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

There is now accumulating evidence for the involvement of genetic factors in the control of immune response against malaria. These arguments come from numerous animal models, from population studies showing associations of red blood cell genetic defects as well as HLA antigens with severe malaria, and from familial studies including a recent segregation analysis, which led to detection of a major gene effect predisposing to high infection levels. The heterogeneity and complexity of this genetic control is one of the main findings of these previous studies, and probably a major cause of the difficulty in developing an effective malaria vaccine. A segregation analysis of blood infection levels is performed here in 44 pedigrees living in the tropical rain forest of southern Cameroon and exposed to high vectorial transmission intensity. The results confirm the existence of complex genetic factors controlling blood infection levels in human malaria but are not consistent with the parent-offspring transmission of a single Mendelian gene. This study also shows the dramatic effect of age on infection levels and its interaction with a putative major gene suggesting that genetic related differences are much more important in children than in adults. Further genetic studies focused on children may help to identify the nature of the genetic factors involved in the expression of human malaria, by means of linkage analyses using both familial information and genetic markers.
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PMID:Genetic control of blood infection levels in human malaria: evidence for a complex genetic model. 957 96

Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious disease in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility ot HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the gamma-interferon receptor lead to increased susceptibility to typical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.
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PMID:The immunogenetics of human infectious diseases. 959 43

There is accumulating evidence for the involvement of genetic factors in the human response to malaria infection, mostly based on results obtained in studies of severe clinical malaria. The role of major gene(s) controlling blood parasitemia levels in human malaria has also been detected by means of segregation analysis. To confirm and to localize such gene(s), we performed a sib-pair linkage analysis investigating the role of five candidate chromosomal regions: 6p21 (HLA-tumor necrosis factor region), 2q13-q21 (genes coding for interleukin-1 alpha and beta), 14q11 (locus coding for the alpha chain of T cell antigen receptor), 7q35 (gene cluster for the beta subunit of T cell receptor), and 5q31-q33, which includes several candidate genes and was recently linked to a locus controlling infection levels by Schistosoma mansoni, denoted as SM1. The analysis was carried out on nine families from a southern Cameroon village, and the phenotype under study was blood infection levels with Plasmodium falciparum. No linkage was found with any of the four markers outside the 5q31-q33 region. A trend in favor of linkage was observed in the distal part of the 5q31-q33 region, especially with the marker D5S636 (P < 0.05 using the Monte Carlo P value), which was the marker that provided the highest evidence for linkage with SM1. These results suggest that a locus influencing P. falciparum levels in malaria could be located in the same genetic region as that containing SM1, indicating that the 5q31-q33 region may be critical in the control of different parasite infections.
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PMID:Linkage analysis of blood Plasmodium falciparum levels: interest of the 5q31-q33 chromosome region. 966 Apr 49

The molecular events controlling sporozoite invasion and exo-erythrocytic (EE) development within hepatocytes are largely not understood, and EE parasites are probably better defined immunologically than biologically. The observation that the Plasmodium falciparum sporozoite antigen TRAP (thrombospondin-related anonymous protein) contains multiple adhesive domains that recognize endothelial and hepatocyte receptors indicates that, like leucocyte passage across capillaries, sporozoite invasion probably involves a co-ordinated interaction between sporozoite and hepatic molecules. The parallel with leucocyte extravasation is strengthened by the finding that TRAP contains a functional, integrin-like, I domain. EE parasites are an important target of immunity elicited by irradiated sporozoites, and much current effort is focused on developing malaria vaccines targeting EE parasites. Only one EE-specific antigen, liver-stage antigen 1 (LSA-1), is known to be expressed during EE development and may contribute to protective immunity elicited by irradiated P. falciparum sporozoites. In a study in Papua New Guinea, resistance to P. falciparum infection correlated with CD8+ T-cell interferon-gamma responses to an LSA-1 epitope that contains an HLA A11-restricted sequence. Since A11 is > 40% frequent in this population it is reasonable to suggest that, as with B53 responses to LSA-1 in The Gambia, P. falciparum has driven genetic selection of certain HLA haplotypes, as proposed by Haldane nearly 50 years ago. LSA-1 is thus an important vaccine candidate, and is being expressed in bacterial and phage vectors.
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PMID:Biology of malarial liver stages: implications for vaccine design. 968 93

Experimental evidence implicates tumor necrosis factor (TNF) in the pathogenesis of malarial anemia, but there are few data relating to this hypothesis. This study found that severely anemic children with Plasmodium falciparum infection have low plasma TNF levels, in contrast to the high levels found in cerebral malaria. A previous case-control study in The Gambia found cerebral malaria, but not severe malarial anemia, was associated with the TNF-308 A allele. This study found that in the same population, severe malarial anemia was associated with the TNF-238 A allele, with an odds ratio of 2.5 (P<.001) after stratification for HLA type. These findings suggest that severe malarial anemia and cerebral malaria are influenced by separate genetic factors situated near the TNF gene.
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PMID:Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. 984 57

The desirability of inducing cytotoxic T cell responses to defined epitopes in humans has led to the development of a variety of recombinant delivery systems. Recombinant protein particles derived from a yeast retrotransposon (Ty) and the modified Ankara vaccinia (MVA) virus can deliver large epitope strings or even whole proteins. Both have previously been administered safely in humans. Immunization with recombinant Ty and MVA containing a single Plasmodium berghei class I-binding epitope provided 95% sterile protection against malaria in mice. The sequence of immunization, Ty followed by MVA, was critical to elicit high levels of IFN-gamma-producing cells and protection. The reciprocal sequence (MVA/TY) or homologous boosting was not protective. Both constructs (Ty and MVA) contain the H-2Kd-restricted pb9 CTL epitope from the circumsporozoite protein of P. berghei among a string of 8-15 human P. falciparum-derived CTL epitopes restricted through 7 common HLA alleles as well as widely recognized CD4 T cell epitopes. Thus, the novel recombinant Ty/MVA prime/boost combination with these constructs provides a safe alternative for evaluation for human vaccination against P. falciparum malaria.
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PMID:Protection from Plasmodium berghei infection by priming and boosting T cells to a single class I-restricted epitope with recombinant carriers suitable for human use. 986 71

HLA-B*3910, which has only been found in African and African American individuals, differs from B*3901 by the single amino acid change of Cys67 to Tyr67. Sequence analysis of the B*3910-bound peptide pool and of several individual ligands revealed that this subtype has strong preference for peptides with Pro2. This is in contrast with the preference of B*3901 for peptides with basic residues (Arg and His) at this position, and indicates that the single amino acid substitution between B*3910 and B*3901 totally changes the repertoire of bound peptides. This is presumably due to the significant decrease in the size of the B pocket, and to its increased hydrophobicity, since Tyr67 takes part in this pocket. B*3910 is similar to various other class I proteins in its preference for peptides with Pro2 and nonpolar C-terminal residues, including HLA-B53, an antigen associated with protection against severe malaria. The role of these two motifs as major peptidic anchors suggests that B*3910 and HLA-B53 may bind common peptides.
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PMID:A single amino acid change makes the peptide specificity of B*3910 unrelated to B*3901 and closer to a group of HLA-B proteins including the malaria-protecting allotype HLA-B53. 986 30

The hypothesis of a possible selective role of malaria in HLA allele frequency variations was investigated in Sardinia by typing completely 1,039 individuals for HLA: 536 from six lowland villages exposed to malaria until 1948, and 503 from six highland villages with no history of malaria. Another 1,928 individuals from 136 villages scattered all over the island were studied to establish if the HLA allele frequencies among villages correlated with the malaria incidence and/or altitude above sea level. Only the HLA-B35 allele yielded significantly higher frequencies in the lowland versus the highland villages (P<1 x 10(-5)). The observed B35 variance was 9.5 times higher than expected in the absence of selection, showing an adaptive origin. The highly significant positive correlation found between HLA-B35 frequency and malaria in 136 villages suggests that malaria has been the selective factor for HLA-B35 in Sardinia.
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PMID:HLA-B35 frequency variations correlate with malaria infection in Sardinia. 986 35

Genetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.
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PMID:A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. 1036 45

Since the identification, in 1954, of the first gene associated with resistance to Plasmodium falciparum, several genes, some of them being implicated in the regulation of the immune response, have been described as possible influences on cerebral pathology. This pathology depends primarily on the capacity of infected red blood cells to adhere to the endothelia of micro-vessels, leading to their occlusion. The major players of cerebral malaria potentially include: receptors expressed on the surface of the endothelial cell and known to interact with infected red blood cells, cytokines modulating the expression of these adhesion molecules, nitric oxide (NO) and Fc epsilon RII/CD23. Cells other than infected red blood cells, such as platelets, monocytes and lymphocytes, have the ability to adhere to these endothelial receptors and to one another, via different ligands, leading to a more complex situation and an increase in the degree of vessel occlusion. The polymorphism of all these molecules, implicated either in adhesion, in modulation of this adhesion or activation of the expression of diverse endothelial mediators should be an important field of study. Polymorphism of five of these molecules has been explored so far: ICAM-1, TNF-alpha, IL-1 beta, iNOS2 (inducible NOS) and CR-1 (complement receptor-1). To these studies, can be added those concerning mannose binding protein (MBP), a protein playing a role in innate immunity, and the class-I antigen HLA-B53. To date the only clear-cut result concerns TNF-alpha. With the other polymorphisms, either no association is found (IL-1RA, CR-1, MBP), or results are geographically heterogeneous (ICAM-1, HLA-B53), or contradictory (iNOS2). Most often, the approach followed has been the candidate gene approach, as part of case control studies. One of the main problems in this approach is the difficulty of establishing the control cohort. This difficulty disappears in family studies, which include their own controls. So far, the only results based on complex segregation analysis have been focused on parasite multiplication and not on cerebral malaria.
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PMID:[Immunogenetics and cerebral malaria]. 1057 60


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