scholarly journals NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e6048 ◽  
Author(s):  
Alassane Thiam ◽  
Sabrina Baaklini ◽  
Babacar Mbengue ◽  
Samia Nisar ◽  
Maryam Diarra ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Genetic Variation ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Leukocyte Count ◽  
Haematological Parameters ◽  
Link Type ◽  
Genome Wide ◽  
Mild Malaria ◽  
Host Genetic

Background Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Methods Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed. Results We evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients. Conclusions Our results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes.

scholarly journals Circulatory hepcidin is associated with the anti-inflammatory response but not with iron or anemic status in childhood malaria

Blood ◽  
2013 ◽  
Vol 121 (15) ◽  
pp. 3016-3022 ◽  
Author(s):  
Florence Burté ◽  
Biobele J. Brown ◽  
Adebola E. Orimadegun ◽  
Wasiu A. Ajetunmobi ◽  
Nathaniel K. Afolabi ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Severe Malarial Anemia ◽  
Key Points ◽  
Mild Malaria ◽  
Anti Inflammatory ◽  
Childhood Malaria ◽  
Malarial Anemia

Key Points Hepcidin rises more dramatically in mild malaria than in severe malaria. Hepcidin levels are linked to inflammation, not anemia, in severe malarial anemia and cerebral malaria.

scholarly journals Endothelial Nitric Oxide Synthase Gene Polymorphisms and Plasmodium falciparum Infection in Indian Adults

2009 ◽  
Vol 77 (7) ◽  
pp. 2943-2947 ◽  
Author(s):  
Gunanidhi Dhangadamajhi ◽  
Biranchi N. Mohapatra ◽  
Shantanu K. Kar ◽  
Manoranjan Ranjit
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Endothelial Nitric Oxide Synthase ◽  
No Production ◽  
Unique Haplotype ◽  
Mild Malaria ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

ABSTRACT To explore the hypothesis that susceptibility to cerebral malaria is influenced by genetic variation in endothelial nitric oxide synthase (eNOS), we genotyped three commonly defined polymorphic loci of eNOS, Glu298→Asp, intron 4 variable number of tandem repeat region, and T-786→C, in 244 patients (mean age, 36.2 years) with mild malaria and 194 patients (mean age, 35.6 years) with severe malaria belonging to same ethnic group in Orissa, an eastern Indian state. We found that there was an association of the Glu298→Asp substitution (P = 0.0037; odds ratio, 1.95; 95% confidence interval, 1.2 to 3.0) and a single unique haplotype defined by “C-b-Asp” (P corrected = 0.0024) for protection against cerebral malaria. Further, the median plasma level of nitrite-nitrate was found to be increased in individuals with the Glu298→Asp substitution and was significantly higher in the mild malaria group (P ≤ 0.0001), but the increase was not significant in the severe malaria group (P = 0.0528). These findings suggest that the Glu298→Asp substitution and the “C-b-Asp” haplotype may enhance eNOS expression and NO production, which leads to protection against cerebral malaria. These findings may increase our understanding of the pathogenesis of malaria.

scholarly journals Evidence of Selective Sweeps in Genes Conferring Resistance to Chloroquine and Pyrimethamine in Plasmodium falciparum Isolates in India

2009 ◽  
Vol 54 (3) ◽  
pp. 997-1006 ◽  
Author(s):  
Tonya Mixson-Hayden ◽  
Vidhan Jain ◽  
Andrea M. McCollum ◽  
Amanda Poe ◽  
Avinash C. Nagpal ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Cerebral Malaria ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Drug Resistant ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Mild Malaria ◽  
Resistant Genotypes

ABSTRACT Treatment of Plasmodium falciparum is complicated by the emergence and spread of parasite resistance to many of the first-line drugs used to treat malaria. Antimalarial drug resistance has been associated with specific point mutations in several genes, suggesting that these single nucleotide polymorphisms can be useful in tracking the emergence of drug resistance. In India, P. falciparum infection can manifest itself as asymptomatic, mild, or severe malaria, with or without cerebral involvement. We tested whether chloroquine- and antifolate drug-resistant genotypes would be more commonly associated with cases of cerebral malaria than with cases of mild malaria in the province of Jabalpur, India, by genotyping the dhps, dhfr, pfmdr-1, and pfcrt genes using pyrosequencing, direct sequencing, and real-time PCR. Further, we used microsatellites surrounding the genes to determine the origins and spread of the drug-resistant genotypes in this area. Resistance to chloroquine was essentially fixed, with 95% of the isolates harboring the pfcrt K76T mutation. Resistant genotypes of dhfr, dhps, and pfmdr-1 were found in 94%, 17%, and 77% of the isolates, respectively. Drug-resistant genotypes were equally likely to be associated with cerebral malaria as with mild malaria. We found evidence of a selective sweep in pfcrt and, to a lesser degree, in dhfr, indicating high levels of resistance to chloroquine and evolving resistance to pyrimethamine. Microsatellites surrounding pfcrt indicate that the resistant genotypes (SVMNT) were most similar to those found in Papua New Guinea.

scholarly journals StabilitySort: assessment of protein stability changes on a genome-wide scale to prioritise potentially pathogenic genetic variation

2021 ◽  
Author(s):  
Aaron Chuah ◽  
Sean Li ◽  
Andrea Do ◽  
Matt A Field ◽  
T. Daniel Andrews
Keyword(s):  
Genetic Variation ◽  
Protein Stability ◽  
Missense Mutations ◽  
Link Type ◽  
Genome Wide ◽  
Pathogenic Variation ◽  
A Genome ◽  
Human Proteins ◽  
Wide Scale ◽  
The Stability

AbstractSummaryMissense mutations that change protein stability are strongly associated with human inherited genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel algorithm to prioritise variants predicted to strongly destabilise essential proteins, available as both a standalone software package and a web-based tool. We demonstrate the utility of this tool by showing that at values of the Stability Sort Z-score above 1.6, pathogenic, protein-destabilising variants from ClinVar are detected at a 58% enrichment, over and above the destabilising (but presumably non-pathogenic) variation already present in the HapMap NA12878 genome.Availability and ImplementationStabilitySort is available as both a web service (http://130.56.244.113/StabilitySort/) and can be deployed as a standalone system (https://gitlab.com/baaron/StabilitySort)[email protected]

scholarly journals Genome Wide Linkage Study, Using a 250K SNP Map, of Plasmodium falciparum Infection and Mild Malaria Attack in a Senegalese Population

PLoS ONE ◽  
2010 ◽  
Vol 5 (7) ◽  
pp. e11616 ◽  
Author(s):  
Jacqueline Milet ◽  
Gregory Nuel ◽  
Laurence Watier ◽  
David Courtin ◽  
Yousri Slaoui ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Linkage Study ◽  
Falciparum Infection ◽  
Plasmodium Falciparum Infection ◽  
Genome Wide ◽  
Mild Malaria ◽  
Snp Map ◽  
Malaria Attack

scholarly journals Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India

2015 ◽  
Vol 83 (10) ◽  
pp. 3793-3799 ◽  
Author(s):  
Esther Dalko ◽  
Bidyut Das ◽  
Fabien Herbert ◽  
Constantin Fesel ◽  
Sulabha Pathak ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Severe Malaria ◽  
Rank Correlation ◽  
Interleukin 10 ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Canonical Correlations ◽  
Cytokines And Chemokines ◽  
Chemotactic Protein ◽  
Mild Malaria

Several immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.

scholarly journals THE CIDR1α-PfEMP1 SEQUENCE FROM INDONESIAN PLASMODIUM FALCIPARUM AND ITS POTENTIAL ASSOCIATION WITH THE CEREBRAL OUTCOME

2021 ◽  
Vol 7 (1) ◽  
pp. 34-39
Author(s):  
Erma Sulistyaningsih ◽  
Yunita Armiyanti ◽  
Rosita Dewi
Keyword(s):  
Plasmodium Falciparum ◽  
Amino Acid ◽  
Cerebral Malaria ◽  
Severe Malaria ◽  
Sequence Similarity ◽  
Malaria Diagnosis ◽  
Severe Case ◽  
Amino Acid Sequences ◽  
Pcr Product ◽  
Potential Association

Background: Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) is an important protein responsible for the pathogenesis of severe malaria, including cerebral malaria. The protein is highly diverse. The CIDR1α-PfEMP1 binds endothelial protein receptor (EPCR) and may associated with the brain swelling in childhood malaria. Objective: To analyze the CIDR1α-PfEMP1 from Indonesian isolate and determine its association with cerebral malaria outcome. Methods: Fifteen blood samples of clinically mild to severe malaria-patient were collected for DNA extraction. Malaria diagnosis was conducted microscopically by Giemsa-stained thin blood smear. The CIDR1α domain was amplified by PCR using specific primer and PCR product was sequenced. The nucleotide sequences were analyzed by NCBI blast, DNASIS MAX 3 and translated into amino acid sequences using Expasy Translation Tool. Results: One out of fifteen samples was severe malaria case and infected with P. falciparum, the rest were clinically mild to moderate malaria and infected with pure P. falciparum or mixed infection of P. falciparum and P. vivax. Amplification for CIDR1α domain resulted a single band of + 550 bp from a severe sample only. Sequencing of PCR product on both strands read 524 nucleotides and BLAST analysis confirmed as CIDR1α sequence. Multiple alignment showed 74-78% nucleotide sequence similarity with reference sequences, but amino acid sequences presented 23.5% homologous. Conclusion: An identified CIDR1α domain only from severe case implicating the potential association with the severe outcome including cerebral malaria, but the highly diverse of the domain needs further studies on the interaction with the pathological-causing receptor in the host.

scholarly journals Differential Regulation of β-Chemokines in Children with Plasmodium falciparum Malaria

2005 ◽  
Vol 73 (7) ◽  
pp. 4190-4197 ◽  
Author(s):  
Daniel O. Ochiel ◽  
Gordon A. Awandare ◽  
Christopher C. Keller ◽  
James B. Hittner ◽  
Peter G. Kremsner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasmodium Falciparum ◽  
Severe Malaria ◽  
Mononuclear Cells ◽  
Chemokine Gene ◽  
Mild Malaria ◽  
Blood Mononuclear Cells ◽  
History Of ◽  
Circulating Levels ◽  
Chemokine Gene Expression

ABSTRACT Chemokines regulate the host immune response to a variety of infectious pathogens. Since the role of chemokines in regulating host immunity in children with Plasmodium falciparum malaria has not previously been reported, circulating levels of β-chemokines (MIP-1α, MIP-1β, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1α and MIP-1β levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. β-Chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating β-chemokines, illustrating that PBMCs are a primary source for the observed pattern of β-chemokine production during acute malaria. Statistical modeling revealed that none of the chemokines was significantly associated with either parasitemia or anemia. Additional investigations in healthy children with a known history of malaria showed that children with prior severe malaria had significantly lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in the ability to produce RANTES in these two groups. Baseline MIP-1α and MIP-1β did not significantly differ between children with prior severe malaria and those with mild malaria. Additional in vitro experiments in PBMCs from healthy, malaria-naïve donors revealed that P. falciparum-derived hemozoin (Hz; malarial pigment) and synthetic Hz (β-hematin) promote a similar pattern of β-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of β-chemokines characterized by increased circulating levels of MIP-1α and MIP-1β and decreased RANTES. Altered patterns of circulating β-chemokines result, at least in part, from Hz-induced changes in β-chemokine gene expression in blood mononuclear cells.

scholarly journals Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

2012 ◽  
Vol 80 (3) ◽  
pp. 1150-1155 ◽  
Author(s):  
Malkie Krupka ◽  
Karl Seydel ◽  
Catherine M. Feintuch ◽  
Kenny Yee ◽  
Ryung Kim ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
T Cell ◽  
Severe Malaria ◽  
Severe Disease ◽  
Gene Set Enrichment Analysis ◽  
Malaria Episode ◽  
Type I ◽  
Asymptomatic Malaria ◽  
Content Type ◽  
Mild Malaria

Infection withPlasmodium falciparumcan lead to a range of severe to minimal symptoms, occasionally resulting in death in young children or nonimmune adults. In areas of high transmission, older children and adults generally suffer only mild or asymptomatic malaria infections and rarely develop severe disease. The immune features underlying this apparent immunity to severe disease remain elusive. To gain insight into host responses associated with severe and mild malaria, we conducted a longitudinal study of five children who first presented with severe malaria and, 1 month later, with mild malaria. Employing peripheral blood whole-genome profiling, we identified 68 genes that were associated with mild malaria compared to their expression in the severe malaria episode (paired Studentsttest,P< 0.05). These genes reflect the interferon (IFN) pathway and T cell biology and include IFN-induced protein transcripts 1 to 3, oligoadenylate synthetases 1 and 3, and the T cell markers cathepsin W and perforin. Gene set enrichment analysis identified Gene Ontology (GO) pathways associated with mild malaria to include the type I interferon-mediated signaling pathway (GO 0060337), T cell activation (GO 0042110), and other GO pathways representing many aspects of immune activation. In contrast, only six genes were associated with severe malaria, including thymidine kinase 1, which was recently found to be a biomarker of cerebral malaria susceptibility in the murine model, and carbonic anhydrase, reflecting the blood's abnormal acid base environment during severe disease. These data may provide potential insights to inform pathogenesis models and the development of therapeutics to reduce severe disease outcomes due toP. falciparuminfection.

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