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BACKGROUND: GWAS have identified several non-functional tagSNPs associated with severe malaria. We hypothesized that causal SNPs could play a significant role in severe malaria by altering promoter or enhancer activity. Here, we sought to identify such regulatory SNPs. METHODS: SNPs in linkage disequilibrium with tagSNPs associated with severe malaria were identified and were further annotated using FUMA. Then, SNPs were prioritized using IW-scoring method to identify regulatory ones. Gene reporter assays were performed to assess the regulatory effect of a region containing candidates. The association between SNPs and severe malaria was assessed using logistic regression models in a Senegalese cohort. RESULTS: Among 418 SNPs, the best candidates were rs116525449 and rs79644959, which were in full disequilibrium between them, and located within the ARL14 promoter. Our gene reporter assay results revealed that the region containing the SNPs exhibited cell-specific promoter or enhancer activity, while the SNPs influenced promoter activity. We detected an association between severe malaria and those two SNPs using the overdominance model and we replicated the association of severe malaria with the tagSNP rs116423146. CONCLUSIONS: We suggest that these SNPs regulate ARL14 expression in immune cells and the presentation of antigens to T lymphocytes, thus influencing severe malaria development.
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Malaria infection is a multifactorial disease partly modulated by host immuno-genetic factors. Recent evidence has demonstrated the importance of Interleukin-17 family proinflammatory cytokines and their genetic variants in host immunity. However, limited knowledge exists about their role in parasitic infections such as malaria. We aimed to investigate IL-17A serum levels in patients with severe and uncomplicated malaria and gene polymorphism's influence on the IL-17A serum levels. In this research, 125 severe (SM) and uncomplicated (UM) malaria patients and 48 free malaria controls were enrolled. IL-17A serum levels were measured with ELISA. PCR and DNA sequencing were used to assess host genetic polymorphisms in IL-17A. We performed a multivariate regression to estimate the impact of human IL-17A variants on IL-17A serum levels and malaria outcomes. Elevated serum IL-17A levels accompanied by increased parasitemia were found in SM patients compared to UM and controls (P < 0.0001). Also, the IL-17A levels were lower in SM patients who were deceased than in those who survived. In addition, the minor allele frequencies (MAF) of two IL-17A polymorphisms (rs3819024 and rs3748067) were more prevalent in SM patients than UM patients, indicating an essential role in SM. Interestingly, the heterozygous rs8193038 AG genotype was significantly associated with higher levels of IL-17A than the homozygous wild type (AA). According to our results, it can be concluded that the IL-17A gene rs8193038 polymorphism significantly affects IL-17A gene expression. Our results fill a gap in the implication of IL-17A gene polymorphisms on the cytokine level in a malaria cohort. IL-17A gene polymorphisms also may influence cytokine production in response to Plasmodium infections and may contribute to the hyperinflammatory responses during severe malaria outcomes.
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Interleucina-17 , Malaria , Humanos , Interleucina-17/genética , Malaria/genética , Frecuencia de los Genes , Polimorfismo Genético , CitocinasRESUMEN
BACKGROUND: Genome-wide association studies have identified ATP2B4 as a severe malaria resistance gene. Recently, 8 potential causal regulatory variants have been shown to be associated with severe malaria. METHODS: Genotyping of rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452 was performed in 154 unrelated individuals (79 controls and 75 mild malaria patients). rs10751450, rs10751451 and rs10751452 were genotyped by Taqman assays, whereas the fragment of the ATP2B4 gene containing the remaining SNPs was sequenced. Logistic regression analysis was used to assess the association between the SNPs and mild malaria. RESULTS: The results showed that mild malaria was associated with rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452. The homozygous genotypes for the major alleles were associated with an increased risk of mild malaria. Furthermore, the haplotype containing the major alleles and that containing the minor alleles were the most frequent haplotypes. Individuals with the major haplotypes had a significantly higher risk of mild malaria compared to the carriers of the minor allele haplotype. CONCLUSIONS: ATP2B4 polymorphisms that have been associated with severe malaria are also associated with mild malaria.
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Estudio de Asociación del Genoma Completo , Malaria , Humanos , Alelos , Genotipo , Polimorfismo de Nucleótido Simple , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genéticaRESUMEN
Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.
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Estudio de Asociación del Genoma Completo , Malaria , Predisposición Genética a la Enfermedad , Humanos , Malaria/genética , ATPasas Transportadoras de Calcio de la Membrana Plasmática/genética , Polimorfismo de Nucleótido Simple , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
BACKGROUND: Ongoing efforts to fight Plasmodium falciparum malaria has reduced malaria in many areas, but new tools are needed to monitor further progress, including indicators of decreasing exposure to parasite infection. Sero-surveillance is considered promising to monitor exposure, transmission and immunity. METHODS: IgG responses to three antigen biomarkers were evaluated in a retrospective study involving: (i) surveys of 798 asymptomatic villagers from 2 Senegalese endemic settings conducted before 2002 and after the 2013 intensification of control measures, and (ii) in 105 symptomatic individuals from different settings in Côte d'Ivoire. Response to up to eight P. falciparum antigens, including recombinant MSP1p9 antigen and LSA141 peptide, were analysed using multiplex technology and responses to whole P. falciparum schizont extract (SE, local strain adapted to culture) were measured by ELISA. RESULTS: MSP1p9 and LSA141 IgG responses were shown to be relevant indicators monitoring immune status in the different study sites both from Côte d'Ivoire and Senegal. Between 2002 and 2013, individuals participating in both studies showed higher decline of sero-positivity in young (< 15 years: range 12% to 50%) than older (> 15 years: no decline to 15%) individuals from Dielmo and Ndiop. A mathematical sero-catalytic model from the complete Dielmo/Ndiop survey was used to reconstruct declining levels of sero-positivity in more detail, demonstrating that anti-SE seroprevalence levels most accurately reflected malaria exposure in the two villages. CONCLUSION: For standard screening of population immune status at sites envisaging elimination, the use of ELISA-based assays targeting selected antigens can contribute to provide important epidemiologic surveillance data to aid malaria control programmes.
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Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Malaria Falciparum/diagnóstico , Malaria Falciparum/prevención & control , Adolescente , Adulto , Anciano , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/clasificación , Infecciones Asintomáticas/epidemiología , Biomarcadores/sangre , Niño , Preescolar , Côte d'Ivoire/epidemiología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Lactante , Estudios Longitudinales , Malaria Falciparum/epidemiología , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Estudios Retrospectivos , Estudios Seroepidemiológicos , Adulto JovenRESUMEN
BACKGROUND: Pathogenic variants associated with hereditary breast cancer have been reported for BRCA1 and BRCA2 (BRCA1/2) genes in patients from multiple ethnicities, but limited information is available from sub-Saharan African populations. We report a BRCA2 pathogenic variant in a Senegalese family with hereditary breast cancer. METHODS: An index case from a consanguineous family and nineteen healthy female relatives were recruited after informed consent. Along with this family, 14 other index cases with family history of breast cancer were also recruited. For the control populations we recruited 48 healthy women with no cancer diagnosis and 48 women diagnosed with sporadic breast cancer without family history. Genomic DNA was extracted from peripheral blood. All BRCA2 exons were amplified by PCR and sequenced. Sequences were compared to the BRCA2 GenBank reference sequence (NM_000059.3) using Alamut Software. RESULTS: We identified a novel nonsense pathogenic variant c.5219 T > G; p.(Leu1740Ter) in exon 11 of BRCA2 in the index case. The pathogenic variant was also identified in three sisters and one daughter, but was absent in the controls and unrelated cases. CONCLUSIONS: This is the first report of a novel BRCA2 pathogenic variant in a Senegalese family with hereditary breast cancer. This result confirms the diversity of hereditary breast cancer pathogenic variants across populations and extends our knowledge of genetic susceptibility to breast cancer in Africa.
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Neoplasias de la Mama/patología , Consanguinidad , Genes BRCA2 , Predisposición Genética a la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Femenino , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , Senegal , Análisis de SupervivenciaRESUMEN
BACKGROUND: Serological markers are potentially useful tools for monitoring the progress of malaria control programs, but a better understanding of antibody response dynamics is necessary. The use of a magnetic bead-based immunoassay (MBA) is advantageous compared to ELISA, due to its multiplexing capacity, but limited information is available on the standardization and validation of this assay. METHODS: Several parameters for multiplex testing of antibodies to Plasmodium antigens were analysed using a set of 4 antigens and 98 sera from Senegalese rural asymptomatic and urban symptomatic individuals. The 4 antigens included Plasmodium falciparum CSP and PfAMA1 peptides, recombinant P. falciparum MSP4p20 and a Plasmodium malariae CSP (PmCSP) peptide. Comparisons with ELISA were done using MSP4p20 and whole schizont extract (SE) antigens. RESULTS: The use of fewer beads (1000 beads per well instead of 2000) and 5 µg of antigen per 106 bead were validated as lower amounts. The use of a carrier protein (BSA) was shown to be critical when using peptides and the effect of a 24 h delayed measures was evaluated (5-25% signal decrease). Analysis of Ab responses showed almost equally high levels and prevalence in all transmission settings. Clear distinctions between rural and urban malaria were noted using PmCSP and SE antigens. CONCLUSIONS: This study underlines the importance of further optimization of the MBA technique and highlights the interest of using multistage/multispecies antigens for surveillance of malaria in endemic settings.
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Antígenos de Protozoos/inmunología , Inmunoensayo/métodos , Separación Inmunomagnética/métodos , Malaria/inmunología , Plasmodium falciparum/inmunología , Plasmodium malariae/inmunología , Proteínas Protozoarias/inmunología , Malaria Falciparum/inmunologíaRESUMEN
BACKGROUND: Severe forms of malaria (SM) are an outcome of Plasmodium falciparum infection and can cause death especially in children under 4 years of age. RNASE3 (ECP) has been identified as an inhibitor of Plasmodium parasites growth in vitro, and genetic analysis in hospitalized Ghanaian subjects has revealed the RNASE3 +371G/C (rs2073342) polymorphism as a susceptibility factor for cerebral malaria. The +371 C allele results in an Arg/Thr mutation that abolishes the cytotoxic activity of the ECP protein. The present study aims to investigate RNASE3 gene polymorphisms and their putative link to severe malaria in a malaria cohort from Senegal. METHODS/RESULTS: Patients enrolled from hospitals were classified as having either uncomplicated (UM) or severe malaria (SM). The analysis of the RNASE3 gene polymorphisms was performed in 241 subjects: 178 falciparum infected (96 SM, 82 UM) and 63 non-infected subjects as population control group (CTR). Six frequent SNPs (MAF > 3%) were identified, and one SNP was associated with malaria severity by performing a logistic regression analysis SM vs.UM: RNASE3 +499G/C (rs2233860) under age, sex as covariates and HbS/HbC polymorphisms adjustment (p = 0.003, OR 0.43, CI 95% 0.20-0.92). The polymorphisms: +371G/C (rs2073342), +499G/C (rs2233860) and +577A/T (rs8019343) defined a haplotype risk (G-G-T) for malaria severity (Fisher exact test, p = 0.03) (OR 4.1, IC 95% (1.1-14.9). CONCLUSION: In addition to the previously described association of +371G/C polymorphism in Ghanaians cohort, the RNASE3 +499G/C polymorphism was associated with susceptibility to SM in a Senegalese population. The haplotype +371G/+499G/+577T defined by RNASE3 polymorphisms was associated with severity. The genetic association identified independently in the Senegalese population provide additional evidence of a role of RNASE3 (ECP) in malaria severity.
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Proteína Catiónica del Eosinófilo/genética , Predisposición Genética a la Enfermedad/genética , Malaria Cerebral , Malaria Falciparum , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Malaria Cerebral/epidemiología , Malaria Cerebral/genética , Malaria Falciparum/epidemiología , Malaria Falciparum/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Senegal/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Identification of plasmodial antigens targeted by protective immune mechanisms is important for malaria vaccine development. Among functional assays, the neutrophil antibody-dependent respiratory burst (ADRB) induced by opsonized Plasmodium falciparum merozoites has been correlated with acquired immunity to clinical malaria in endemic areas, but the target merozoite antigens are unknown. Here, the contribution of antibodies to the conserved C-terminal domain of the P. falciparum merozoite surface protein-1 (PfMSP1p19) in mediating ADRB was investigated in sera from individuals living in two Senegalese villages with differing malaria endemicity. METHODS: Anti-PfMSP1p19 antibody levels in sera from 233 villagers were investigated and the involvement of anti-PfMSP1p19 antibodies in ADRB was explored in a subset of samples using (1) isogenic P. falciparum parasite clones expressing P. falciparum or Plasmodium chabaudi MSP1p19; (2) PfMSP1p19-coated plaque ADRB; and, (3) ADRB triggering using sera depleted from PfMSP1p19 antibodies by absorption onto the baculovirus recombinant antigen. RESULTS: ADRB activity correlated with anti-PfMSP1p19 IgG levels (P < 10(-3)). A substantial contribution of PfMSP1p19 antibody responses to ADRB was confirmed (P < 10(-4)) in an age-adjusted linear regression model. PfMSP1p19 antibodies accounted for 33.1 % (range 7-54 %) and 33.2 % (range 0-70 %) of ADRB activity evaluated using isogenic merozoites (P < 10(-3)) and depleted sera (P = 0.0017), respectively. Coating of PfMSP1p19 on plates induced strong ADRB in anti-PfMSP1p19-positive sera. CONCLUSION: These data show that naturally acquired P. falciparum MSP1p19 antibodies are potent inducers of neutrophil ADRB and support the development of PfMSP1p19-based malaria vaccine using ADRB assay as a functional surrogate for protection.
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Anticuerpos Antiprotozoarios/inmunología , Proteína 1 de Superficie de Merozoito/inmunología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Plasmodium chabaudi/inmunología , Plasmodium falciparum/inmunología , Estallido Respiratorio , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antiprotozoarios/sangre , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Senegal , Adulto JovenRESUMEN
Galectin-3 is a member of the lectin family encoded by the LGALS3 gene on chromosome 14. It is secreted by a wide range of immune cells and mammary tumor cells. Through its activity on the tumor microenvironment, in particular on tumor-infiltrating leukocytes, galectin-3 improves the proliferation, survival, and colonizing ability of mammary neoplastic cells. Consequently, galectin-3 expression in the tumor microenvironment could worsen therapeutic outcomes of breast neoplasms and become a biomarker and a therapeutic target in combined immunotherapy in breast neoplasms. There is a limited amount of information that is available on galectin-3 in breast cancer in Africa. In this review, we analyze how galectin-3 influences the tumor microenvironment and its potential as a biomarker and therapeutic target in breast neoplasms. We aim to emphasize the significance of investigating galectin-3 in breast neoplasms in Africa based on the results of studies conducted elsewhere.
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Neoplasias de la Mama , Galectina 3 , Femenino , Humanos , Biomarcadores , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Galectina 3/genética , Microambiente TumoralRESUMEN
Background: Host genetic factors contribute to the variability of malaria phenotypes and can allow a better understanding of mechanisms involved in susceptibility and/or resistance to Plasmodium falciparum infection outcomes. Several genetic polymorphisms were reported to be prevalent among populations living in tropical malaria-endemic regions and induce protection against malaria. The present study aims to investigate the prevalence of HBB (chr11) and G6PD (chrX) deficiencies polymorphisms among Senegalese populations and their associations with the risk for severe Plasmodium falciparum malaria occurrence. Methods: We performed a retrospective study with 437 samples, 323 patients recruited in hospitals located in three different endemic areas where malaria episodes were confirmed and 114 free malaria controls. The patients enrolled were classified into two groups: severe malaria (SM) (153 patients) and uncomplicated malaria (UM) (170 patients). PCR and DNA sequencing assessed host genetic polymorphisms in HBB and G6PD. Using a multivariate regression and additive model, estimates of the impact of human HBB and G6PD polymorphisms on malaria incidence were performed. Results: Six frequent SNPs with minor allele frequencies (MAF) > 3% were detected in the HBB gene (rs7946748, rs7480526, rs10768683, rs35209591, HbS (rs334) and rs713040) and two in the G6PD gene (rs762515 and rs1050828 (G6PD-202 G > A). Analysis of selected HbS polymorphism showed significant association with protective effect against severe malaria with a significant p-value = 0.033 (OR 0.38, 95% CI [0.16-0.91]) for SM vs. UM comparison. Surprisingly, our study did not identify the protective effect of variant HbC polymorphism against severe malaria. Finally, we found some of the polymorphisms, like HbS (rs334), are associated with age and biological parameters like eosinophils, basophils, lymphocytes etc. Conclusion: Our data report HBB and G6PD polymorphisms in the Senegalese population and their correlation with severe/mild malaria and outcome. The G6PD and HBB deficiencies are widespread in West Africa endemic malaria regions such as The Gambia, Mali, and Burkina Faso. The study shows the critical role of genetic factors in malaria outcomes. Indeed, genetic markers could be good tools for malaria endemicity prognosis.
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Malaria Falciparum , Malaria , Humanos , Malaria/complicaciones , Malaria Falciparum/epidemiología , Malí , Polimorfismo de Nucleótido Simple/genética , Prevalencia , Estudios Retrospectivos , Subunidades de HemoglobinaRESUMEN
Founder mutations have been reported in BRCA1 and BCRA2 in different ethnic groups with inherited breast cancer. Testing of targeted mutations in specific populations is important for cancer prevention in mutation carriers. In Sub-Saharan Africa, only a few studies have reported specific founder mutations in inherited breast cancer. The pathogenic variant c.815_824dup of BRCA1 has been reported as the most frequent among African American populations with inherited breast cancer and was supposed to have a West African origin. Recent report from Senegal identified this variant in women with inherited breast cancer at the highest frequency ever reported. The variant was linked to a common haplotype confirming its founder effect in West Africa. In this article, we review the mutation history of c.815_824dup and discuss how it spread out of Africa through the transatlantic slave trade.
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BRCA1 and BRCA2 are the most incriminated genes in inherited breast/ovarian cancers. Several pathogenic variants of these genes conferring genetic predisposition have been described in different populations but rarely in sub-Saharan Africa. The objectives of this study were to identify pathogenic variants of the BRCA genes involved in hereditary breast cancer in Senegal and to search for a founder effect. We recruited after free informed consent, 27 unrelated index cases diagnosed with breast cancer and each having a family history. Mutation screening of the genes identified a duplication of ten nucleotides c.815_824dupAGCCATGTGG, (p.Thr276Alafs) (NM_007294.3) located in exon 11 of BRCA1 gene, in 15 index cases (allelic frequency 27.7%). The pathogenic variant has been previously reported in African Americans as a founder mutation of West African origin. Haplotypes analysis of seven microsatellites surrounding the BRCA1 gene highlights a shared haplotype encompassing ~400 kb between D17S855 and D17S1325. This haplotype was not detected in none of 15 healthy controls. Estimation of the age of the pathogenic variant suggested that it occurred ~1400 years ago. Our study identified a founder pathogenic variant of BRCA1 predisposing to breast cancer and enabled the establishment of an affordable genetic test as a mean of prevention for Senegalese women at risk.
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The COVID-19 pandemic is shining a spotlight on the field of immunology like never before. To appreciate the diverse ways in which immunologists have contributed, Nature Reviews Immunology invited the president of the International Union of Immunological Societies and the presidents of 15 other national immunology societies to discuss how they and their members responded following the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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COVID-19/epidemiología , Infecciones por Coronavirus/epidemiología , Cooperación Internacional , Pandemias , Neumonía Viral/epidemiología , Síndrome Respiratorio Agudo Grave/epidemiología , Sociedades Científicas/organización & administración , Antivirales/síntesis química , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/terapia , Vacunas contra la COVID-19 , Relaciones Comunidad-Institución , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/terapia , Salud Global/tendencias , Humanos , Educación del Paciente como Asunto/organización & administración , Equipo de Protección Personal/provisión & distribución , Neumonía Viral/inmunología , Neumonía Viral/terapia , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/terapia , Vacunas Virales/biosíntesisRESUMEN
BACKGROUND: Plasmodium falciparum malaria remains a major health problem in Africa. The mechanisms of pathogenesis are not fully understood. Transcriptomic studies may provide new insights into molecular pathways involved in the severe form of the disease. METHODS: Blood transcriptional levels were assessed in patients with cerebral malaria, non-cerebral malaria, or mild malaria by using microarray technology to look for gene expression profiles associated with clinical status. Multi-way ANOVA was used to extract differentially expressed genes. Network and pathways analyses were used to detect enrichment for biological pathways. RESULTS: We identified a set of 443 genes that were differentially expressed in the three patient groups after applying a false discovery rate of 10%. Since the cerebral patients displayed a particular transcriptional pattern, we focused our analysis on the differences between cerebral malaria patients and mild malaria patients. We further found 842 differentially expressed genes after applying a false discovery rate of 10%. Unsupervised hierarchical clustering of cerebral malaria-informative genes led to clustering of the cerebral malaria patients. The support vector machine method allowed us to correctly classify five out of six cerebral malaria patients and six of six mild malaria patients. Furthermore, the products of the differentially expressed genes were mapped onto a human protein-protein network. This led to the identification of the proteins with the highest number of interactions, including GSK3B, RELA, and APP. The enrichment analysis of the gene functional annotation indicates that genes involved in immune signalling pathways play a role in the occurrence of cerebral malaria. These include BCR-, TCR-, TLR-, cytokine-, FcεRI-, and FCGR- signalling pathways and natural killer cell cytotoxicity pathways, which are involved in the activation of immune cells. In addition, our results revealed an enrichment of genes involved in Alzheimer's disease. CONCLUSIONS: In the present study, we examine a set of genes whose expression differed in cerebral malaria patients and mild malaria patients. Moreover, our results provide new insights into the potential effect of the dysregulation of gene expression in immune pathways. Host genetic variation may partly explain such alteration of gene expression. Further studies are required to investigate this in African populations.
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Malaria Cerebral/patología , Transcriptoma/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Análisis por Conglomerados , Femenino , Glucógeno Sintasa Quinasa 3 beta/genética , Humanos , Lactante , Malaria Cerebral/sangre , Malaria Cerebral/genética , Masculino , Persona de Mediana Edad , Mapas de Interacción de Proteínas/genética , Senegal , Índice de Severidad de la Enfermedad , Transducción de Señal , Factor de Transcripción ReIA/genética , Adulto JovenRESUMEN
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.
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Identification of parasite antigens targeted by immune effector mechanisms that confer protection against malaria is important for the design of a multi-component malaria vaccine. Here, the association of antibodies reacting with the Plasmodium falciparum merozoite surface protein-4 (MSP4) with protection against clinical malaria was investigated in a Senegalese community living in an area of moderate, seasonal malaria transmission. Blood samples were collected at the end of an 8-month long dry season without any recorded parasite transmission from 206 residents enrolled in a prospective follow-up study. Active daily clinical monitoring was implemented during the subsequent five months. Entomologic monitoring documented parasite transmission during the first three months of follow-up. Serum IgG levels were determined by ELISA against three MSP4 baculovirus-encoded recombinant protein constructs, namely the full-length MSP4p40, MSP4p30 devoid of a highly polymorphic sequence stretch and the conserved C-terminal EGF-containing MSP4p20, as well as against a merozoite crude extract. Community seroprevalence against all three constructs was quite high, the lowest being against MSP4p30. Seroprevalence and antibody levels against the three MSP4 constructs were age-dependent. IgG1 dominated the anti-MSP4p20 responses, while both IgG1 and IgG3 were observed against MSP4p40. Anti-MSP4 antibodies were associated with the antibody-dependent respiratory burst (ADRB) activity in a functional assay of merozoite phagocytosis by polymorphonuclear cells. Importantly, high antibody levels against each of the three MSP4 constructs at the end of the dry season were associated with reduced morbidity during the subsequent transmission season in an age-adjusted Poisson regression model (IRRâ¯=â¯0.65 [0.50-0.83], P<0.001 for responses over the median values). These data are consistent with a protective role for the naturally acquired anti-MSP4 antibodies and support further development of MSP4 as a candidate component of malaria vaccine.
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Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Malaria Falciparum/epidemiología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Adolescente , Adulto , Anciano , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/química , Antígenos de Protozoos/genética , Niño , Preescolar , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Malaria Falciparum/prevención & control , Masculino , Merozoítos/inmunología , Persona de Mediana Edad , Neutrófilos/inmunología , Fagocitosis , Estudios Prospectivos , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/inmunología , Estallido Respiratorio/inmunología , Senegal/epidemiología , Estudios Seroepidemiológicos , Adulto JovenRESUMEN
Recent control scale-up has reduced malaria in many areas but new tools are needed to monitor further progress, including indicators of decreasing exposure to parasite infection. Although serology is considered a promising approach in this regard, the serological impact of control interventions has been so far studied using indirect quantification of exposure. Cohort surveys concomitantly recording entomological and malariometric indices have been conducted in two Senegalese settings where supervised control intensification implemented in 2006 shifted malaria from historically holoendemic in Dielmo and mesoendemic in Ndiop to hypoendemic in both settings by 2013. We analyse here serological signatures of declining transmission using archived blood samples. Responses against ten pre-erythrocytic and erythrocytic antigens from Plasmodium falciparum and P. malariae alongside an Anopheles gambiae salivary gland antigen were analysed. Cross-sectional surveys conducted before (2002) and after (2013) control intensification showed a major impact of control intensification in both settings. The age-associated prevalence, magnitude and breadth of the IgG responses to all antigens were village-specific in 2002. In 2013, remarkably similar patterns were observed in both villages, with marginal responses against all parasite antigens in the 0-5y children and reduced responses in all previously seropositive age groups. Waning of humoral responses of individuals who were immune at the time of control intensification was studied from 2006 to 2013 using yearly samplings. Longitudinal data were analysed using the Cochran-Armittage trend test and an age-related reversible catalytic conversion model. This showed that the antigen-specific antibody declines were more rapid in older children than adults. There was a strong association of antibody decline with the declining entomological inoculation rate. We thus identified serological markers of declining exposure to malaria parasites that should help future monitoring of progress towards malaria elimination.
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Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Salud Rural/estadística & datos numéricos , Población Rural/estadística & datos numéricos , Adolescente , Adulto , Animales , Anopheles/inmunología , Anopheles/parasitología , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/sangre , Antígenos de Protozoos/inmunología , Niño , Estudios de Cohortes , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Encuestas Epidemiológicas/métodos , Encuestas Epidemiológicas/estadística & datos numéricos , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Malaria Falciparum/epidemiología , Malaria Falciparum/parasitología , Masculino , Plasmodium falciparum/fisiología , Prevalencia , Glándulas Salivales/inmunología , Senegal/epidemiología , Adulto JovenRESUMEN
Pro-inflammatory cytokines induced by glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum contribute to malaria pathogenesis and hence, the naturally acquired anti-GPI antibody thought to provide protection against severe malaria (SM) by neutralizing the stimulatory activity of GPIs. In previous studies, the anti-GPI antibody levels increased with age in parallel with the development of acquired immunity, and high levels of anti-GPI antibodies were associated with mild malaria (MM) cases. In the present study, the relationship between the levels of pro-inflammatory cytokines and anti-GPI IgG antibody responses, parasitemia, and the clinical outcomes were evaluated in SM and mild malaria (MM) patients. Sera from a total of 110 SM and 72 MM cases after excluding of ineligible patients were analyzed for the levels of anti-GPI antibodies, IgG subclasses, and cytokine responses by ELISA. While the total anti-GPI antibody levels were similar in overall SM and MM groups, they were significantly higher in surviving SM patients than in fatal SM cases. In the case of cytokines, the TNF-α and IL-6 levels were significantly higher in SM compared to MM, whereas the IL-10 levels were similar in both groups. The data presented here demonstrate that high levels of the circulatory pro-inflammatory, TNF-α, and IL-6, are indicators of malaria severity, whereas anti-inflammatory cytokine IL-10 level does not differentiate SM and MM cases. Further, among SM patients, relatively low levels of anti-GPI antibodies are indicators of fatal outcomes compared to survivors, suggesting that anti-GPI antibodies provide some level of protection against SM fatality.