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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SUMMARY Disruption of the lymphotoxin beta receptor (LTbetaR) gene has been shown to result in enhanced resistance of female mice to blood-stage Plasmodium chabaudi malaria. Here, we investigate the effect of LTbetaR deletion on host defence of males. In contrast to females, male LTbetaR(-/-) mice do not exhibit any increase in resistance. Conversely, they are even more susceptible than wild-type C57BL/6 mice, which becomes evident after lowering circulating levels of testosterone by castration, which makes C57BL/6 males resistant, whereas LTbetaR(-/-) remain susceptible. Gene-expression analysis using cDNA arrays revealed no differences in immunological responses in spleen of malaria-resistant female and malaria-susceptible castrated male LTbetaR(-/-) mice. In the liver, however, expression levels of plasminogen activator inhibitor PAI1, chemokine CXCL10, dual specificity phosphatase DUSP1, and hydroxysteroid-specific sulfotransferases Sult2a1/2 were decreased 6- to 85-fold in susceptible castrated male LTbetaR(-/-) mice in comparison to resistant female LTbetaR(-/-) mice at maximal parasitaemia, as evidenced by Northern blot analyses. The present data support our previous view that the liver is involved in the combat against malarial blood stages and that down-regulation of the genes DUSP1 and Sult2a1/2 signals dysregulation of protective liver responses, thus possibly contributing to male susceptibility of LTbetaR(-/-) mice.
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PMID:Deletion of LTbetaR augments male susceptibility to Plasmodium chabaudi. 1604 39

Cerebral malaria (CM), one of the most common fatal complications of the heterogenous syndrome named severe malaria, is indubitably a post-infectious neurovascular pathology, as evidenced by histopathological analyses. This neurological syndrome is characterised not only by the cytoadherence of Plasmodium falciparum-infected erythrocytes, but also by morphological and functional alterations of brain microvascular endothelial cells subsequent to their interactions with circulating cells, such as platelets, monocytes, lymphocytes, and dendritic cells. During CM, host cells, in particular immune cells, are found recruited and activated at the site of sequestration, where they release various soluble molecules. Among these, cytokines play a major role in CM pathogenesis. Indeed, cerebral complications appear to be due to an imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokines (notably interferon-gamma, tumour necrosis factor, lymphotoxin) and chemokine receptors (notably CCR5) are also responsible for blood-brain barrier alterations and biochemical changes leading to the brain parenchymal lesions that can be observed in CM. In return, glial cells can influence blood-borne elements, and thereby worsen the pathology. Numerous problems remain to be solved, especially the sequence of pathological events, namely the order in which the circulating cells sequester on the endothelial wall. A better understanding of the molecular mechanisms involved in CM pathogenesis is needed if we are capable of preventing cerebral complications and improving the quality of patient management.
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PMID:Cerebral malaria -- a neurovascular pathology with many riddles still to be solved. 1618 87

IFN-gamma secretion by natural killer (NK) cells is pivotal to several tumor and viral immune responses, during which NK and dendritic cells cooperation is required. We show here that macrophages are mandatory for NK cell IFN-gamma secretion in response to erythrocytes infected with Plasmodium falciparum (Pf), a causative agent of human malaria. In addition, direct sensing of Pf infection by NK cells induces their production of the proinflammatory chemokine CXCL8, without triggering their granule-mediated cytolytic programs. Despite their reported role in Pf recognition, Toll-like receptor (TLR) 2, TLR9, and TLR11 are individually dispensable for NK cell activation induced by Pf-infected erythrocytes. However, IL-18R expression on NK cells, IL-18 production by macrophages, and MyD88 on both cell types are essential components of this previously undescribed pathway of NK cell activation in response to a parasite infection.
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PMID:Natural killer cell and macrophage cooperation in MyD88-dependent innate responses to Plasmodium falciparum. 1620 71

Systemic disease, either genetic or acquired, may prevent or decrease the severity of another disease. These observations have led to important therapeutic advances. The best-known examples are Edward Jenner's use in 1798 of cowpox to prevent smallpox and J.B. Haldane's 1942 observation that erythrocyte disorders such as thalassemia and sickle cell disease modify the severity of malaria. Patients with and carriers of cystic fibrosis may have genetic resistance to tuberculosis and/or secretory diarrhea. The beneficial effects of undernutrition have led to therapeutic diets for seizures, celiac disease, type 2 diabetes, and inflammatory bowel disease. Finasteride for prostatic hypertrophy was developed after the observation that patients with male pseudohermaphrodism resulting from 5-alpha-reductase mutations do not develop prostatic hypertrophy. Rh immunoglobulin for Rh hemolytic disease prevention followed the observation that ABO incompatibility prevented Rh sensitization. The natural immunosuppression of measles may cause remission of nephrosis, and that of leprosy prevents psoriasis. Patients with one form of agammaglobulinemia (X-linked) never get Epstein-Barr virus infection, and patients with another form (common variable) are seemingly cured by HIV infection. HIV/AIDS is prevented or modified by co-receptor mutations (notably the CCRDelta32 chemokine mutation), HIV-2, or GB virus C infection. Additional exploration of these genetic, infectious, and metabolic influences on disease severity may provide new therapeutic approaches to HIV and other diseases.
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PMID:Disease versus disease: how one disease may ameliorate another. 1639 76

Changes of serum cytokines including interferon gamma inducible protein-10 (IP-10) chemokine were analyzed in a total of eight vivax malarial patients before and after chemotherapy by immunostaining for human cytokine antibodies attached to membranes. IP-10 was strongly reactive in the period before chloroquine/primaquine combined chemotherapy and disappeared after chemotherapy in all patients. Therefore, IP-10 chemokine may be of importance in the pathogenesis of vivax malaria and a good marker of a complete cure.
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PMID:Changes of serum cytokine profiles in Korean vivax malarial patients after chemotherapy. 1683

The pathogenesis of cerebral malaria from Plasmodium falciparum infection is thought to involve inflammation of the central nervous system. Since monocyte chemoattractant protein 1 (MCP-1) is a chemokine strongly involved in the inflammatory process, we here study MCP-1 gene polymorphisms in association with severe or cerebral malaria in Thailand. Malaria patients in the northwest of Thailand were grouped into mild (n=206), severe (165), and cerebral (110) malaria case groups. Five single nucleotide polymorphisms (SNPs) in the promoter (-2518A/G, -2348G/C, -2158C/T, -2076A/T, and -2072T/C), and 1 SNP in intron 1 (764C/G) were analyzed by PCR-RFLP, PCR-SSP, or direct sequencing. The SNP -2158 was a novel polymorphism found in this study. For all SNPs, genotype and allele frequencies were not significantly different between mild and severe or mild and cerebral malaria. Strong linkage disequilibrium was found among 4 SNPs (-2518A/G, -2348G/C, -2076A/T, and 764C/G), resulting in 4 major estimated haplotypes. The most common haplotype was GGAC. The results indicated that MCP-1 gene polymorphisms were not associated with malaria severity, implying that MCP-1 was not a cause of malaria severity in this Thai population.
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PMID:Monocyte chemoattractant protein 1 (MCP-1) gene polymorphism is not associated with severe and cerebral malaria in Thailand. 1693 42

Innate immune response against Plasmodium falciparum (Pf), a causative agent of human malaria, is the result of several thousand years of co-evolution between the parasite and his host. An early IFN-gamma production during infection is associated with a better evolution of the disease. Natural killer (NK) cells are among the first cells in peripheral blood to produce IFN-gamma in response to Pf-infected erythrocytes (Pf-E). NK cells are found in blood, in secondary lymphoid organs as well as in peripheral non-lymphoid tissues. They participate in host innate responses that occur upon viral and intracytoplasmic bacterial infections, but also during the course of tumor development and allogeneic transplantation. These lymphocytes are not only important players of innate effector responses, but also participate in the initiation and development of adaptive immune responses. In addition, direct sensing of Pf infection by NK cells induces their production of the proinflammatory chemokine IL-8, suggesting a role for NK cells in the recruitment and the activation of other cells during malaria infection. Several other cell subsets are involved in the innate immune response to Pf. Dendritic cells, macrophages, gamma delta T cells, NKT cells are able to sense the presence of the parasite. Along this line, the presence of IL-12 is necessary to NK cell IFN-gamma production and a functional cooperation takes place between macrophages and NK cells in the context of this parasitic infection. In particular, IL-18 produced by macrophages is a key factor for this NK response. However, the molecular basis of Pf-E recognition by NK cells as well as the functional role of NK cell responses during the course of the disease remain to be adressed.
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PMID:[NK cells and innate immunity to malaria]. 1696 49

Malaria infects 5-10% of humanity and causes around two million deaths annually, mostly in children. The disease is of significant interest to immunologists, as acquired host immunity can limit the clinical impact of infection and partially reduces parasite replication; however, immunological reactions also contribute significantly to pathogenesis and fatalities. This review addresses the view that immunopathology in severe malaria arises predominantly from intravascular lesions resulting from a pathogen-initiated cascade of activated immune effector and regulatory cells infiltrating the vascular beds of diverse target organs, including bone marrow, spleen, brain, placenta and lungs. The main feature distinguishing these processes from classical cellular inflammation is the absence of extravasation, resulting from the intravascular location of the pathogen. Clinical and epidemiological observations combined with experimental infections in animal models suggest that parasite 'molecular patterns' or toxins cause cytokine and chemokine enhancement of infiltrates, composed of macrophages, neutrophils, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells and both CD4(+) and CD8(+) effector T cells, leading to local vascular and organ derangement. Diverse pattern recognition and NK receptors crucially regulate these responding cell populations. Thus, innate immune mechanisms lie at the heart of this massive global public health problem.
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PMID:Intravascular infiltrates and organ-specific inflammation in malaria pathogenesis. 1734 7

NK cells are cytotoxic lymphocytes that also secrete regulatory cytokines and can therefore influence adaptive immune responses. NK cell function is largely controlled by genes present in a genomic region named the NK complex. It has been shown that the NK complex is a genetic determinant of murine cerebral malaria pathogenesis mediated by Plasmodium berghei ANKA. In this study, we show that NK cells are required for cerebral malaria disease induction and the control of parasitemia. NK cells were found infiltrating brains of cerebral malaria-affected mice. NK cell depletion resulted in inhibition of T cell recruitment to the brain of P. berghei-infected animals. NK cell-depleted mice displayed down-regulation of CXCR3 expression and a significant reduction of T cells migrating in response to IFN-gamma-inducible protein 10, indicating that this chemokine pathway plays an essential role in leukocyte trafficking leading to cerebral disease and fatalities.
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PMID:NK cells stimulate recruitment of CXCR3+ T cells to the brain during Plasmodium berghei-mediated cerebral malaria. 1744 62

Quinacrine (QC) is an anti-inflammatory drug that has been used for the treatment of malaria and rheumatoid diseases. The mechanism(s) underlying the anti-inflammatory activity of QC remains poorly understood. We recently reported the QC-mediated inhibition of the NF-kappaB pathway using an in vitro model. To test this potential mechanism in vivo, we used the contact hypersensitivity response (CHS) to chemical allergen sensitization and challenge in mice as a model of skin inflammation. The results indicated that QC treatment inhibited NF-kappaB activation in the skin during allergen sensitization. This inhibition was reflected by decreased mRNA expression and protein production of the NF-kappaB-dependent cytokines TNF-alpha and IL-1beta and the chemokine CCL21 in the skin. The decreases in these cytokines resulted in reduced migration of allergen-presenting dendritic cells from the skin into skin-draining lymph nodes and markedly decreased activation of effector CD8+ T cells for the CHS response to allergen challenge (inhibitory concentration 50% or IC50 was 55 mg/kg). These findings reveal a previously unrecognized mechanism of QC-mediated inhibition of inflammation.
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PMID:Quinacrine inhibits the epidermal dendritic cell migration initiating T cell-mediated skin inflammation. 1763 53


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