Biology subjects

Takala-Harrison, S.

Publications and source records attributed to Takala-Harrison, S..

8 recordsLinked to original sources

bioRxiv2025

Computational Prioritization of T Cell Epitopes to Overcome HLA Restriction and Antigenic Diversity in Plasmodium falciparum

Developing a highly effective malaria vaccine remains challenging due to Plasmodium falciparums antigenic diversity and human leukocyte antigen (HLA) polymorphisms, which complicate vaccine antigen selection and limit immune protection. The first recommended malaria vaccine, RTS,S, provides only partial, allele-specific protection with waning immunity over time, and the more recently developed R21 vaccine will likely encounter the same hurdles. To address these challenges, we developed a computational tool that integrates P. falciparum sequence diversity, predicted T cell epitope-HLA binding affinities, and HLA allele frequencies from sub-Saharan Africa to identify conserved, immunogenic epitopes with broad population coverage. We analyzed 42 P. falciparum proteins, previously identified as vaccine candidate antigens, and generated consensus sequences using data from 18 African countries, and then incorporated HLA allele frequencies from 24 sub-Saharan populations. CD8+ and CD4+ T cell epitopes were predicted using NetMHCpan-4.1 and NetMHCIIpan-4.1. Our novel tool, T cell Epitope Nomination (TEpiNom), used greedy optimization to filter and select epitopes based on epitope sequence conservation (>95%), binding affinity (median rank <10%), and broad HLA coverage, minimizing redundancy to reduce immune escape risk. Our tool identified 2,265 MHC I and 1,992 MHC II conserved epitopes spanning pre-erythrocytic, erythrocytic, and sexual stage proteins. Key MHC I epitopes from pre-erythrocytic antigens HSP70-2, SLARP/SAP1, p36, FabZ, LISP1, LSA1, UIS3, p24_2, PL, and FabG achieved near 100% HLA-A, HLA-B, and HLA-C coverage, and MHC II epitopes from pre-erythrocytic, erythrocytic, or sexual antigens provided 98.5%-100% coverage for a given parasite life stage. This strategy advances malaria vaccine design by integrating epitope promiscuity and multistage antigen selection to support broad, durable protection and identify promising multi-epitope malaria vaccine candidates for subsequent experimental validation. Our computational framework is adaptable for vaccine development against other genetically diverse and immunologically evasive pathogens.

bioinformatics↗

bioRxiv2024

Variation in spatial population structure in the Anopheles gambiae species complex

Anopheles gambiae, Anopheles coluzzii, and Anopheles arabiensis are three of the most widespread vectors of malaria parasites, with geographical ranges stretching across wide swaths of Africa. Understanding the population structure of these closely related species, including the extent to which populations are connected by gene flow, is essential for understanding how vector control implemented in one location might indirectly affect vector populations in other locations. Here, we assessed the population structure of each species based on a combined data set of publicly available and newly processed whole-genome sequences. The data set included single nucleotide polymorphisms from whole genomes of 2,410 individual mosquitoes sampled from 128 locations across 19 African countries. We found that A. gambiae sampled from several countries in West and Central Africa showed low genetic differentiation from each other according to principal components analysis (PCA) and ADMIXTURE modeling. Using Estimated Effective Migration Surfaces (EEMS), we showed that this low genetic differentiation indicates high effective migration rates for A. gambiae across this region. Outside of this region, we found eight groups of sampling locations from Central, East, and Southern Africa for which A. gambiae showed higher genetic differentiation, and lower effective migration rates, between each other and the West/Central Africa group. These results indicate that the barriers to and corridors for migration between populations of A. gambiae differ across the geographical range of this malaria vector species. Using the same methods, we found higher genetic differentiation and lower migration rates between populations of A. coluzzii in West and Central Africa than for A. gambiae in the same region. In contrast, we found lower genetic differentiation and higher migration rates between populations of A. arabiensis in Tanzania, compared to A. gambiae in the same region. These differences between A. gambiae, A. coluzzii, and A. arabiensis indicate that migration barriers and corridors may vary, even between very closely related species. Overall, our results demonstrate that migration rates vary both within and between species of Anopheles mosquitoes, presumably based on species-specific responses to the ecological or environmental conditions that may impede or facilitate migration, and the geographical patterns of these conditions across the landscape. Together with previous findings, this study provides robust evidence that migration rates between populations of malaria vectors depend on the ecological context, which should be considered when planning surveillance of vector populations, monitoring for insecticide resistance, and evaluating interventions.

ecology↗

bioRxiv2024

Benchmarking and Optimization of Methods for the Detection of Identity-By-Descent in Plasmodium falciparum

Genomic surveillance is crucial for identifying at-risk populations for targeted malaria control and elimination. Identity-by-descent (IBD) is increasingly being used in Plasmodium population genomics to estimate genetic relatedness, effective population size (Ne), population structure, and signals of positive selection. Despite its potential, a thorough evaluation of IBD segment detection tools for species with high recombination rates, such as P. falciparum, remains absent. Here, we perform comprehensive benchmarking of IBD callers - probabilistic (hmmIBD, isoRelate), identity-by-state-based (hap-IBD, phased IBD) and others (Refined IBD) - using population genetic simulations tailored for high recombination, and IBD quality metrics at both the IBD segment level and the IBD-based downstream inference level. Our results demonstrate that low marker density per genetic unit, related to high recombination relative to mutation, significantly compromises the accuracy of detected IBD segments. In genomes with high recombination rates resembling P. falciparum, most IBD callers exhibit high false negative rates for shorter IBD segments, which can be partially mitigated through optimization of IBD caller parameters, especially those related to marker density. Notably, IBD detected with optimized parameters allows for more accurate capture of selection signals and population structure; IBD-based Ne inference is very sensitive to IBD detection errors, with IBD called from hmmIBD uniquely providing less biased estimates of Ne in this context. Validation with empirical data from the MalariaGEN Pf 7 database, representing different transmission settings, corroborates these findings. We conclude that context-specific evaluation and parameter optimization are essential for accurate IBD detection in high-recombining species and recommend hmmIBD for Plasmodium species, especially for quality-sensitive analyses, such as estimation of Ne. Our optimization and high-level benchmarking methods not only improve IBD segment detection in high-recombining genomes but also enhance overall genomic analysis, paving the way for more accurate genomic surveillance and targeted intervention strategies for malaria.

evolutionary biology↗

bioRxiv2024

Immune gene expression changes more during a malaria transmission season than between consecutive seasons.

Plasmodium parasites caused over 600,000 deaths in 2022. In Mali, P. falciparum is responsible for the majority of malaria cases and deaths and is transmitted seasonally. Anti-malarial immunity develops slowly over repeated exposures to P. falciparum but some aspects of this immunity (e.g., antibody titers) wane during the non-transmission, dry season. Here, we sequenced RNA from 33 pediatric blood samples collected during P. falciparum infections at the beginning or end of a transmission season and characterized the host and parasite gene expression profiles of paired, consecutive infections. Our analyses showed that human gene expression changes more over the course of one transmission season than it does between seasons, with signatures consistent with the partial development of adaptive immunity during one transmission season, contrasting with the stability in gene expression during the dry season. By contrast, P. falciparum gene expression did not seem to vary significantly and remained stable both across and between seasons. Overall, our results provide novel insights into the dynamics of anti-malarial immunity development over short timeframes.

bioinformatics↗

bioRxiv2023

Gene expression analyses reveal differences in children's response to malaria according to their age

In Bandiagara, Mali, children experience on average two clinical malaria episodes per season. However, even in the same transmission area, the number of uncomplicated symptomatic infections, and their parasitemia, vary dramatically among children. To examine the factors contributing to these variations, we simultaneously characterized the host and parasite gene expression profiles from 136 children with symptomatic falciparum malaria and analyzed the expression of 9,205 human and 2,484 Plasmodium genes. We used gene expression deconvolution to estimate the relative proportion of immune cells and parasite stages in each sample and to adjust the differential gene expression analyses. Parasitemia explained much of the variation in both host and parasite gene expression and revealed that infections with higher parasitemia had more neutrophils and fewer T cells, suggesting parasitemia-dependent neutrophil recruitment and/or T cell extravasation to secondary lymphoid organs. The childs age was also strongly correlated with gene expression variations. Plasmodium falciparum genes associated with age suggested that older children carried more male gametocytes, while host genes associated with age indicated a stronger innate response (through TLR and NLR signaling) in younger children and stronger adaptive immunity (through TCR and BCR signaling) in older children. These analyses highlight the variability in host responses and parasite regulation during P. falciparum symptomatic infections and emphasize the importance of considering the childrens age when studying and treating malaria infections. One Sentence SummaryHuman and P. falciparum gene expression differs according to the infections parasitemia and the childs age, highlighting an age-dependent response to malaria and complex cellular and molecular -host/parasite interactions.

microbiology↗

bioRxiv2023

Strong Positive Selection Biases Identity-By-Descent-Based Inferences of Recent Demography and Population Structure in Plasmodium falciparum

Malaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD). Yet, strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we utilized simulations, a true IBD inference algorithm, and empirical datasets from different malaria transmission settings to investigate the extent of such bias and explore potential correction strategies. We analyzed whole genome sequence data generated from 640 new and 4,026 publicly available Plasmodium falciparum clinical isolates. Our findings demonstrated that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discovered that the removal of IBD peak regions partially restored the accuracy of IBD-based inferences, with this effect contingent on the populations background genetic relatedness. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.

evolutionary biology↗

bioRxiv2022

Malian children infected with Plasmodium ovale and Plasmodium falciparum display very similar gene expression profiles.

Plasmodium parasites caused 241 million cases of malaria and over 600,000 deaths in 2020. Both P. falciparum and P. ovale are endemic to Mali and cause malaria illness, with P. falciparum infections typically being more severe. Here, we sequenced RNA from nine pediatric blood samples collected during uncomplicated, symptomatic infections with either P. falciparum or P. ovale and characterized the host and parasite gene expression profiles. We found that human gene expression varies more between individuals than according to the parasite species causing the infection, while parasite gene expression profiles cluster by species. Additionally, we characterized DNA polymorphisms of the parasites directly from the RNA-seq reads and found comparable levels of genetic diversity in both species despite dramatic differences in prevalence. Our results provide unique insights into host-pathogen interactions during malaria infections and their variations according to the infecting Plasmodium species, which will be critical to develop better elimination strategies against all human Plasmodium parasites. Author SummaryMultiple species of Plasmodium parasites can cause human malaria. Most studies and elimination efforts target P. falciparum, the most common cause of malaria worldwide and the species responsible for the vast majority of the mortality. Other Plasmodium species, such as P. ovale, typically lead to less severe forms of the disease but little is known about the molecular mechanisms at play during malaria infections with different parasites. We analyzed host and parasite gene expression from children successively infected with P. ovale and P. falciparum and found that, while the parasite gene expression differed significantly, the transcriptional profiles of the host immune cells were similar in P. ovale or P. falciparum infections. This suggests that infected individuals respond to uncomplicated malaria infections similarly, regardless of the Plasmodium species causing the infection, and that alternative immune processes may become important during the progression to severe P. falciparum malaria (rather than being inherent features of P. falciparum infections). Additionally, we observed similar levels of genetic diversity among P. ovale and P. falciparum parasites, suggesting that the P. ovale population might be larger than currently thought, possibly due to extensive misdiagnosis or the existence of hidden reservoirs of parasites.

microbiology↗

bioRxiv2019

Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential

BackgroundPlasmodium falciparum (Pf) whole-organism sporozoite vaccines have provided excellent protection against controlled human malaria infection (CHMI) and naturally transmitted heterogeneous Pf in the field. Initial CHMI studies showed significantly higher durable protection against homologous than heterologous strains, suggesting the presence of strain-specific vaccine-induced protection. However, interpretation of these results and understanding of their relevance to vaccine efficacy (VE) have been hampered by the lack of knowledge on genetic differences between vaccine and CHMI strains, and how these strains are related to parasites in malaria endemic regions.\n\nMethodsWhole genome sequencing using long-read (Pacific Biosciences) and short-read (Illumina) sequencing platforms was conducted to generate de novo genome assemblies for the vaccine strain, NF54, and for strains used in heterologous CHMI (7G8 from Brazil, NF166.C8 from Guinea, and NF135.C10 from Cambodia). The assemblies were used to characterize sequence polymorphisms and structural variants in each strain relative to the reference Pf 3D7 (a clone of NF54) genome. Strains were compared to each other and to clinical isolates from South America, Sub-Saharan Africa, and Southeast Asia.\n\nResultsWhile few variants were detected between 3D7 and NF54, we identified tens of thousands of variants between NF54 and the three heterologous strains both genome-wide and within regulatory and immunologically important regions, including in pre-erythrocytic antigens that may be key for sporozoite vaccine-induced protection. Additionally, these variants directly contribute to diversity in immunologically important regions of the genomes as detected through in silico CD8+ T cell epitope predictions. Of all heterologous strains, NF135.C10 consistently had the highest number of unique predicted epitope sequences when compared to NF54, while NF166.C8 had the lowest. Comparison to global clinical isolates revealed that these four strains are representative of their geographic region of origin despite long-term culture adaptation; of note, NF135.C10 is from an admixed population, and not part of recently-formed drug resistant subpopulations present in the Greater Mekong Sub-region.\n\nConclusionsThese results are assisting the interpretation of VE of whole-organism vaccines against homologous and heterologous CHMI, and may be useful in informing the choice of strains for inclusion in region-specific or multi-strain vaccines.

genomics↗