Biology subjects

Pearson, R.

Publications and source records attributed to Pearson, R..

7 recordsLinked to original sources

bioRxiv2026

Pfcrt copy number amplification detected in a Plasmodium falciparum outbreak

Antimalarial resistance is one of the greatest threats to malaria elimination. Following an outbreak of Plasmodium falciparum infection in Sabah Malaysia in 2019, 98 samples were sequenced to search for adaptations driving the outbreak. The genomic data revealed evidence of clonal expansion of a strain carrying multiple copies of the chloroquine resistance transporter gene (pfcrt) in 86 cases. A TaqMan qPCR assay was developed to quantify pfcrt copy number, confirming the in silico evidence of duplication. Whilst point mutations in pfcrt have been associated with resistance to chloroquine and other drugs, copy number amplification has not been widely explored as a resistance mechanism. We investigated the genetic architecture of the duplication, revealing a wildtype haplotype (3D7 reference-type with 76K variant) and a novel mutant (with 76T mutation). Application of the TaqMan assay in 43 P. falciparum cases from neighbouring Palawan Island, the Philippines, identified a further two cases with pfcrt duplication. Assessment of the global genomic data in the MalariaGEN Pf8 repository identified a further 86 cases, including 73 (85%) from West Africa with evidence of pfcrt duplication. Amongst 47 monoclonal MalariaGEN cases, majority (95%) comprised wild type and mutant variants at codon 76. Our study reveals a potential previously unconsidered antimalarial resistance mechanism for P. falciparum and provides an assay for surveillance in other populations.

genomics↗

bioRxiv2025

Pf-PeptideFilter: An Interactive Catalogue of Peptide Vaccine Candidates for Plasmodium falciparum

In the last decade, there has been substantial progress in vaccine development for malaria, with two WHO-recommended vaccines now available-RTS,S/AS01 (Mosquirix) and R21/Matrix-M. While these vaccines represent significant milestones, their partial efficacy underscores the need to develop next-generation vaccine approaches capable of broader, longer-lasting protection. Peptide vaccines are a promising strategy, as they focus on short, synthetic peptides specifically selected to trigger a T-cell immune response. However, developing effective peptide vaccines for malaria remains challenging, due to the extensive genetic diversity of Plasmodium falciparum. Currently, tools for comparing and prioritising immunogenic targets remain limited, and existing approaches overlook key factors, including genetic variation, lifecycle-stage expression, and peptide-level properties, each of which are critical for vaccine efficacy. To address these gaps, we developed Pf-PeptideFilter, an interactive web-based application and curated database designed for filtering peptide vaccine targets across the P. falciparum genome. By integrating population-scale genomic information (Pf7), liver-stage transcriptomics, and other biological annotations, Pf-PeptideFilter enables users to interactively filter potential vaccine candidates from the P. falciparum genome, based on several criteria relevant to vaccine design. The app allows users to prioritise candidate genes and peptides with immunogenic potential and export shortlists for incorporation into experimental workflows, offering an interactive platform for rational peptide vaccine design in P. falciparum. Author SummaryMalaria vaccines are challenging to design because the parasite responsible for most infections, Plasmodium falciparum, is highly genetically diverse. If a vaccine targets part of the parasite proteome that varies between strains, it may protect against only a subset of parasites and perform poorly across regions. Peptide vaccines offer a promising approach, by focusing immune responses on short, synthetic peptides selected to trigger T-cell immunity. However, identifying which peptides to include in a vaccine is difficult, as the parasite genome contains thousands of genes and huge numbers of potential peptide targets. Here, we introduce Pf-PeptideFilter, an interactive tool that helps researchers prioritise peptide vaccine candidates using a series of biologically relevant filters. We integrate population-scale genome variation from thousands of parasite samples with information on gene expression during liver infection, similarity to human proteins, and conservation across related parasite species. Users can adjust filtering thresholds and immediately see how these choices affect which genes and peptides are retained. Pf-PeptideFilter generates downloadable shortlists designed to support experimental follow-up, providing a robust and transparent platform for the early stages of vaccine design.

genomics↗

bioRxiv2024

A complex Plasmodium falciparum cryptotype circulating at low frequency across the African continent

The population structure of the malaria parasite Plasmodium falciparum can reveal underlying demographic and adaptive evolutionary processes. Here, we analyse population structure in 4,376 P. falciparum genomes from 21 countries across Africa. We identified a strongly differentiated cluster of parasites, comprising [~]1.2% of samples analysed, geographically distributed over 13 countries across the continent. Members of this cluster, named AF1, carry a genetic background consisting of a large number of highly differentiated variants, rarely observed outside this cluster, at a multitude of genomic loci distributed across most chromosomes. At these loci, the AF1 haplotypes appear to have common ancestry, irrespective of the sampling location; outside the shared loci, however, AF1 members are genetically similar to their sympatric parasites. AF1 parasites sharing up to 23 genomic co-inherited regions were found in all major regions of Africa, at locations over 7,000 km apart. We coined the term cryptotype to describe a complex common background which is geographically widespread, but concealed by genomic regions of local origin. Most AF1 differentiated variants are functionally related, comprising structural variations and single nucleotide polymorphisms in components of the MSP1 complex and several other genes involved in interactions with red blood cells, including invasion and erythrocyte antigen export. We propose that AF1 parasites have adapted to some as yet unidentified evolutionary niche, by acquiring a complex compendium of interacting variants that rarely circulate separately in Africa. As the cryptotype spread across the continent, it appears to have been maintained mostly intact in spite of recombination events, suggesting a selective advantage. It is possible that other cryptotypes circulate in Africa, and new analysis methods may be needed to identify them.

genomics↗

bioRxiv2021

Cystathionine-β-synthase is essential for AKT-induced senescence and suppresses the development of gastric cancers with PI3K/AKT activation

Hyperactivation of oncogenic pathways downstream of RAS and PI3K/AKT in normal cells induces a senescence-like phenotype that acts as a tumor-suppressive mechanism that must be overcome during transformation. We previously demonstrated that AKT-induced senescence (AIS) is associated with profound transcriptional and metabolic changes. Here, we demonstrate that human fibroblasts undergoing AIS display increased Cystathionine-{beta}-synthase (CBS) expression and consequent activation of the transsulfuration pathway controlling hydrogen sulfide (H2S) and glutathione (GSH) metabolism. Activated transsulfuration pathway during AIS maintenance enhances the antioxidant capacity, protecting senescent cells from ROS-induced cell death via GSH and H2S. Importantly, CBS depletion allows cells that have undergone AIS to escape senescence and re-enter the cell cycle, indicating the importance of CBS activity in maintaining AIS. Mechanistically, we show this restoration of proliferation is mediated through suppressing mitochondrial respiration and reactive oxygen species (ROS) production and increasing GSH metabolism. These findings implicate a potential tumor-suppressive role for CBS in cells with inappropriately activated PI3K/AKT signaling. Consistent with this concept, in human gastric cancer cells with activated PI3K/AKT signaling, we demonstrate that CBS expression is suppressed due to promoter hypermethylation. CBS loss cooperates with activated PI3K/AKT signaling in promoting anchorage-independent growth of gastric epithelial cells, while CBS restoration suppresses the growth of gastric tumors in vivo. Taken together, we find that CBS is a novel regulator of AIS and a potential tumor suppressor in PI3K/AKT-driven gastric cancers, providing a new exploitable metabolic vulnerability in these cancers.

cell biology↗

bioRxiv2020

Intrinsic multiplication rate variation and plasticity of human blood stage malaria parasites

Pathogen multiplication rate is theoretically an important determinant of virulence, although often poorly understood. We show intrinsic multiplication rate variation of the major human malaria parasite Plasmodium falciparum to be associated with blood-stage infection intensity. A panel of clinical isolates from a highly endemic West African population was analysed repeatedly during five months of continuous culture, showing a range of exponential multiplication rates at all timepoints tested, mean rates increasing over time. All isolates had different genome sequences, many containing within-isolate diversity that decreased over time, but increases in multiplication rates were not primarily attributable to genomic selection. New mutants, including premature stop codons emerging in a few isolates, did not attain sufficiently high frequencies to substantially affect overall multiplication rates. Significantly, multiplication rate variation at each of the cultured timepoints robustly correlated with parasite levels in patients at clinical presentation, indicating parasite control of multiplication that contributes to virulence.

microbiology↗

bioRxiv2020

Whole Genome Sequencing of Plasmodium vivax Isolates Reveals Frequent Sequence and Structural Polymorphisms in Erythrocyte Binding Genes

Plasmodium vivax malaria is much less common in Africa than the rest of the world because the parasite relies primarily on the Duffy antigen/chemokine receptor (DARC) to invade human erythrocytes, and the majority of Africans are Duffy negative. Recently, there has been a dramatic increase in the reporting of P. vivax cases in Africa, with a high number of them being in Duffy negative individuals, potentially indicating P. vivax has evolved an alternative invasion mechanism that can overcome Duffy negativity. Here, we analyzed single nucleotide polymorphism (SNP) and copy number variation (CNV) in Whole Genome Sequence (WGS) data from 44 P. vivax samples isolated from symptomatic malaria patients in southwestern Ethiopia, where both Duffy positive and Duffy negative individuals are found. A total of 236,351 SNPs were detected, of which 21.9% was nonsynonymous and 78.1% was synonymous mutations. The largest number of SNPs were detected on chromosomes 9 (33,478 SNPs; 14% of total) and 10 (28,133 SNPs; 11.9%). There were particularly high levels of polymorphism in erythrocyte binding gene candidates including reticulocyte binding protein 2c (RBP2c), merozoite surface protein 1 (MSP1), and merozoite surface protein 3 (MSP3.5, MSP3.85 and MSP3.9). Thirteen genes related to immunogenicity and erythrocyte binding function were detected with significant signals of positive selection. Variation in gene copy number was also concentrated in genes involved in host-parasite interactions, including the expansion of the Duffy binding protein gene (PvDBP) on chromosome 6 and several PIR genes. Based on the phylogeny constructed from the whole genome sequences, the expansion of these genes was an independent process among the P. vivax lineages in Ethiopia. We further inferred transmission patterns of P. vivax infections among study sites and showed various levels of gene flow at a small geographical scale. The genomic features of P. vivax provided baseline data for future comparison with those in Duffy-negative individuals, and allowed us to develop a panel of informative Single Nucleotide Polymorphic markers diagnostic at a micro-geographical scale.

genomics↗

bioRxiv2016

Natural diversity of the malaria vector Anopheles gambiae

The sustainability of malaria control in Africa is threatened by rising levels of insecticide resistance, and new tools to prevent malaria transmission are urgently needed. To gain a better understanding of the mosquito populations that transmit malaria, we sequenced the genomes of 765 wild specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa. The data reveal high levels of genetic diversity, with over 50 million single nucleotide polymorphisms across the 230 Mbp genome. We observe complex patterns of population structure and marked variations in local population size, some of which may be due at least in part to malaria control interventions. Insecticide resistance genes show strong signatures of recent selection associated with multiple independent mutations spreading over large geographical distances and between species. The genetic variability of natural populations substantially reduces the target space for novel gene-drive strategies for mosquito control. This large dataset provides a foundation for tracking the emergence and spread of insecticide resistance and developing new vector control tools.

genomics↗