Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-gamma receptor (IFN-gamma R) deficient mice parasitized with blood-stage Plasmodium chabaudi chabaudi were used to assess the anti-malarial activity of interferon-gamma (IFN-gamma). There was no significant difference in the parasitaemia between the two types of mice during the first peak of parasitaemia. However, IFN-gamma R deficient mice displayed an increased leucocytosis and a high mortality rate, whereas all of the wild type mice survived. IFN-gamma R deficient mice, unlike wild type mice, developed a pronounced second parasitaemia peak, 9 to 11 days after the first one, with a parasitaemia of up to 65% associated with mortality. Furthermore, increased serum levels of nitric oxide (NO) were only found in wild type mice at the peak of parasitaemia, whereas it remained at background levels in IFN-gamma R deficient mice. Parasite-specific antibody production was not significantly different in IFN-gamma R deficient mice, as compared to wild type mice. In addition, both wild type and IFN-gamma R deficient mice were equally protected upon reinfection. These results indicate a delayed development of protective immunity and imply a crucial function for the IFN-gamma R in the control of blood stage malaria during the initial three weeks of infection.
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PMID:The course of Plasmodium chabaudi chabaudi infections in interferon-gamma receptor deficient mice. 929 96

A fundamental question for the intensivist is why some individuals but not others succumb to life-threatening infection. A growing body of evidence indicates that both the risk of acquiring infection and the risk of developing severe complications are determined by host genetic factors. These include a number of single gene defects with devastating consequences, e. g. interferon-gamma receptor mutations that lead to fatal infections with ubiquitous mycobacteria, but such examples are relatively rare. Of greater importance for routine clinical practice is the potentially vast number of genetic variants with subtle effects on the regulation or function of specific immunological, physiological and metabolic mediators. Such polygenic traits do not obey simple patterns of familial segregation seen for monogenic disorders, and their clinical investigation is further complicated by the environmental variability of infectious exposure. Recent advances in this field have therefore largely stemmed from hospital-based case-controlled studies that have uncovered disease associations with specific DNA polymorphisms in candidate gene regions. For example, tumour necrosis factor polymorphisms have been associated with susceptibility to malaria and other infections; chemokine receptor polymorphisms with susceptibility to HIV; natural resistance-associated macrophage protein 1 with tuberculosis; and mannose binding lectin polymorphisms with meningococcal disease. A much greater number of genetic associations will emerge as the full extent of human genomic diversity becomes known. The challenge for clinical investigators is to generate an epidemiological framework for population- and family-based association studies, which is sufficiently robust to exclude population artifacts and sufficiently powerful to be able to dissect true disease-causing polymorphisms from linked genetic markers. In the long term this approach promises to identify host mediators that are critical for pathogenesis and immunity and to yield molecular insights into the complex processes of human gene regulation. This information is likely to be of considerable value in designing more effective approaches to the treatment and prevention of life-threatening infectious disease.
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PMID:Genetic dissection of the molecular pathogenesis of severe infection. 1078 64

We analyzed a single nucleotide polymorphism (SNP) at position -56 (T-->C) in the promoter region of the gene encoding the human interferon-gamma receptor ligand-binding chain I (IFN-gammaR1). The mutation was present at similar frequencies in Gabonese children with either mild or severe malaria. Functional investigations of the promoter in a transfected human B-cell line showed lower levels of luciferase reporter gene expression in the presence of the mutation, indicating the importance of this position for promoter activity, and suggesting that this SNP might negatively influence the expression level of IFN-gammaR1 at the cell surface. Further examinations of the DNA sequence at this polymorphic site showed a perfectly matched binding site for the transcription factor activator protein 4 (AP-4) on both strands. Binding sites for other important transcription factors involved in gene expression and regulation of the immune response against infections, including Ikaros 2 (Ik-2), nuclear factor kappaB (NFkappaB), and CETS1p54, are also situated in this region.
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PMID:Functional analysis of a promoter variant of the gene encoding the interferon-gamma receptor chain I. 1255 53

We report evidence of a polymorphism in the promoter region of IFNGR1 (encoding interferon-gamma receptor 1) that has opposite functional effects in different cellular contexts. It is a deletion/insertion polymorphism that is found in Africans but not Europeans or Asians, and has been associated with resistance to severe malaria. We find that the IFNGR1-470del allele acts to suppress binding of nuclear proteins to the IFNGR1 promoter region in a manner that is specific for cell type. In B-lymphocytes, the IFNGR1-470del allele suppresses the binding of a approximately 35 kDa nuclear protein and acts to increase reporter gene expression. In epithelial cells, the same allele acts to decrease gene expression and suppresses the binding of approximately 90 kDa STAT-1 and STAT-2 proteins. In T-lymphocytes, this allele causes only subtle differences in nuclear protein binding and has no significant effect on gene expression. These findings suggest a mechanism by which a single genetic variant may cause a broad range of phenotypic consequences.
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PMID:Context-specific functional effects of IFNGR1 promoter polymorphism. 1660 Sep 93

Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.
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PMID:Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. 1770 79