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

Many microbial coinfections accelerate the progression of human immunodeficiency virus (HIV) disease. Coinfections of Plasmodium falciparum malaria and HIV-1 are common; however, past studies of the effects of P. falciparum malaria on HIV-1 infection have shown little effect. The present study found that P. falciparum antigens (PF-Ags) variably regulate the expression of HIV-1 coreceptors and modulate the infectability of CD4 cells by HIV-1. Shortly after PF-Ag stimulation, CCR5 expression was down-regulated, but CXCR4 expression was modestly up-regulated. Subsequently, CCR5 expression on CD4 cells was induced. Infectability of PF-Ag-stimulated peripheral blood mononuclear cells (PBMC) by R5 HIV-1 was decreased, regardless of the duration of PF-Ag stimulation or CCR5 expression levels. In contrast, X4 HIV-1 replication was enhanced briefly in PBMC stimulated with PF-Ags but was inhibited with longer stimulation. Decreased HIV-1 infectability resulted, in part, from endogenous production of interferon-gamma. These results may explain why malaria previously did not appear to accelerate HIV-1 disease progression.
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PMID:Dichotomous effects of Plasmodium falciparum antigens on expression of human immunodeficiency virus (HIV) coreceptors and on infectability of CD4 cells by HIV. 1235 76

Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA infection involves T lymphocytes. However, the mechanisms of T cell-mediated pathogenesis remain unknown. We found that, in contrast to ECM-susceptible C57BL6 mice, perforin-deficient (PFP-KO) mice were resistant to ECM in the absence of brain lesions, whereas cytoadherence of parasitized erythrocytes and massive accumulation of activated/effector CD8 lymphocytes were observed in both groups of mice. ECM is induced in PFP-KO mice after adoptive transfer of cytotoxic CD8+ cells from infected C57BL6 mice, which were directed to the brain of PFP-KO mice. This specific recruitment might involve chemokine/chemokine receptors, since their expression was up-regulated on activated CD8 cells, and susceptibility to ECM was delayed in CCR5-KO mice. Thus, lymphocyte cytotoxicity and cell trafficking are key players in ECM pathogenesis.
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PMID:Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. 1257 96

During malaria infection, high levels of proinflammatory molecules (e.g., cytokines, chemokines) correlate with disease severity. Even if their role as activators of the host immune response has been studied, the direct contribution of hemozoin (HZ), a parasite metabolite, to such a strong induction is not fully understood. Previous in vitro studies demonstrated that both Plasmodium falciparum HZ and synthetic HZ (sHZ), beta-hematin, induce macrophage/monocyte chemokine and proinflammatory cytokine secretion. In the present study, we investigated the proinflammatory properties of sHZ in vivo. To this end, increasing doses of sHZ were injected either i.v. or into an air pouch generated on the dorsum of BALB/c mice over a 24-h period. Our results showed that sHZ is a strong modulator of leukocyte recruitment and more specifically of neutrophil and monocyte populations. In addition, evaluation of chemokine and cytokine mRNA and protein expression revealed that sHZ induces the expression of chemokines, macrophage-inflammatory protein (MIP)-1alpha/CCL3, MIP-1beta/CCL4, MIP-2/CXCL2, and monocyte chemoattractant protein-1/CCL2; chemokine receptors, CCR1, CCR2, CCR5, CXCR2, and CXCR4; cytokines, IL-1beta and IL-6; and myeloid-related proteins, S100A8, S100A9, and S100A8/A9, in the air pouch exudates. Of interest, chemokine and cytokine mRNA up-regulation were also detected in the liver of i.v. sHZ-injected mice. In conclusion, our study demonstrates that sHZ is a potent proinflammatory agent in vivo, which could contribute to the immunopathology related to malaria.
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PMID:Hemozoin-inducible proinflammatory events in vivo: potential role in malaria infection. 1497 16

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.
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PMID:Regulatory polymorphisms underlying complex disease traits. 1559 5

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

To examine the hormonal and immunological mechanisms that mediate sex differences in susceptibility to malaria infection, intact and gonadectomized (gdx) C57BL/6 mice were inoculated with Plasmodium chabaudi AS-infected erythrocytes, and the responses to infection were monitored. In addition to reduced mortality, intact females recovered from infection-induced weigh loss and anemia faster than intact males. Expression microarrays and real-time reverse transcription-PCR revealed that gonadally intact females exhibited higher expression of interleukin-10 (IL-10), IL-15Ralpha, IL-12Rbeta, Gadd45gamma, gamma interferon (IFN-gamma), CCL3, CXCL10, CCR5, and several IFN-inducible genes in white blood cells and produced more IFN-gamma than did intact males and gdx females, with these differences being most pronounced during peak parasitemia. Intact females also had higher anti-P. chabaudi immunoglobulin G (IgG) and IgG1 responses than either intact males or gdx females. To further examine the effector mechanisms mediating sex differences in response to P. chabaudi infection, responses to infection were compared among male and female wild-type (WT), T-cell-deficient (TCRbetadelta-/-), B-cell-deficient (microMT), combined T- and B-cell-deficient (RAG1), and IFN-gamma knockout (IFN-gamma-/-) mice. Males were 3.5 times more likely to die from malaria infection than females, with these differences being most pronounced among TCRbetadelta-/-, microMT, and RAG1 mice. Male mice also exhibited more severe weight loss, anemia, and hypothermia, and higher peak parasitemia than females during infection, with WT, RAG1, TCRbetadelta-/-, and microMT mice exhibiting the most pronounced sexual dimorphism. The absence of IFN-gamma reduced the sex difference in mortality and was more detrimental to females than males. These data suggest that differential transcription and translation of IFN-gamma, that is influenced by estrogens, may mediate sex differences in response to malaria.
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PMID:Involvement of gonadal steroids and gamma interferon in sex differences in response to blood-stage malaria infection. 1671 46

In a cross-sectional study, monocyte subsets in placental, cord, and maternal peripheral blood from pregnant Malawian women with human immunodeficiency virus (HIV)-1 infection and/or malaria were analyzed. HIV-uninfected Malawian women had higher baseline proportions of CD16(+) monocytes than those reported for healthy adults in developed countries. Malaria was associated with an increase in the proportion of CD16(+) monocytes that was significant in women coinfected with HIV-1. CD16(+) monocytes expressed higher CCR5 levels than did CD14(hi)/CD16(-) monocytes and were significantly more likely to harbor HIV-1. These data suggest a role for CD16(+) monocytes in the pathogenesis of maternal malaria and HIV-1 infections.
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PMID:CD16+ monocyte subset preferentially harbors HIV-1 and is expanded in pregnant Malawian women with Plasmodium falciparum malaria and HIV-1 infection. 1753 81

Tyrosine sulfation is one of the most common post-translational modifications in secreted and transmembrane proteins and a key modulator of extracellular protein-protein interactions. Several proteins known to be tyrosine sulfated play important roles in physiological processes, and in some cases a direct link between protein function and tyrosine sulfation has been established. In blood coagulation, tyrosine sulfation of factor VIII is required for efficient binding of von Willebrand factor; in leukocyte adhesion, tyrosine sulfation of the P-selectin glycoprotein ligand-1 mediates high-affinity binding to P-selectin; and in leukocyte chemotaxis, tyrosine sulfation of chemokine receptors is required for optimal interaction with chemokine ligands. Furthermore, tyrosine sulfation has been implicated in several infectious diseases. In particular, tyrosine sulfation of the HIV-1 co-receptor CCR5 is required for viral entry into host cells and tyrosine sulfation of the Duffy antigen/receptor for chemokines is crucial for erythrocyte invasion by the malaria parasite plasmodium vivax. Despite increasing interest in tyrosine sulfation in recent years, the sulfoproteome still remains largely unexplored. To date, only a relatively small number of sulfotyrosine-containing peptides and proteins have been identified, and a specific role for tyrosine sulfation has not been established for most of these. Here, we provide an overview of the biology and enzymology of tyrosine sulfation and discuss recent developments in preparative and analytical methods that are central to sulfoproteome research.
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PMID:Toward a framework for sulfoproteomics: Synthesis and characterization of sulfotyrosine-containing peptides. 1768 Jul 2

Previous studies have shown that IFN-gamma is essential for the pathogenesis of cerebral malaria (CM) induced by Plasmodium berghei ANKA (PbA) in mice. However, the exact role of IFN-gamma in the pathway (s) leading to CM has not yet been described. Here, we used 129P2Sv/ev mice which develop CM between 7 and 14 days post-infection with PbA. In this strain, both CD4(+) and CD8(+) T cells were involved in the effector phase of CM. When 129P2Sv/ev mice deficient in the IFN-gamma receptor alpha chain (IFN-gammaR1) were infected with PbA, CM did not occur. Migration of leucocytes to the brain at the time of CM was observed in wild type (WT) but not in deficient mice. However, in the latter, there was an accumulation of T cells in the lungs. Analysis of chemokines and their receptors in WT and in deficient mice revealed a complex, organ-specific pattern of expression. Up-regulation of RANTES/CCL5, IP-10/CCL3 and CCR2 was associated with leucocyte migration to the brain and increased expression of MCP-1/CCL2, IP-10/CCL3 and CCR5 with leucocyte migration to the lung. This shows that IFN-gamma controls trafficking of pathogenic T cells in the brain, thus providing an explanation for the organ-specific pathology induced by PbA infection.
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PMID:Control of pathogenic CD8+ T cell migration to the brain by IFN-gamma during experimental cerebral malaria. 1866 3

A genetic contribution to infectious disease in human populations has long been suspected and is now supported by more than 50 years of epidemiological evidence showing, for example, infection rates to be much higher than disease rates. In successful family studies of high-penetrance effects, single gene mutations have been identified that reveal a molecular mechanism leading to increased risk of a specific infectious disease. However, in population-based studies, genetic variants conferring host susceptibility to various infectious diseases have been difficult to uncover. Although mutations such as that in the CCR5 gene, which confers protection against HIV infection, have been reliably discovered, polymorphisms affecting larger proportions of a population have been hard to prove definitively. The recent arrival of the genome-wide association study format, currently being applied to Kawasaki disease, tuberculosis, malaria, HIV, dengue and others, gives us hope that these challenges can finally be met, with implications for population-based treatment and prognosis strategies.
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PMID:Genome-wide association studies are coming for human infectious diseases. 1934 90


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