Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms of malaria parasite clearance in the host are not well understood, but are ascribed to the intact spleen, the site for parasite clearance. The infection induces a huge increase in spleen volume and cellularity. There is, however, a lack of studies on the splenic production of chemokines, which are small proteins that control homing and activation of immune cells and must be crucial for organized tissue growth. We studied the spleen cell production of SDF-1, a primordial chemokine of the CXCL12 class, through mRNA Reverse transcriptase and polymerase chain reaction of both isoforms, alpha and beta, in lethal (Plasmodium berghei ANKA) and non-lethal recrudescent malaria (Plasmodium chabaudi CR) in BALB/c and C57BL/6 mouse strains. In non-lethal P. chabaudi malaria in C57BL/6 mice, SDF-1alpha mRNA production clearly peaked before the control of parasitemia, a fact not observed in the same mouse strain infected with lethal P. berghei, when this production was lower and without peaks. The infection of BALB/c mice infected with the same Plasmodium species led to a similar evolution of parasitemia and also chemokine production, albeit at lower levels. SDF-1beta synthesis was more constant and regular during both infections, presenting some variation but usually occurring at all the experimental times. Supplementation of lethal models with SDF-1alpha i.p., at the time when endogenous stromal cell chemokine production peaked in non-lethal models, induced a clear reduction in parasitemia, probably with prolonged host survival. Blocking SDF-1 action by administration of T-140, a CXCR4 receptor blocker, caused an increase in circulating parasites in the usually benign non-lethal P. chabaudi malaria in C57BL/6 mice, mainly at recrudescence of parasitemia. These data suggest that SDF-1alpha production in the spleen plays an important role in rodent malaria, and its supplementation was found to partially correct defects in the control of malaria in lethal models.
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PMID:Stromal cell derived factor 1 synthesis by spleen cells in rodent malaria, and the effects of in vivo supplementation of SDF-1alpha and CXCR4 receptor blocker. 1205 54

The dynamics of gametocyte production in Plasmodium falciparum clones were studied in inhabitants of an area of highly seasonal malaria transmission in eastern Sudan. Reverse-transcriptase polymerase chain reaction was used to detect expression of 2 genes that encode gametocyte-specific proteins, pfs25 and pfg377, in parasites sampled from individuals throughout one year. Some patients who acquired infections during the wet season were found to harbor subpatent gametocytemia through the following dry season in the apparent absence of mosquito transmission. Genotyping of parasites in multiclonal infections showed considerable fluctuation of gametocyte production by individual clones. The gametocytes present at the end of the dry season provide the most probable source of the genetically complex cyclical malaria outbreaks following the rainy season in this region.
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PMID:Dynamics of gametocytes among Plasmodium falciparum clones in natural infections in an area of highly seasonal transmission. 1208 37

At the beginning of the 20th century malaria was a major problem of tropical medicine until eradication campaigns succeeded in reducing its occurrence. Its recent epidemic resurgence in Madagascar, Namibia, Sao Tome and Principe, and Sudan shows the vulnerability of populations. The World Health Organization estimates that 110 million cases of malaria occur annually, most of them in Africa (90 million cases in sub-Saharan Africa). 1-2 million people die because of malaria. The matter is complicated by the resistance of Plasmodium falciparum to chloroquine and other drugs. In some parts of the world the mosquitos have developed resistance to insecticides, which makes vector control more difficult. This serious situation prompted a ministerial conference on malaria in Amsterdam in 1992, which resulted in the declaration that the fight against malaria necessitates the participation of the community concerning water resources, sanitation, and general development. The transmission of AIDS is connected to sexuality having social, behavioral, and ethical aspects. The first cases occurred among hemophiliacs, homosexuals, and intravenous drug addicts. HIV-1 was identified in 1983 and HIV-2 in 1987. In June 1994 the number of AIDS cases were approximately 4 million in the world, more than 2.5 million of them in sub-Saharan Africa. In Mozambique, in June 1993, a total of 826 cases had been diagnosed. In the area of treatment, inverse transcriptase inhibitors and the use of azidothimidine (AZT) are promising, the latter having prevented maternal-fetal transmission during pregnancy and labor. The toxicity of AZT is a major drawback. There is hope that eventually a vaccine can be developed. WHO developed a global strategy for the prevention and fight against AIDS in 1985, which was revised and adopted in 1987 by the World Health Assembly. The strategy aims to prevent HIV infection, to reduce its social and individual impact, and to gather national and international forces.
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PMID:[Malaria and AIDS: the great genocides]. 1229 61

The human protein CD36 is a major receptor for Plasmodium falciparum-infected erythrocytes and contributes to the pathology of P. falciparum malaria. We performed variation screening of the CD36 gene and examined the possible association between CD36 polymorphisms and the severity of malaria in 475 adult Thai patients with P. falciparum malaria. Accordingly, we identified nine CD36 polymorphisms with a high-frequency (>15%) minor allele. Of these, the frequencies of the -14T-->C allele in the upstream promoter region and the -53G-->T allele in the downstream promoter region were significantly decreased in patients with cerebral malaria compared to those with mild malaria (P=.016 for -14T-->C and P=.050 for -53G-->T). The analysis of linkage disequilibrium (LD) between the nine common polymorphisms revealed that there are two blocks with strong LD in the CD36 gene and that the -14T-->C and -53G-->T polymorphisms are within the upstream block of 35 kb from the upstream promoter to exon 8. Further association testing after the second variation screening in the upstream block indicated that the in3(TG)(12) (i.e., 12 TG repeats in intron 3) allele is most strongly associated with the reduction in the risk of cerebral malaria (odds ratio 0.59; 95% confidence interval 0.40-0.87; P=.0069). We found, by reverse-transcriptase PCR amplification, that in3(TG)(12) is involved in the nonproduction of the variant CD36 transcript that lacks exons 4 and 5. Since exon 5 of the gene is known to encode the ligand-binding domain for P. falciparum-infected erythrocytes, in3(TG)(12) itself or a primary variant on the haplotype with in3(TG)(12) may be responsible for protection from cerebral malaria in Thailand. Results of the present study suggest that LD mapping has potential for detecting a disease-associated variant on the basis of haplotype blocks.
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PMID:CD36 polymorphism is associated with protection from cerebral malaria. 1250 36

The control of Plasmodium falciparum malaria by vaccination will require immunization with multiple parasite antigens effectively formulated in combination. In this regard, proteins expressed on the surface of blood-stage merozoites are attractive as vaccine targets given their functional importance in the invasion of erythrocytes and accessibility to serum antibodies. We have utilized a Plasmodium chabaudi vaccine model to begin to evaluate the efficacy of immunization with combined formulations of apical membrane antigen-1 (AMA-1) and merozoite surface protein-1 (MSP-1). Using a pET/T7 RNA polymerase bacterial expression system, we have expressed, purified and refolded recombinant antigens representing the 54 kDa ectodomain of Pc AMA-1 and the 42 kDa C-terminus of Pc MSP-1. Immunization with recombinant Pc AMA-1+Pc MSP-1(42) induced a high level of protection against P. chabaudi malaria with protective efficacy varying with antigen dose, choice of adjuvant, and immunization protocol. Based on the reduction of P. chabaudi parasitemia, Alum proved effective for use with the combination of Pc AMA-1 and Pc MSP-1(42). The use of Quil A was similarly effective with single or combined antigen immunizations, particularly with low antigen dose. In general, serological analysis of prechallenge sera indicated a dominant IgG1 response. For a given formulation, immunization with the combination of Pc AMA-1 and Pc MSP-1(42) elicited IgG responses comparable to those observed following immunization with each antigen alone. However, prechallenge antibody titers alone were not predictive of protective efficacy. While Pc AMA-1 and Pc MSP-1(42) can be effectively formulated in combination, further study is needed to define measurable parameters of protective T cell and B cell responses induced by Pc AMA-1+Pc MSP-1(42) that are predictive of vaccine efficacy.
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PMID:Immunization against Plasmodium chabaudi malaria using combined formulations of apical membrane antigen-1 and merozoite surface protein-1. 1270 68

Several observations suggest that bacteria induce autoimmunity in primary biliary cirrhosis (PBC). Since no PBC-specific bacterial species could be identified, it can be speculated that the triggers are non-species-specific bacterial proteins. This hypothesis would imply that several or even all bacterial species can trigger PBC. Therefore, we investigated whether PBC exhibits immune reactions to non-species-specific bacterial antigens. Yersinia enterocolitica O3 was screened for the presence of proteins that were labeled by immunoblotting using PBC sera. We focused our investigations on a 160-kDa protein, which was further enriched and characterized by partial N-terminal amino acid sequencing. The prevalence of antibodies to this protein was determined by immunoblotting in a variety of diseases. The 160-kDa protein was identified as the beta-subunit of bacterial RNA-polymerase, a highly conserved bacterial protein with a very high degree of sequence identity among all bacterial species. Antibodies to the beta-subunit of bacterial RNA polymerase were specific for this protein. Until now no mammalian protein could be found that cross-reacts with these antibodies. The prevalence of antibodies to the beta-subunit of bacterial RNA polymerase (ARPA) using the protein from Yersinia enterocolitica O3 (serum dilution 1:1000) was: healthy controls (HC, N = 101) 7.9%, primary biliary cirrhosis (PBC, N = 61) 32.8%, autoimmune hepatitis type 1 (AIH, N = 46) 26.1%, alcoholic liver cirrhosis (ALC, N = 44) 9.1%, Crohn's disease (CD, N = 38) 7.9%, ulcerative colitis (UC, N = 24) 8.3%, primary sclerosing cholangitis + UC (PSC/UC, N = 11) 0%, acute yersiniosis (Yers, N = 36) 19.4%, acute infection with Campylobacter jejuni (Camp, N = 10) 0%, acute Q-fever (QF, N = 16) 6.25%, chronic hepatitis C (HCV, N = 39) 7.7%, c-ANCA-positive vasculitis (Vasc, N = 40) 15%, systemic lupus erythematosus (SLE, N = 28) 10.7%, and malaria tropica (MT, N = 24) 16.7%. There was no significant difference between PBC and AIH. The group of autoimmune liver diseases (PBC + AIH, N = 107, 29.9%) differed highly significantly from HC, chronic inflammatory bowel diseases (CD + UC + PSC/UC, N = 73, 6.8%), ALC, and HCV and also differed significantly (P = 0.01) from the group with bacterial and parasitic diseases (Yers + Camp + QF + MT, N = 86,13.95%) and from the group with Vasc + SLE (N = 68,13.2%). Testing of ARPA using the protein from E. coli yielded nearly identical results. In conclusion, an increased prevalence of antibodies to the beta-subunit of bacterial RNA polymerase, a highly conserved non-species-specific bacterial protein, can be found in primary biliary cirrhosis, but also in autoimmune hepatitis type I. These findings do not add an argument for a bacterial trigger of PBC. Rather, they suggest that ARPA belong to the pool of natural antibodies that are up-regulated in autoimmune liver diseases.
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PMID:Identification of beta-subunit of bacterial RNA-polymerase--a non-species-specific bacterial protein--as target of antibodies in primary biliary cirrhosis. 1275 71

Introduction of double stranded RNA into invertebrate cells often results in posttranscriptional silencing of target genes through a mechanism termed RNA interference (RNAi). Double-stranded RNA is cleaved by an RNAse III-like enzyme, termed dicer, to small interfering RNAs (siRNAs). In Drosophila, these siRNAs are incorporated in the RNA induced silencing complex (RISC) and mediate degradation of target mRNA. The RISC complex contains members of Argonaute (Ago) family of proteins. We show here that RNAi in a hemocyte cell line of Anopheles gambiae, the principal malaria vector in Africa, requires expression of dicer-2, Ago2 and Ago3 proteins. Furthermore, we demonstrate that RNAi in the mosquito does not spread outside of the target region, suggesting that RNA dependent RNA polymerase mediated transitive amplification is absent in the mosquito.
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PMID:Characterization of RNA interference in an Anopheles gambiae cell line. 1291 86

Malaria in eastern Sudan is characterised by limited seasonal transmission, with the majority of the year remaining transmission-free. Some inhabitants who contract malaria during the transmission season retain long-lasting sub-patent infections, which probably initiate transmission the following year. Here we have monitored Plasmodium falciparum infection prevalence and gametocyte production during the dry season, and examined the impact of parasite genetic multiplicity on infection longevity. A cohort of 38 individuals who were infected with P. falciparum in November 2001 was monitored monthly by microscopy and PCR until December 2002. Reverse transcriptase polymerase chain reaction of the pfg377 gene was used to detect sub-patent gametocytes. In addition, all isolates were examined for msp-2 alleles and the mean number of parasite clones per infection was estimated. We found that a large proportion (40%) of the cohort retained gametocytes throughout the dry season. The majority of patients retained asexual infection for at least 7 months. Genetic multiplicity of P. falciparum significantly influenced longevity of asexual infection and its gametocyte production. Gametocytes from mixed genotype P. falciparum infections persisted three times longer than those from single genotype infections, suggesting that genetic diversity promotes persistence. These findings are discussed in the context of the parasite biology and malaria epidemiology in the study area.
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PMID:Impact of genetic complexity on longevity and gametocytogenesis of Plasmodium falciparum during the dry and transmission-free season of eastern Sudan. 1561 15

The recent identification of antisense RNA in the transcriptomes of many eukaryotes has generated enormous interest. The presence of antisense RNA in Plasmodium falciparum, the causative agent of severe malaria, remains controversial. Elucidation of the mechanism of antisense RNA in P. falciparum synthesis is critical in order to demonstrate the origin and function of these transcripts. Therefore, a systematic analysis of antisense and sense RNA synthesis was performed using direct labeling experiments. Nuclear run on experiments with single-stranded DNA probes demonstrated that antisense RNA is synthesized in the nucleus at several genomic loci. Antisense RNA synthesis is sensitive to the potent RNA polymerase II inhibitor alpha-amanitin. Antisense and sense transcription was also detected in nuclei isolated from synchronized parasites, suggesting concurrent synthesis. In summary, our experiments directly demonstrate that antisense RNA synthesis is a common transcriptional phenomenon in P. falciparum, and is catalyzed by RNA polymerase II.
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PMID:RNA polymerase II synthesizes antisense RNA in Plasmodium falciparum. 1570 43

RNA polymerase II promoters in Plasmodium spp., like in most eukaryotes, have a bipartite structure. However, the identification of a functional TATA box located within the Plasmodium spp. core promoters has been difficult, mainly because of its high A+T content. Only few putative trans-acting elements have been identified in the malaria parasite genome such as a gene orthologous to the TATA box binding protein (PfTBP). In this study, we demonstrate that PfTBP is part of the DNA-protein complexes formed in the kahrp and gbp-130 gene promoter regions. Supershift and footprinting assays performed with a GST-PfTBP fusion protein showed that PfTBP associates with a consensus TATA box sequence located 81 base pairs upstream of the transcription start site in the kahrp promoter region and with a TATA box-like (TGTAA) sequence at position -186 of the gbp-130 gene promoter region. Chromatin immunoprecipitation assays confirmed that native PfTBP is able to associate in vivo with both TATA box elements. This is the first study that reports the identification of cis-acting sequences (TATAA and TGTAA) and their corresponding trans-acting (PfTBP) factor in P. falciparum.
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PMID:Recombinant and native Plasmodium falciparum TATA-binding-protein binds to a specific TATA box element in promoter regions. 1576 Jun 58


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