Browsing by Author "Tukwasibwe, Stephen"
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Item Associations between Aminoquinoline Resistance Genotypes and Clinical Presentations of Plasmodium falciparum Infection in Uganda(Antimicrobial Agents and Chemotherapy, 2020) Cuu, Gloria; Asua, Victor; Tukwasibwe, Stephen; Nsobya, Sam L.; Nanteza, Ann; Kimuda, Magambo Phillip; Mpimbaza, Arthur; Rosenthal, Philip J.Mutations that mediate resistance of Plasmodium falciparum to aminoquinoline antimalarials are selected by prior drug use and may alter parasite fitness, but associations with clinical presentations are uncertain. We evaluated genotypes in samples from a case-control study of determinants of severe malaria in Ugandan children 4 months to 10 years of age. We studied 274 cases with severe malaria matched by age and geography to 275 uncomplicated malaria controls and 179 asymptomatic parasitemic controls. The overall prevalence of mutations of interest (considering mixed results as mutant) was 67.0% for PfCRT K76T, 8.5% for PfMDR1 N86Y, 71.5% for PfMDR1 Y184F, and 14.7% for PfMDR1 D1246Y. Compared to asymptomatic controls, the odds of mutant PfCRT 76T were lower for uncomplicated (odds ratio, 0.42 [95% confidence interval, 0.24 to 0.72]; P < 0.001) or severe (0.56 [0.32 to 0.97]; P = 0.031) malaria; the odds of mutant PfMDR1 86Y were lower for uncomplicated (0.33 [0.16 to 0.65]; P < 0.001) or severe (0.21 [0.09 to 0.45]; P < 0.001) malaria; and the odds of mutant PfMDR1 1246Y were higher for uncomplicated (1.83 [0.90 to 3.98]; P = 0.076) or severe (2.06 [1.01 to 4.55]; P = 0.033) malaria. The odds of mutant PfMDR1 184F were lower in severe than asymptomatic (0.59 [0.37 to 0.92]; P = 0.016) or uncomplicated (0.61 [0.41 to 0.90]; P = 0.009) malaria. Overall, the PfCRT 76T and PfMDR1 86Y mutations were associated with decreased risk of symptomatic malaria, PfMDR1 1246Y was associated with increased risk of symptomatic malaria, and PfMDR1 184F was associated with decreased risk of severe malaria. These results offer insights into parasite genotypes in children with different presentations, although the basis for the identified associations is likely complex.Item Balanced impacts of fitness and drug pressure on the evolution of PfMDR1 polymorphisms in Plasmodium falciparum(Malaria journal, 2021) Duvalsaint, Marvin; Conrad, Melissa D.; Tukwasibwe, Stephen; Tumwebaze, Patrick K.; Cooper, Roland A.; Rosenthal, Philip J.Anti-malarial drug resistance may be limited by decreased fitness in resistant parasites. Important contributors to resistance are mutations in the Plasmodium falciparum putative drug transporter PfMDR1.Impacts on in vitro fitness of two common PfMDR1 polymorphisms, N86Y, which is associated with sensitivity to multiple drugs, and Y184F, which has no clear impact on drug sensitivity, were evaluated to study associations between resistance mediators and parasite fitness, measured as relative growth in competitive culture experiments. NF10 P. falciparum lines engineered to represent all PfMDR1 N86Y and Y184F haplotypes were co-cultured for 40 days, and the genetic make-up of the cultures was characterized every 4 days by pyrosequencing. The impacts of culture with anti-malarials on the growth of different haplotypes were also assessed. Lastly, the engineering of P. falciparum containing another common polymorphism, PfMDR1 D1246Y, was attempted. Co-culture results were as follows. With wild type (WT) Y184 fixed (N86/Y184 vs. 86Y/Y184), parasites WT and mutant at 86 were at equilibrium. With mutant 184 F fixed (N86/184F vs. 86Y/184F), mutants at 86 overgrew WT. With WT N86 fixed (N86/Y184 vs. N86/184F), WT at 184 overgrew mutants. With mutant 86Y fixed (86Y/Y184 vs. 86Y/184F), WT and mutant at 86 were at equilibrium. Parasites with the double WT were in equilibrium with the double mutant, but 86Y/Y184 overgrew N86/184F. Overall, WT N86/mutant 184F parasites were less fit than parasites with all other haplotypes. Parasites engineered for another mutation, PfMDR1 1246Y, were unstable in culture, with reversion to WT over time. Thus, the N86 WT is stable when accompanied by the Y184 WT, but incurs a fitness cost when accompanied by mutant 184F. Culturing in the presence of chloroquine favored 86Y mutant parasites and in the presence of lumefantrine favored N86 WT parasites; piperaquine had minimal impact.These results are consistent with those for Ugandan field isolates, suggest reasons for varied haplotypes, and highlight the interplay between drug pressure and fitness that is guiding the evolution of resistance-mediating haplotypes in P. falciparum.Item High Schistosoma mansoni infection intensity is associated with distinct gut microbiome and low levels of systemic cytokines in children along the Albert-Nile, Northern Uganda(Research Square, 2024) Mulindwa, Julius; Lujumba, Ibra; Musiime, Caroline; Namulondo, Joyce; Magambo, Phillip Kimuda; Nyangiri, Oscar; Gloria, Cuu; Mwubaha, Caroline; Tukwasibwe, Stephen; Ssemaganda, Aloysious; Ssewanyana, Isaac; Nerima , Barbara; Baingana, Rhona; Harry, Noyes; Annette, MacLeod; Matovu, EnockBackground Schistosomiasis is a chronic neglected disease that affects millions of people in sub Saharan Africa, with a range of impacts on both host immune responses and the gut microbiome. The gut microbiota plays a fundamental in role in the host’s nutrition, metabolism, protection against pathogens, and modulation of host immunity. There is a need to understand the role of the gut microbiome in pathophysiology of Schistosoma mansoni infection and how this influences the host’s immune response. Methodology: A cross sectional study was carried out on 140 faecal samples collected from school children aged 10-15years residing in the schistosomiasis endemic hot spots of the Albert-Nile, Pakwach district, Northern Uganda. The samples were categorised by S. mansoni infection intensity based on the Kato Katz test. Faecal DNA was isolated and microbiome composition was determined by 16S rRNA V3-V4 sequencing. Plasma Th1/Th2 profiling of 13 cytokines was carried out on the Luminex platform and compared with respect to S. mansoni infection intensities. Results The genera Phascolarctobaterium and Prevotella_7 were significantly enriched (padj < 0.05, LDA > 3.0) in the high S. mansoni infection intensity group whereas, Ruminobacter and Alloprevotella were enriched in the Low infection intensity group. We observed significantly lower systemic Th1/Th2 cytokine levels between the high intensity infection and the control samples (padj < 0.05). Linear regression analysis using all cytokines as covariates showed that the genus Alloprevotella, Streptococcus, Gastranaerophilales and Ruminobacter were associated with systemic IL6 response. Conclusion There are alterations in the gut microbiome of S. mansoni infected children with distinct genera that discriminate the high and low infection intensity that could be potentially used as biomarkers. There is an association between the gut microbiome and systemic cytokine response whose mechanism in chronic disease pathophysiology can be further investigated.Item Killer cell immunoglobulin-like receptor (KIR) genes and their HLA-C ligands in a Ugandan population(Immunogenetics, 2013) Nakimuli, Annettee; Chazara, Olympe; Farrell, Lydia; Hiby, Susan E.; Tukwasibwe, Stephen; Knee, Olatejumoye; Jayaraman, Jyothi; Traherne, James A.; Elliott, Alison M.; Kaleebu, Pontiano; Mirembe, Florence; Moffett, AshleyKiller cell immunoglobulin-like receptor (KIR) genes are expressed by natural killer cells and encoded by a family of genes exhibiting considerable haplotypic and allelic variation. HLA-C molecules, the dominant ligands for KIR, are present in all individuals and are discriminated by two KIR epitopes, C1 and C2.We studied the frequencies of KIR genes and HLA-C1 and C2 groups in a large cohort (n=492) from Kampala, Uganda, East Africa and compared our findings with published data from other populations in sub-Saharan Africa (SSA) and several European populations. We find considerably more KIR diversity and weaker linkage disequilibrium in SSA compared to the European populations and describe several novel KIR genotypes. C1 and C2 frequencies were similar to other SSA populations with a higher frequency of the C2 epitope (54.9 %) compared to Europe (average 39.7 %). Analysis of this large cohort from Uganda in the context of other African populations reveals variations in KIR and HLA-C1 and C2 that are consistent with migrations within Africa and potential selection pressures on these genes. Our results will help understand how KIR/HLA-C interactions contribute to resistance to pathogens and reproductive success.Item A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia.(A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia., 2015) Nakimuli, Annettee; Chazara, Olympe; Hiby, Susan E.; Farrell, Lydia; Tukwasibwe, Stephen; Jayaraman, Jyothi; Traherne, James A.; Trowsdale, John; Colucci, Francesco; Lougee, Emma; Vaughan, Robert W.; Elliott, Alison M.; Byamugisha, Josaphat; Kaleebu, Pontiano; Mirembe, Florence; Nemat-Gorgani, Neda; Parham, Peter; Norman, Paul J.; MoffettMoffett, AshleyItem Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda(The American journal of tropical medicine and hygiene, 2014) Mbogo, George W.; Nankoberanyi, Sheila; Tukwasibwe, Stephen; Baliraine, Frederick N.; Nsobya, Samuel L.; Conrad, Melissa D.; Arinaitwe, Emmanuel; Kamya, Moses; Tappero, Jordan; Staedke, Sarah G.; Dorsey, GrantStandard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistancemediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003–2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008–2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.Item The dawn of a cure for sickle cell disease through CRISPR-based treatment: A critical test of equity in public health genomics(Annals of Human Genetics, 2024) Mboowa, Gerald; Sserwadda, Ivan; Kanyerezi, Stephen; Tukwasibwe, Stephen; Kidenya, BensonEquity in access to genomic technologies, resources, and products remains a great challenge. This was evident especially during the coronavirus disease 2019 (COVID‐19) pandemic when the majority of lower middle‐income countries were unable to achieve at least 10% population vaccination coverage during initial COVID‐19 vaccine rollouts, despite the rapid development of those vaccines. Sickle cell disease (SCD) is an inherited monogenic red blood cell disorder that affects hemoglobin, the protein that carries oxygen through the body. Globally, the African continent carries the highest burden of SCD with at least 240,000 children born each year with the disease. SCD has evolved from a treatable to a curable disease. Recently, the UK medical regulator approved its cure through clustered regularly interspaced short palindromic repeat (CRISPR)‐based treatment, whereas the US Food and Drug Administration has equally approved two SCD gene therapies. This presents a remarkable opportunity to demonstrate equity in public health genomics. This CRISPR‐based treatment is expensive and therefore, a need for an ambitious action to ensure that they are affordable and accessible where they are needed most and stand to save millions of lives.