interleukin-8 and Malaria--Falciparum

We examined transcriptional changes in CD4+ T cells during blood-stage Plasmodium falciparum infection in individuals without a history of previous parasite exposure. Transcription of CXCL8 (encoding interleukin 8) in CD4+ T cells was identified as an early biomarker of submicroscopic P. falciparum infection, with predictive power for parasite growth. Following antiparasitic drug treatment, a CD4+ T-cell regulatory phenotype developed. PD1 expression on CD49b+CD4+ T (putative type I regulatory T) cells after drug treatment negatively correlated with earlier parasite growth. Blockade of PD1 but no other immune checkpoint molecules tested increased interferon γ and interleukin 10 production in an ex vivo antigen-specific cellular assay at the peak of infection. These results demonstrate the early development of an immunoregulatory CD4+ T-cell phenotype in blood-stage P. falciparum infection and show that a selective immune checkpoint blockade may be used to modulate early developing antiparasitic immunoregulatory pathways as part of malaria vaccine and/or drug treatment protocols.

Topics: Adolescent; Adult; Biomarkers; CD4-Positive T-Lymphocytes; Computational Biology; Humans; Interleukin-8; Lymphocyte Activation; Malaria Vaccines; Malaria, Falciparum; Middle Aged; Parasitemia; Phenotype; Plasmodium falciparum; T-Lymphocytes, Regulatory; Young Adult

Cerebral malaria (CM) is a neuropathology which remains one of the deadliest forms of malaria among African children. The kinetics of the pathophysiological mechanisms leading to neuroinflammation and the death or survival of patients during CM are still poorly understood. The increasing production of cytokines, chemokines and other actors of the inflammatory and oxidative response by various local actors in response to neuroinflammation plays a major role during CM, participating in both the amplification of the neuroinflammation phenomenon and its resolution. In this study, we aimed to identify risk factors for CM death among specific variables of inflammatory and oxidative responses to improve our understanding of CM pathogenesis.. Children presenting with CM (n = 70) due to P. falciparum infection were included in southern Benin and divided according to the clinical outcome into 50 children who survived and 20 who died. Clinical examination was complemented by fundoscopic examination and extensive blood biochemical analysis associated with molecular diagnosis by multiplex PCR targeting 14 pathogens in the patients' cerebrospinal fluid to rule out coinfections. Luminex technology and enzyme immunoassay kits were used to measure 17 plasma and 7 urinary biomarker levels, respectively. Data were analysed by univariate analysis using the nonparametric Mann‒Whitney U test and Pearson's Chi2 test. Adjusted and multivariate analyses were conducted separately for plasma and urinary biomarkers to identify CM mortality risk factors.. Univariate analysis revealed higher plasma levels of tumour necrosis factor (TNF), interleukin-1beta (IL-1β), IL-10, IL-8, C-X-C motif chemokine ligand 9 (CXCL9), granzyme B, and angiopoietin-2 and lower urinary levels of prostanglandine E2 metabolite (PGEM) in children who died compared to those who survived CM (Mann-Whitney U-test, P-values between 0.03 and < 0.0001). The multivariate logistic analysis highlighted elevated plasma levels of IL-8 as the main risk factor for death during CM (adjusted odd ratio = 14.2, P-value = 0.002). Values obtained during follow-up at D3 and D30 revealed immune factors associated with disease resolution, including plasma CXCL5, C-C motif chemokine ligand 17 (CCL17), CCL22, and urinary 15-F2t-isoprostane.. The main risk factor of death during CM was thus elevated plasma levels of IL-8 at inclusion. Follow-up of patients until D30 revealed marker profiles of disease aggravation and resolution for markers implicated in neutrophil activation, endothelium activation and damage, inflammatory and oxidative response. These results provide important insight into our understanding of CM pathogenesis and clinical outcome and may have important therapeutic implications.

Topics: Biomarkers; Child; Cytokines; Humans; Interleukin-8; Ligands; Malaria, Cerebral; Malaria, Falciparum; Neuroinflammatory Diseases; Risk Factors

Malaria elicits inflammatory responses, which, if not well regulated, may exert detrimental effects. When activated, triggering receptor expressed on myeloid cells 1 (TREM-1) enhances inflammatory responses by increasing secretion of IL-8 and other Th1 cytokines. In contrast, TREM-like transcript 1 (TREML-1) promotes anti-inflammatory responses by binding to TREM-1 ligands and competing with TREM-1, thus antagonizing TREM-1 activation to reduce inflammation. Endothelial protein C receptor (EPCR) also mediates anti-inflammatory responses by activating endothelial protein C (PC). Upon microbial stimulation, soluble forms of TREM-1 (sTREM-1) and soluble EPCR (sEPCR) are released. Their plasma levels reflect the degree of inflammation and the severity of infection.. In a cross-sectional study comparing patients with severe with uncomplicated malaria, sTREM-1, soluble TREML-1 (sTREML-1) and sEPCR plasma levels as well as plasma levels of sEPCR derived from convalescent patients were quantified. Samples were collected on admittance of paediatric patients infected with Plasmodium falciparum to hospitals in Accra, Ghana. Distinct genetic regions of the genes encoding TREM-1, EPCR, interleukin (IL)-8 and IL-18 encompassing known genetic polymorphisms that influence plasma levels underwent DNA sequencing.. Higher sTREM-1 levels were observed among children suffering from severe malaria compared to those with uncomplicated malaria (P = 0.049). Low TREM-1 to TREML-1 ratios were associated with uncomplicated malaria (P = 0.033). The TREM1 rs2234237T variant causing the amino acid exchange Thr25Ser, which has been associated with higher TREM-1 plasma levels, was significantly more frequent among patients with severe malaria than in those with uncomplicated malaria (P = 0.036). Low levels of sEPCR were observed in severe and uncomplicated malaria, while variant genotypes of IL8, IL18 and EPCR did not show any association.. Higher plasma levels of sTREM-1 alone or relative to sTREML-1 during malaria predispose to the phenotype of severe malaria. Carriage of the TREM1 rs2234237T allele appears to be a risk factor for the development of severe malaria.

Topics: Alleles; Antigens, CD; Child; Child, Preschool; Cytokines; Endothelial Protein C Receptor; Female; Genotype; Ghana; Humans; Infant; Interleukin-18; Interleukin-8; Malaria, Falciparum; Male; Membrane Glycoproteins; Phenotype; Polymorphism, Genetic; Receptors, Cell Surface; Receptors, Immunologic; Sequence Analysis, DNA; Severity of Illness Index; Solubility; Triggering Receptor Expressed on Myeloid Cells-1

Haematological and cytokine alterations in malaria are a broad and controversial subject in the literature. However, few studies have simultaneously evaluated various cytokines in a single patient group during the acute and convalescent phases of infection. The aim of this study was to sequentially characterise alterations in haematological patters and circulating plasma cytokine and chemokine levels in patients infected with Plasmodium vivax or Plasmodium falciparum from a Brazilian endemic area during the acute and convalescent phases of infection. During the acute phase, thrombocytopaenia, eosinopaenia, lymphopaenia and an increased number of band cells were observed in the majority of the patients. During the convalescent phase, the haematologic parameters returned to normal. During the acute phase, P. vivax and P. falciparum patients had significantly higher interleukin (IL)-6, IL-8, IL-17, interferon-γ, tumour necrosis factor (TNF)-α, macrophage inflammatory protein-1β and granulocyte-colony stimulating factor levels than controls and maintained high levels during the convalescent phase. IL-10 was detected at high concentrations during the acute phase, but returned to normal levels during the convalescent phase. Plasma IL-10 concentration was positively correlated with parasitaemia in P. vivax and P. falciparum-infected patients. The same was true for the TNF-α concentration in P. falciparum-infected patients. Finally, the haematological and cytokine profiles were similar between uncomplicated P. falciparum and P. vivax infections.

Topics: Acute Disease; Adult; Brazil; Case-Control Studies; Chemokine CCL4; Chemokines; Convalescence; Cytokines; Female; Granulocyte Colony-Stimulating Factor; Hematocrit; Humans; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-1beta; Interleukin-4; Interleukin-6; Interleukin-8; Malaria, Falciparum; Malaria, Vivax; Male; Parasitemia; Plasmodium falciparum; Plasmodium vivax; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Co-infection with malaria and HIV increases the severity and mortality of both diseases, but the cytokine responses related to this co-infection are only partially characterised. The aim of this study was to explore cytokine responses in relation to severity and mortality in malaria patients with and without HIV co-infection.. This was a prospective cross-sectional study. Clinical data and blood samples were collected from adults in Mozambique. Plasma was analysed for 21 classical pro- and anti-inflammatory cytokines, including interleukins, interferons, and chemokines.. We included 212 in-patients with fever and/or suspected malaria and 56 healthy controls. Falciparum malaria was diagnosed in 131 patients, of whom 70 were co-infected with HIV-1. The malaria patients had marked increases in their cytokine responses compared with the healthy controls. Some of these changes, particularly interleukin 8 (IL-8) and interferon-γ-inducing protein 10 (IP-10) were strongly associated with falciparum malaria and disease severity. Both these chemokines were markedly increased in patients with falciparum malaria as compared with healthy controls, and raised levels of IL-8 and IP-10 were associated with increased disease severity, even after adjusting for relevant confounders. For IL-8, particularly high levels were found in malaria patients that were co-infected with HIV and in those who died during hospitalization.. Our findings underscore the complex role of inflammation during infection with P. falciparum, and suggest a potential pathogenic role for IL-8 and IP-10. However, the correlations do not necessarily mean any causal relationship, and further both clinical and mechanistic research is necessary to elucidate the role of cytokines in pathogenesis and protection during falciparum malaria.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Chemokine CXCL10; Coinfection; Female; HIV Infections; HIV-1; Hospitals; Humans; Interleukin-8; Malaria, Falciparum; Male; Middle Aged; Mozambique; Young Adult

Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria.

Topics: Animals; Capillary Permeability; Cells, Cultured; Endothelium, Vascular; Histones; Humans; Interleukin-8; Life Cycle Stages; Lung; Malaria, Falciparum; MAP Kinase Signaling System; Merozoites; Microvessels; p38 Mitogen-Activated Protein Kinases; Plasmodium falciparum; Protein C; Recombinant Proteins; Skin; src-Family Kinases

The role of proinflammatory cytokine production in the pathogenesis of malaria is well established, but the identification of the parasite products that initiate inflammation is not complete. Hemozoin is a crystalline metabolite of hemoglobin digestion that is released during malaria infection. In the present study, we characterized the immunostimulatory activity of pure synthetic hemozoin (sHz) in vitro and in vivo. Stimulation of naive murine macrophages with sHz results in the MyD88-independent activation of NF-kappaB and ERK, as well as the release of the chemokine MCP-1; these responses are augmented by IFN-gamma. In macrophages prestimulated with IFN-gamma, sHz also results in a MyD88-dependent release of TNF-alpha. Endothelial cells, which encounter hemozoin after schizont rupture, respond to sHz by releasing IL-6 and the chemokines MCP-1 and IL-8. In vivo, the introduction of sHz into the peritoneal cavity produces an inflammatory response characterized by neutrophil recruitment and the production of MCP-1, KC, IL-6, IL-1alpha, and IL-1beta. MCP-1 and KC are produced independently of MyD88, TLR2/4 and TLR9, and components of the inflammasome; however, neutrophil recruitment, the localized production of IL-1beta, and the increase in circulating IL-6 require MyD88 signaling, the IL-1R pathway, and the inflammasome components ICE (IL-1beta-converting enzyme), ASC (apoptosis-associated, speck-like protein containing CARD), and NALP3. Of note, inflammasome activation by sHz is reduced by allopurinol, which is an inhibitor of uric acid synthesis. These data suggest that uric acid is released during malaria infection and may serve to augment the initial host response to hemozoin via activation of the NALP3 inflammasome.

Topics: Allopurinol; Animals; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Carrier Proteins; Chemokine CCL2; Chemokine CXCL1; Cytoskeletal Proteins; Endothelial Cells; Extracellular Signal-Regulated MAP Kinases; Hemeproteins; Inflammation; Interferon-gamma; Interleukin-1alpha; Interleukin-1beta; Interleukin-6; Interleukin-8; Macrophages; Malaria, Falciparum; Mice; Myeloid Differentiation Factor 88; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Plasmodium falciparum; Signal Transduction; Toll-Like Receptors; Tumor Necrosis Factor-alpha; Uric Acid

Macrophage migration inhibitory factor (MIF) has recently been implicated in the pathogenesis of malarial anaemia. However, field studies have reported contradictory results on circulating MIF concentrations in patients with clinically overt Plasmodium falciparum malaria. We determined plasma MIF levels over time in 10 healthy volunteers during experimental P. falciparum infection. Under fully controlled conditions, MIF levels decreased significantly during early blood-stage infection and reached a nadir at day 8 post-infection. A decrease in the number of circulating lymphocytes, which are an important source of MIF production, paralleled the decrease in MIF levels. Monocyte/macrophage counts remained unchanged. At MIF nadir, the anti-inflammatory cytokine interleukin (IL)-10, which is an inhibitor of T-cell MIF production, was detectable in only 2 of 10 volunteers. Plasma concentrations of the pro-inflammatory cytokines IL-8 and IL-1beta were only marginally elevated. We conclude that circulating MIF levels decrease early in blood-stage malaria as a result of the decline in circulating lymphocytes.

Topics: Adolescent; Adult; Animals; Female; Humans; Interleukin-10; Interleukin-1beta; Interleukin-8; Lymphocyte Count; Lymphocytes; Macrophage Migration-Inhibitory Factors; Macrophages; Malaria, Falciparum; Male; Monocytes; Plasmodium falciparum; Time Factors

Inflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparum malaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P = <0.001), IL-10 (1,099.3 versus 14.1; P = <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P = <0.001), and IL-12(p70) (48.9 versus 31.3; P = 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P = <0.001) and IL-10 (1,099.3 versus 133.9; P = <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P = <0.001) and IL-10 (1,405.6 versus 868.6; P = 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P = 0.03) and IL-10 (391.1 versus 1,160.9; P = 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P = 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparum malaria.

Topics: Adolescent; Aging; Case-Control Studies; Child; Child, Preschool; Cytokines; Female; Health; Humans; Infant; Inflammation Mediators; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-6; Interleukin-8; Malaria, Falciparum; Male; Mali; Tumor Necrosis Factor-alpha

The Plasmodium falciparum translationally controlled tumor protein (TCTP) is a homolog of the mammalian histamine-releasing factor (HRF), which causes histamine release from human basophils and IL-8 secretion from eosinophils. Histamine, IL-8, and eosinophils have been reported to be elevated in patients with malaria. This study was undertaken to determine whether malarial TCTP is found in the plasma of malaria-infected patients and to determine whether it has HRF biologic activity. Malarial TCTP was found in lightly infected human volunteers and in heavily infected Malawian children, but not in uninfected patients. Recombinant malarial TCTP, like HRF, stimulated histamine release from basophils and IL-8 secretion from eosinophils in vitro. Whereas malarial TCTP was less active than HRF, the concentrations that were effective in vitro could be achievable in vivo. These data suggest that malarial TCTP, present in human plasma during a malarial illness, may affect host immune responses in vivo.

Topics: Adult; Animals; Basophils; Biomarkers, Tumor; Cells, Cultured; Child; Child, Preschool; Culture Media; Eosinophils; Erythrocytes; Histamine; Humans; Infant; Interleukin-8; Lymphokines; Malaria, Falciparum; Molecular Mimicry; Plasmodium falciparum; Tumor Protein, Translationally-Controlled 1

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.

Topics: Adolescent; Adult; Aged; Animals; Antimalarials; Area Under Curve; Artemisinins; Artesunate; Female; Humans; Immunoassay; Immunoglobulin Fab Fragments; Intercellular Adhesion Molecule-1; Interferon-gamma; Interleukin-1; Interleukin-2; Interleukin-6; Interleukin-8; Kinetics; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Parasitemia; Pilot Projects; Plasmodium falciparum; Sesquiterpenes; Tumor Necrosis Factor-alpha

Cytokine regulation was compared in three groups of Gabonese patients with Plasmodium falciparum malaria before and after therapy; adults with uncomplicated malaria, children with uncomplicated malaria, and children with severe malaria. Plasma levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-8, TNF receptors (TNF R), and the TNF/TNF R ratios were significantly higher in severe malaria compared with uncomplicated malaria. High plasma levels of all immunoregulatory molecules were associated with slow cure after therapy. In all patients, phytohemagglutinin-induced cytokine production was depressed on admission compared with convalescence. A significant difference was the higher TNF production capacity in patients with severe malaria on day 2 and day 5 compared with that in patients with uncomplicated malaria. In contrast to IL-6 and IL-8, a high TNF production capacity during the acute phase of malaria predicted a rapid clinical and parasitologic cure in the patients. These findings illustrate the dual role of TNF in the protection and pathology of malaria.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Interleukin-6; Interleukin-8; Leukocytes; Lymphocyte Activation; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Phytohemagglutinins; Receptors, Tumor Necrosis Factor; Treatment Outcome; Tumor Necrosis Factor-alpha

The chemokines are a superfamily of small proteins secreted primarily by leukocytes and related by a conserved four-cystein motif. In the present study we investigated the serum levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) and interleukin-8 (IL-8). MIP-1 alpha is a neutrophil chemotactic protein important in acute and chronic inflammation. Recent studies demonstrated that MIP-1 alpha may also act as potent inhibitor of hemopoetic stem cell proliferation, which may be important in the development of prolonged anemia in patients suffering from Plasmodium falciparum malaria. IL-8 serum concentrations correlate with severity and outcome of infectious diseases. Moreover, recent reports indicate that IL-8 plays a major role in fatal gram-negative sepsis. It was the aim of this study to investigate the time course of MIP-1 alpha and IL-8 concentrations in patients suffering from acute P. falciparum infection. Blood samples of 20 patients suffering from severe P. falciparum malaria were investigated. MIP-1 alpha and IL-8 concentrations were determined using ELISA technique at admission, on Days 7, 14, 21, and 28. Maximal concentrations of MIP-1 alpha and IL-8 were found on Day 14, at a time when parasites were not detected in the smears. The serum levels of IL-8 on the day of admission were correlated to the parasite count. No correlation was seen between the hematokrit values and the MIP-1 alpha concentrations at any time.

Topics: Adolescent; Adult; Aged; Anemia; Artemisinins; Artesunate; Blood; Body Temperature; Chemokine CCL3; Chemokine CCL4; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Hematocrit; Humans; Interleukin-8; Macrophage Inflammatory Proteins; Malaria, Falciparum; Male; Middle Aged; Monokines; Sesquiterpenes; Thailand