the role of Toll-like receptors (TLRs) in promoting immunopathology associated with cerebral malaria, with a particular focus on the understudied TLR7.

Using the Plasmodium berghei ANKA mouse model of experimental cerebral malaria, C57BL/6 mice deficient in various TLRs were infected, and their resistance to cerebral malaria and immune activation through cytokine production were measured.

Loss of TLR7 conferred partial protection against fatal experimental cerebral malaria. Additionally, loss of TLR signalling dysregulated the cytokine profile, resulting in a shift in the cytokine balance towards those with more anti-inflammatory properties.

This work identifies signalling through TLR7 as a source of pathology in experimental cerebral malaria.

• IL-1
• Kuwait
• Leptin
• Malaria
• Tumor necrosis factor alpha (TNFα)

• Blood brain barrier
• Endothelin
• Inflammation
• Neuroinflammation
• Parasitic disease
• Pneumonia
• Sepsis

Cerebral malaria (CM) is a life-threatening complication of falciparum malaria, associated with high mortality rates, as well as neurological impairment in surviving patients. Despite disease severity, the etiology of CM remains elusive. Interestingly, although the Plasmodium parasite is sequestered in cerebral microvessels, it does not enter the brain parenchyma: so how does Plasmodium induce neuronal dysfunction? Several independent research groups have suggested a mechanism in which increased blood–brain barrier (BBB) permeability might allow toxic molecules from the parasite or the host to enter the brain. However, the reported severity of BBB damage in CM is variable depending on the model system, ranging from mild impairment to full BBB breakdown. Moreover, the factors responsible for increased BBB permeability are still unknown. Here we review the prevailing theories on CM pathophysiology and discuss new evidence from animal and human CM models implicating BBB damage. Finally, we will review the newly-described role of matrix metalloproteinases (MMPs) and BBB integrity. MMPs comprise a family of proteolytic enzymes involved in modulating inflammatory response, disrupting tight junctions, and degrading sub-endothelial basal lamina. As such, MMPs represent potential innovative drug targets for CM.

• FITC
• IL-12
• Malaria
• Plasmodium falciparum
• Profilin
• SD
• Subtilisin-like protease
• TLR
• TNF-α
• fluoresceine isothiocyanate
• interleukin 12
• synthetic defined
• toll-like receptor
• tumor necrosis factor-alpha

Enhanced inflammatory host responses have been attributed as the cellular basis for development of severe malaria as well as sepsis. In contrast to this, filarial infections have been consistently reported to be associated with an immunological hypo-responsive phenotype. This suggests that successful control of filariasis by employing mass drug administration, could potentially contribute to an increase in incidence of sepsis and cerebral malaria in human communities. A case control study was undertaken to address this critical and urgent issue.

Eighty-nine patients with sepsis and one hundred and ninety-six patients with P. falciparum malaria all originating from Odisha, were tested for prevalence of circulating filarial antigens - a quantitative marker of active filarial infection. Antibodies to four stage specific malarial recombinant proteins were measured by solid phase immunoassays and circulating CD4+CD25^high T-cells were quantified by flow cytometry with an objective to study if pre-existing filarial infections influence antibody responses to malarial antigens or the levels of circulating T-regulatory cells in P. falciparum infected patients.

Prevalence of filarial antigenemia was significantly less in sepsis patients as compared to controls suggesting that pre-existing filariasis could influence development of sepsis. On the other hand, levels of circulating filarial antigen were comparable in severe malaria cases and healthy controls suggesting that development of severe malaria is independent of pre-existing W. bancrofti infections. Plasma TNF-a, RANTES and antibodies to recombinant malarial proteins as well as levels of circulating CD4+ CD25^high cells were comparable in malaria patients with or without filarial infections.

These observations imply that successful control of filariasis could have adverse consequences on public health by increasing the incidence of sepsis, while the incidence of severe malaria may not adversely increase as a consequence of elimination of filariasis.