| 1. |
- Ayres Pereira, Marina, et al.
(författare)
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Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1
- 2016
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- During placental malaria, Plasmodium falciparum infected erythrocytes sequester in the placenta, causing health problems for both the mother and fetus. The specific adherence is mediated by the VAR2CSA protein, which binds to placental chondroitin sulfate (CS) on chondroitin sulfate proteoglycans (CSPGs) in the placental syncytium. However, the identity of the CSPG core protein and the cellular impact of the interaction have remain elusive. In this study we identified the specific CSPG core protein to which the CS is attached, and characterized its exact placental location. VAR2CSA pull-down experiments using placental extracts from whole placenta or syncytiotrophoblast microvillous cell membranes showed three distinct CSPGs available for VAR2CSA adherence. Further examination of these three CSPGs by immunofluorescence and proximity ligation assays showed that syndecan-1 is the main receptor for VAR2CSA mediated placental adherence. We further show that the commonly used placental choriocarcinoma cell line, BeWo, express a different set of proteoglycans than those present on placental syncytiotrophoblast and may not be the most biologically relevant model to study placental malaria. Syncytial fusion of the BeWo cells, triggered by forskolin treatment, caused an increased expression of placental CS-modified syndecan-1. In line with this, we show that rVAR2 binding to placental CS impairs syndecan-1-related Src signaling in forskolin treated BeWo cells, but not in untreated cells.
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| 2. |
- Elghazali, Gehad, 1962-
(författare)
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Regulatory immune responses in humans naturally primed to Plasmodium falciparum or vaccinated with tetanum toxoid or purified protein derivative
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is well established that the balance between functionally distinct regulatory CD4+ T cells plays a major role in the development of immunity and/or pathogenesis to many different infections. In spite of the importance of Th lineage commitment in disease, the critical questions how the balance between Th1 and Th2 cells is regulated is largely unresolved. This thesis describes work aimed at assessing CD4+ T cell heterogeneity and how this is regulated in humans naturally primed to P. falciparum malaria or vaccinated with tetanus toxoid or BCG.Different types of antigens have been implicated to be of importance in the polarization of Th1 or Th2 cells. To investigate this, we stimulated peripheral blood mononuclear cells (PBMC) with tetanus toxoid (TT) and the mycobacterial antigen, purified protein derivative (PPD) in vitro and determined the number of IFN-g (Th1 cytokine) and IL-4 (Th2 cytokine) producing cells using the ELISPOT assay. PPD preferentially induced IFN-g and very few IL-4 producing cells, while TT- induced both IL-4 and IFN-g. These differences probably reflect the different types of immune responses the two antigens induce, mycobacteria preferentially a cell-mediated Th1 type of immunity, while immunity to tetanus is an antibody-dependent, Th2 type of response.To investigate the role of Th1 and Th2 cells in the regulation of anti-malarial IgE in individuals living in P.falciparum endemic areas, the number of IL-4 and IFN-g producing cells was correlated to the plasma anti-malarial IgE levels. A negative correlation between the number of IFN-g producing cells and anti-P.falciparum IgE was found. For IL-4 there was a weak positive correlation with anti-malarial IgE levels, suggesting that other cells than T cells can produce IL-4. The anti-malarial IgE levels correlated significantly with an increased ratio of IL-4/IFN-g producing cells. These data suggest a regulatory role for IL-4 in the induction of anti-P.falciparum IgE antibodies.When PBMC from two groups of individuals naturally exposed to P.falciparum, living in two different parts of Africa (Burkina Faso and Tanzania), were stimulated in vitro with P.falciparum antigens, no malaria-specific IL-4 producing cells were detected. The levels of IgE were lower in the Burkina individuals as compared to the Tanzania ones. This might reflect differences in malaria exposure or genetic (ethnic) differences between the two study groups.To study the influence of genetic and/or environmental factors on the development and shaping of the human peripheral T cell repertoire, the T cell receptor (TCR) Vb usage in ten adult monozygous (Mz) and nine dizygous (Dz) twin pairs living in a P.falciparum endemic area in The Gambia was studied. The results revealed that the frequencies of cells expressing particular TCR Vb genes were not influenced by the parasitaemia, indicating that malaria exposure is not a dominating factor in shaping the peripheral TCR repertoire in humans. The mean within-pair difference was significantly lower for the Mz than for the Dz pairs. The mean within-pair difference for a group of MHC-class II identical twin pairs was significantly higher than for the Mz group but similar to that of the Dz as a whole. These data indicate that genetic factors other than MHC class II genes (i.e non-MHC) influence the shaping of the peripheral TCR Vb repertoire in humans.To study whether or not IgE-containing malaria sera have the capacity to induce IL-4 in human basophils, IgE containing sera from malaria immune donors were added to tissue culture plates coated with anti-human IgE antibodies. IgE-anti-IgE complexes induced IL-4 in basophils. Serum depleted of IgE induced significantly less IL-4. These data show that malaria IgE can induce IL-4 production in cells of basophil origin that can subsequently amplify Th2 type of responses.Taken together, our data show the existence of functionally distinct T cells in individuals naturally primed to P.falciparum or vaccinated with TT or BCG.
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| 3. |
- Giha, Hayder A., et al.
(författare)
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Age-dependent association between IgG2 and IgG3 subclasses to Pf332-C231 antigen and protection from malaria, and induction of protective antibodies by sub-patent malaria infections, in Daraweesh
- 2010
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Ingår i: Vaccine. - : Elsevier BV. - 0264-410X .- 1873-2518. ; 28:7, s. 1732-1739
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Tidskriftsartikel (refereegranskat)abstract
- The certainty of the protective role of acquired immunity in malaria is the major drive for malaria vaccine development. In this study, we measured the levels of total IgG and IgG subclasses to four candidate malaria vaccine antigens; MSP2-3D7, MSP2-FC27, AMA-1 and Pf332-C231, in plasma obtained from a cohort of 136 donors from Daraweesh in Sudan. The cohort was followed for malaria infection for 9 years. After an initial analysis, the immune response to Pf332-C231 antigen was the only one found associated with protection, thus taken for further analysis. The number of previous clinical malaria episodes experienced by the donors was used as an index for relative protection. The number of these episodes was found to be negatively correlated with the levels of pre-existing total IgG, IgG2 and IgG3 to Pf332-C231 (correlation coefficient, CC - 0.215, p=0.012; CC - 0.195, p=0.023 and CC - 0.211, p=0.014, respectively), and also with age (CC - 0.311, p<0.001). Unexpectedly, equal levels of Pf332-C231 antibodies were induced by both patent and sub-patent infections regardless of the number of previous malaria episodes (1-7). Combining the correlation analysis with a multi-linear regression, three variable markers for protection were emerged, two age-dependent, the antibody response to Pf332-C231 and an unidentified marker (likely immune response to other antigens), and the third was an age-independent unidentified marker (possibly gene polymorphisms). In conclusion, this report suggests a protective effect for IgG subclasses to Pf332-C231 antigen against malaria.
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| 4. |
- Giha, Hayder A., et al.
(författare)
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Antigen-specific influence of GM/KM allotypes on IgG isotypes and association of GM allotypes with susceptibility to Plasmodium falciparum malaria.
- 2009
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Plasmodium falciparum malaria is a complex disease in which genetic and environmental factors influence susceptibility. IgG isotypes are in part genetically controlled, and GM/KM allotypes are believed to be involved in this control. METHODS: In this study, 216 individuals from Daraweesh, an area of seasonal malaria transmission in Sudan, were followed for nine years for malaria infection. Total IgG and IgG isotypes against four malaria antigens, MSP2-3D7, MSP2-FC27, AMA1, and Pf332-C231 were measured in plasma obtained from the cohort at the end of the study, during the dry malaria-free period. The GM/KM allotypes of the donors were determined. RESULTS: The GM 1,17 5,13,14,6 phenotype was associated with a higher incidence of malaria compared with the non-1,17 5,13,14,6 phenotypes (P = 0.037). Paradoxically, the carriers of the GM 1,17 5,13,14,6 phenotype had significantly higher baseline levels of total IgG and non-cytophilic IgG isotypes as compared to non-carriers. The KM allotypes influence on IgG isotypes level was limited. Finally, the differences in the baseline concentrations of total IgG and IgG isotypes between the different GK/KM phenotype carriers were antigen-dependent. DISCUSSION: The results show that GM but not KM allotypes appeared to influence host susceptibility to uncomplicated malaria as well as the antibody profile of the donors, and the carriers of the GM 1,17 5,13,14,6 phenotype were the most susceptible CONCLUSIONS: The GM allotypes have significant influence on susceptibility to uncomplicated P. falciparum malaria and antigen-dependent influence on total IgG and IgG subclasses.
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| 5. |
- Giha, Hayder A, et al.
(författare)
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Association of a single nucleotide polymorphism in the C-reactive protein gene (-286) with susceptibility to Plasmodium falciparum malaria
- 2010
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Ingår i: Molecular Medicine. - : Springer Science and Business Media LLC. - 1076-1551 .- 1528-3658. ; 16:1-2, s. 27-33
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Tidskriftsartikel (refereegranskat)abstract
- The role of inflammation in malaria pathogenesis is not fully understood, although C-reactive protein (CRP) may have a negative influence on host immunity to infections. An upstream polymorphism, -286 (C > T > A), in the CRP gene is known to influence CRP levels. In this study, a cohort of 192 Sudanese donors, followed for malaria infection for 9 years, had their CRP -286 gene locus genotyped by pyrosequencing. The number of malaria episodes experienced by each individual over the study period was used as an index for malaria susceptibility. The prevalence of the CRP alleles A, C and T were 21%, 52% and 27%, respectively. Importantly, the A-allele, unlike the C- and T-alleles or CRP genotypes, was significantly associated with an increased number of malaria episodes, P = 0.007. The proportion of A-allele carriers among donors not known to have had malaria during the study period was 18%, whereas it was 43% and 63% among donors who had experienced 1-4 and > or =5 malaria episodes, respectively, over the same period (P = 0.002). Furthermore, the A-allele was associated with higher parasite counts. In conclusion, the CRP -286 A-allele was associated with an increased susceptibility to uncomplicated Plasmodium falciparum malaria.
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| 6. |
- Giha, Hayder A., et al.
(författare)
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Clustering of malaria treatment failure (TF) in Daraweesh : hints for host genetic susceptibility to TF with emphasis on immune-modulating SNPs
- 2010
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Ingår i: Infection, Genetics and Evolution. - : Elsevier BV. - 1567-1348 .- 1567-7257. ; 10:4, s. 481-6
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Tidskriftsartikel (refereegranskat)abstract
- In malaria, drug resistance and treatment failure (TF) are not synonymous, although are escalating together. Over 9 years of surveillances for malaria morbidity and TF in Daraweesh village in eastern Sudan (1991-2004), 136 donors (15-78 years) from 43 households, treated for 278 malaria episodes and had experienced 46 incident of TF, were included in this study. Blood obtained from the donors in 2005, was used for measurement of IgG subclasses against Pf332-C231 antigen and GM/KM allotyping and for genotyping of the donors for; FcgammaRIIA 131 (HH, RH, RR), CRP 286 (C
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| 7. |
- Hatem, Gad, et al.
(författare)
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Mapping the cord blood transcriptome of pregnancies affected by early maternal anemia to identify signatures of fetal programming
- 2022
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 107:5, s. 1303-1316
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Anemia during early pregnancy (EP) is common in developing countries and is associated with adverse health consequences for both mother and children. Offspring of women with EP anemia often have low birth-weight, the latter being a risk factor for cardiometabolic diseases including type 2 diabetes (T2D) later in life. Mechanisms underlying developmental programming of adult cardiometabolic disease include epigenetic and transcriptional alterations potentially detectable in umbilical cord blood (UCB) at time of birth.METHODS: We leveraged global transcriptome- and accompanying epigenome-wide changes in 48 UCB from newborns of EP-anemic Tanzanian mothers and 50 controls to identify differentially expressed genes (DEG) in UCB exposed to maternal EP-anemia. DEGs were assessed for association with neonatal anthropometry and cord insulin levels. These genes were further studied in expression data from human fetal pancreas and adult islets to understand their role in beta-cell development and/or function.RESULTS: The expression of 137 genes was altered in UCB of newborns exposed to maternal EP anemia. These putative signatures of fetal programming which included the birth-weight locus LCORL, were potentially mediated by epigenetic changes in 27 genes and associated with neonatal anthropometry. Among the DEGs were P2RX7, PIK3C2B, and NUMBL which potentially influence beta-cell development. Insulin levels were lower in EP anemia exposed UCB, supporting the notion of developmental programming of pancreatic beta-cell dysfunction and subsequently increased risk of T2D in offspring of EP anemic mothers.CONCLUSIONS: Our data provide proof-of-concept on distinct transcriptional and epigenetic changes detectable in UCB from newborns exposed to maternal EP anemia.
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| 8. |
- Hjort, Line, et al.
(författare)
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FOETAL for NCD-FOetal Exposure and Epidemiological Transitions : the role of Anaemia in early Life for Non-Communicable Diseases in later life: a prospective preconception study in rural Tanzania
- 2019
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Low-income and middle-income countries such as Tanzania experience a high prevalence of non-communicable diseases (NCDs), including anaemia. Studying if and how anaemia affects growth, placenta development, epigenetic patterns and newborns' risk of NCDs may provide approaches to prevent NCDs.PARTICIPANTS: The FOETALforNCD (FOetal Exposure and Epidemiological Transitions: the role of Anaemia in early Life for Non-Communicable Diseases in later life) Study is a population-based preconception, pregnancy and birth cohort study (n=1415, n=538, n=427, respectively), conducted in a rural region of North-East Tanzania. All participants were recruited prior to conception or early in pregnancy and followed throughout pregnancy as well as at birth. Data collection included: maternal blood, screening for NCDs and malaria, ultrasound in each trimester, neonatal anthropometry at birth and at 1 month of age, cord blood, placental and cord biopsies for stereology and epigenetic analyses.FINDINGS TO DATE: At preconception, the average age, body mass index and blood pressure of the women were 28 years, 23 kg/m2 and 117/75 mm Hg, respectively. In total, 458 (36.7%) women had anaemia (haemoglobin Hb <12 g/dL) and 34 (3.6%) women were HIV-positive at preconception. During pregnancy 359 (66.7%) women had anaemia of which 85 (15.8%) women had moderate-to-severe anaemia (Hb ≤9 g/dL) and 33 (6.1%) women had severe anaemia (Hb ≤8 g/dL). In total, 185 (34.4%) women were diagnosed with malaria during pregnancy.FUTURE PLANS: The project will provide new knowledge on how health, even before conception, might modify the risk of developing NCDs and how to promote better health during pregnancy. The present project ended data collection 1 month after giving birth, but follow-up is continuing through regular monitoring of growth and development and health events according to the National Road Map Strategic Plan in Tanzania. This data will link fetal adverse event to childhood development, and depending on further grant allocation, through a life course follow-up.
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| 9. |
- Minja, Daniel T. R., et al.
(författare)
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Plasmodium falciparum Mutant Haplotype Infection during Pregnancy Associated with Reduced Birthweight, Tanzania
- 2013
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Ingår i: Emerging Infectious Diseases. - : Centers for Disease Control and Prevention (CDC). - 1080-6040 .- 1080-6059. ; 19:9, s. 1446-1454
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Tidskriftsartikel (refereegranskat)abstract
- Intermittent preventive treatment during pregnancy with sulfadoxine pyrimethamine (IPTp-SP) is a key strategy in the control of pregnancy-associated malaria. However, this strategy is compromised by widespread drug resistance from single-nucleotide polymorphisms in the Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthetase genes. During September 2008 October 2010, we monitored a cohort of 924 pregnant women in an area of Tanzania with declining malaria transmission. P falciparum parasites were genotyped, and the effect of infecting haplotypes on birthweight was assessed. Of the genotyped parasites, 9.3%, 46.3%, and 44.4% had quadruple or less, quintuple, and sextuple mutated haplotypes, respectively. Mutant haplotypes were unrelated to SP doses. Compared with infections with the less-mutated haplotypes, infections with the sextuple haplotype mutation were associated with lower (359 g) birth-weights. Continued use of the suboptimal IPTp-SP regimen should be reevaluated, and alternative strategies (e.g., intermittent screening and treatment or intermittent treatment with safe and effective alternative drugs) should be evaluated.
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| 10. |
- Minja, Daniel T. R., et al.
(författare)
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Reliability of rapid diagnostic tests in diagnosing pregnancy associated malaria in North Eastern Tanzania
- 2012
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 11, s. 211-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accurate diagnosis and prompt treatment of pregnancy-associated malaria (PAM) are key aspects in averting adverse pregnancy outcomes. Microscopy is the gold standard in malaria diagnosis, but it has limited detection and availability. When used appropriately, rapid diagnostic tests (RDTs) could be an ideal diagnostic complement to microscopy, due to their ease of use and adequate sensitivity in detecting even sub-microscopic infections. Polymerase chain reaction (PCR) is even more sensitive, but it is mainly used for research purposes. The accuracy and reliability of RDTs in diagnosing PAM was evaluated using microscopy and PCR. Methods: A cohort of pregnant women in north-eastern Tanzania was followed throughout pregnancy for detection of plasmodial infection using venous and placental blood samples evaluated by histidine rich protein 2 (HRP-2) and parasite lactate dehydrogenase (pLDH) based RDTs (Parascreen (TM)) or HRP-2 only (Paracheck Pf (R) and ParaHIT (R) f), microscopy and nested Plasmodium species diagnostic PCR. Results: From a cohort of 924 pregnant women who completed the follow up, complete RDT and microscopy data was available for 5,555 blood samples and of these 442 samples were analysed by PCR. Of the 5,555 blood samples, 49 ((proportion and 95% confidence interval) 0.9% [0.7 - 1.1]) samples were positive by microscopy and 91 (1.6% [1.3-2.0]) by RDT. Forty-six (50.5% [40.5 - 60.6]) and 45 (49.5% [39.4 - 59.5]) of the RDT positive samples were positive and negative by microscopy, respectively, whereas nineteen (42.2% [29.0 - 56.7]) of the microscopy negative, but RDT positive, samples were positive by PCR. Three (0.05% [0.02 - 0.2]) samples were positive by microscopy but negative by RDT. 351 of the 5,461 samples negative by both RDT and microscopy were tested by PCR and found negative. There was no statistically significant difference between the performances of the different RDTs. Conclusions: Microscopy underestimated the real burden of malaria during pregnancy and RDTs performed better than microscopy in diagnosing PAM. In areas where intermittent preventive treatment during pregnancy may be abandoned due to low and decreasing malaria risk and instead replaced with active case management, screening with RDT is likely to identify most infections in pregnant women and out-performs microscopy as a diagnostic tool.
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