Browsing by Author "Amoako-Sakyi, D."
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Item High Plasma Levels of Soluble Intercellular Adhesion Molecule (ICAM)-1 Are Associated with Cerebral Malaria(PLoS ONE, 2017-12-27) Adukpo, S.; Kusi, K.A.; Ofori, M.F.; Tetteh, J.K.A.; Amoako-Sakyi, D.; Goka, B.Q.; Adjei, G.O.; Edoh, D.A.; Akanmori, B.D.; Gyan, B.A.; Dodoo, D.Background: Cerebral malaria (CM) is responsible for most of the malaria-related deaths in children in sub-Saharan Africa. Although, not well understood, the pathogenesis of CM involves parasite and host factors which contribute to parasite sequestration through cytoadherence to the vascular endothelium. Cytoadherence to brain microvasculature is believed to involve host endothelial receptor, CD54 or intercellular adhesion molecule (ICAM)-1, while other receptors such as CD36 are generally involved in cytoadherence of parasites in other organs. We therefore investigated the contributions of host ICAM- 1 expression and levels of antibodies against ICAM-1 binding variant surface antigen (VSA) on parasites to the development of CM. Methodology/Principal Findings: Paediatric malaria patients, 0.5 to 13 years were recruited and grouped into CM and uncomplicated malaria (UM) patients, based on well defined criteria. Standardized ELISA protocol was used to measure soluble ICAM-1 (sICAM-1) levels from acute plasma samples. Levels of IgG to CD36- or ICAM-1-binding VSA were measured by flow cytometry during acute and convalescent states. Wilcoxon sign rank-test analysis to compare groups revealed association between sICAM-1 levels and CM (p,0.0037). Median levels of antibodies to CD36-binding VSA were comparable in the two groups at the time of admission and 7 days after treatment was initiated (p.0.05). Median levels of antibodies to CD36-binding VSAs were also comparable between acute and convalescent samples within any patient group. Median levels of antibodies to ICAM-1-binding VSAs were however significantly lower at admission time than during recovery in both groups. Conclusions/Significance: High levels of sICAM-1 were associated with CM, and the sICAM-1 levels may reflect expression levels of the membrane bound form. Anti-VSA antibody levels to ICAM-binding parasites was more strongly associated with both UM and CM than antibodies to CD36 binding parasites. Thus, increasing host sICAM-1 levels were associated with CM whilst antibodies to parasite expressing non-ICAM-1-binding VSAs were not.Item Identification of Plasmodium falciparum circumsporozoite protein-specific CD8+ T cell epitopes in a malaria exposed population(Plos One, 2020-02-10) Kusi, K.A.; Aggor, F.E.; Amoah, L.E.; Anum, D.; Nartey, Y.; Amoako-Sakyi, D.; Obiri-Yeboah, D.; Hollingdale, M.; Ganeshan, H.; Belmonte, M.; Peters, B.; Kim, Y.; Tetteh, J.; Kyei-Baafour, E.; Dodoo, D.; Villasante, E.; Sedegah, M.Background Sterile protection against malaria, most likely mediated by parasite-specific CD8+ T cells, has been achieved by attenuated sporozoite vaccination of animals as well as malarianaïve and malaria-exposed subjects. The circumsporozoite protein (CSP)-based vaccine, RTS,S, shows low efficacy partly due to limited CD8+ T cell induction, and inclusion of such epitopes could improve RTS,S. This study assessed 8-10mer CSP peptide epitopes, present in predicted or previously positive P. falciparum 3D7 CSP 15mer overlapping peptide pools, for their ability to induce CD8+ T cell IFN-γ responses in natural malaria-exposed subjects. Methods Cryopreserved PBMCs from nine HLA-typed subjects were stimulated with 23 8-10mer CSP peptides from the 3D7 parasite in IFN-γ ELISpot assays. The CD8+ T cell specificity of IFN-γ responses was confirmed in ELISpot assays using CD8+ T cell-enriched PBMC fractions after CD4+ cell depletion. Results Ten of 23 peptide epitopes elicited responses in whole PBMCs from five of the nine subjects. Four peptides tested positive in CD8+ T cell-enriched PBMCs from two previously positive responders and one new subject. All four immunodominant peptides are restricted by globally common HLA supertypes (A02, A03, B07) and mapped to regions of the CSP antigen with limited or no reported polymorphism. Association of these peptide-specific responses with anti-malarial protection remains to be confirmed. Conclusions The relatively conserved nature of the four identified epitopes and their binding to globally common HLA supertypes makes them good candidates for inclusion in potential multi-epitope malaria vaccinesItem The Role of Genetic and Epigenetic Factors in Endothelial Damage and Repair among Ghanaian Children with Cerebral Malaria(University of Ghana, 2019-03) Amoako-Sakyi, D.The declining malaria burden in endemic regions is predicted to increase the proportion of malaria infections that progress to cerebral malaria (CM). This epidemiologic scenario appears ominous against the backdrop of a poor understanding of CM pathogenesis, lack of effective adjunctive therapies, and poor prognosis after onset. Thus, the need to better understand the pathogenesis of CM has become more apparent. To better understand the pathogenesis of CM, this study explored both genetic and epigenetic aspects of the emerging malaria pathophysiologic paradigm, which pivots on imbalances in endothelial damage and repair in cerebral microvasculature during P. falciparum infections. The Sequenom MassARRA Y platform (iPLEX) was used to genotype a focused panel of 27 single nucleotide polymorphisms (SNPs) in a cross-sectional study involving 221 children. In silico techniques were used to characterize the epigenetic context of SNPs and assess their potential effect on microRNAs and transcription factors. Immune cells and angiogenic factors were measured with Human Magnetic Luminex Assay and flow cytometry, respectively. A striking find of this study was the association of a CDH5 SNP (rs2304527) and an MMP9 SNP (rs3918256) with CM and endothelial integrity respectively. CDH5 SNP (rs2304527) offered protection from CM under the over-dominant inheritance model assumption and children with the heterozygote T/G genotype were approximately three times less likely to have CM relative to their colleagues with the IT -GG genotype. On the other hand, MMP9 SNP (rs3918256) was a risk factor for endothelial damage. Relative to the reference genotype (GG), children with the AA genotype ofrs3918256 were approximately 4 times more likely to be classified as ProDamage under the recessive inheritance model. These two SNPs were subsequently found to disrupt the binding sites of several transcription factors involved in the angiopoietin and tie signalling pathway. Several other SNPs were found to influence the binding affinity of transcription factors but only two (rs3918211 and rs20544) affected micro RNA target sites. Receiver operating characteristic (ROC) analysis to test the ability of angiogenic factors to discriminate between malaria and endothelial integrity phenotypes gave middling results. The best performing angiogenic factor for discriminating eM from UM was NGRI which had only a 66% chance of accurately discriminating eM from UM. Similarly, all angiogenic factors performed poorly in discriminating endothelial integrity phenotypes. This is the first study to implicate rs2304527 and rs3918256 in the pathogenesis of eM. Although in silico analysis suggests some epigenetic roles for these SNPs, future studies may want to further explore their functional roles. Unfortunately, the prospects of using angiogenic factors considered in this study to discriminate between malaria and endothelial integrity phenotypes appear dim. Taken together, this study provides valuable insights on the genetic and epigenetic aspects of endothelial damage and repair during a P. falciparum malaria in Ghanaian children.Item A STAT6 intronic single-nucleotide polymorphism is associated with clinical malaria in Ghanaian children(Libertas Academica Ltd, 2016) Amoako-Sakyi, D.; Adukpo, S.; Kusi, K.A.; Dodoo, D.; Ofori, M.F.; Adjei, G.O.; Edoh, D.E.; Asmah, R.H.; Brown, C.; Adu, B.; Obiri-Yeboah, D.; Futagbi, G.; Abubakari, S.B.; Troye-Blomberg, M.; Akanmori, B.D.; Goka, B.Q.; Arko-Mensah, J.; Gyan, B.A.