Biology subjects

Duffy, P.

Publications and source records attributed to Duffy, P..

7 recordsLinked to original sources

bioRxiv2026

Prenatal immune priming to Plasmodium falciparum is characterized by multi-lineage T-cell responses that are influenced by maternal microchimerism and predict malaria outcomes

In malaria endemic settings, the fetus may be exposed to Plasmodium falciparum (Pf) antigens leading to prenatal immune primming (PIP). The fetus also acquires a graft of maternal cells in utero, a phenomenon known as maternal microchimerism (MMc). We have previously identified that MMc at birth predicts altered malaria susceptibility in early childhood, and we hypothesized that this association may be mediated via two potential mechanisms. First, the fetus may acquire Pf-specific MMc T-cells that directly respond to postnatal parasitemia. Alternatively, MMc may indirectly influence the quantity or quality of PIP. To investigate this hypothesis, infant cord bloods from 97 Malian primigravidae were screened for MMc using qPCR. A subset of ten cord blood mononuclear cells with variable MMc levels were stimulated with purified Pf merozoite extract and activated T-cells were sorted by flow cytometry for scRNAseq analysis. Transcriptional profile was used to differentiate Pf-responsive versus bystander activated T-cells, and MMc cells were identified using the Cellector algorithm. Among Pf-responsive cells, we identified four key populations: activated CD4 T-cells, ZBTB16+ CD4 T-cells, activated V{delta}1+ {gamma}{delta} T-cells, and cytotoxic V{gamma}9V{delta}2+ {gamma}{delta} T-cells. The minority of sorted cells were of MMc origin; however, there was a strong association between the presence of MMc and the quantity and quality of PIP. MMc+ infants had significantly fewer Pf-responsive T-cells, as well as a shifted distribution of these cells with fewer ZBTB16+ CD4 and cytotoxic V{gamma}9V{delta}2+ {gamma}{delta} T-cells. Clinically, MMc was protective from incident parasitemia and febrile malaria, whereas the frequencies of ZBTB16+ CD4 and activated CD4 T-cells were associated with increased risk. Together, these data demonstrate that MMc influences malaria outcomes through regulation of offspring inflammatory responses to Pf.

immunology↗

bioRxiv2026

EVEE: Interpretable variant effect prediction from genomic foundation model embeddings

Scientific foundation models learn high-dimensional representations from diverse data modalities, yet what they encode and how to extract that knowledge remain open questions. Here we show that probing the internal representations of Evo 2, a 7-billion-parameter genomic foundation model, enables accurate and interpretable genetic variant effect prediction. We introduce a covariance-based probe that captures second-order structure from Evo 2 sequence embeddings to predict variant pathogenicity across variant types and functional consequences, matching or exceeding specialized predictors within their domains. To ground these predictions in known biological mechanisms, we train a complementary panel of probes on existing annotations to detect which genomic properties are disrupted by a variant. This categorized evidence is then integrated with each variants genomic context through a language model to generate variant-specific mechanistic hypotheses. Our pathogenicity predictions correlate with experimental measures of variant function, clinical penetrance, and biobank disease associations while the mechanistic hypotheses are consistent with expert reviews, known mechanism classes, and downstream molecular readouts. We release pathogenicity scores, disruption profiles, and contextualized interpretations for 4.2 million variants from the ClinVar database as an open resource through the Evo Variant Effect Explorer (EVEE). More broadly, this structured probing approach offers a general framework for interrogating foundation models across scientific disciplines and grounding their outputs in existing domain concepts.

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↗

bioRxiv2023

Antibody gene features associated with binding and functional activity in vaccine-derived human mAbs targeting malaria parasites

Adjuvants have been essential to malaria vaccine development, but their impact on the vaccine-induced antibody repertoire is poorly understood. Here, we used cDNA sequences from antigen-specific single memory B cells to express 132 recombinant human anti-Pfs230 monoclonal antibodies (mAbs). Alhydrogel(R)-induced mAbs demonstrated higher binding to Pfs230D1, although functional activity was similar between adjuvants. All Alhydrogel(R) mAbs using IGHV1-69 gene bound to recombinant Pfs230D1, but none blocked parasite transmission to mosquitoes; similarly, no AS01 mAb using IGHV1-69 blocked transmission. Functional mAbs from both Alhydrogel(R) and AS01 vaccines used IGHV3-21 and IGHV3-30 genes. Antibodies with the longest CDR3 sequences were associated with binding but not functional activity. This study assesses adjuvant effects on antibody clonotype diversity during malaria vaccination.

immunology↗

bioRxiv2020

A high affinity human monoclonal antibody against Pfs230 binds multiple parasite stages and blocks oocyst formation in mosquitoes

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterized B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230kDa gamete surface protein Pfs2301-3 to neutralize sexual stage P. falciparum parasites and halt their further spread. We generated nine Pfs230 human monoclonal antibodies (mAbs). One mAb potently blocked transmission to mosquitoes in a complement-dependent manner and reacted strongly to gamete surface while eight mAbs showed only low or no blocking activity. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.

immunology↗

bioRxiv2020

A novel fluorescence and DNA combination for complex, long-term marking of mosquitoes

BackgroundCurrent mark release recapture methodologies are limited in their ability to address complex problems in vector biology, such as studying multiple groups overlapping in space and time. Additionally, limited mark retention, reduced post-marking survival, and the large effort in marking, collection and recapture, all complicate effective insect tracking. MethodWe have developed and evaluated a marking method using a fluorescent dye (Smartwater(R)) combined with synthetic DNA tags to informatively and efficiently mark adult mosquitoes using an airbrush pump and nebulizer. Using handheld UV flashlights, the fluorescent marking enabled quick and simple initial detection of recaptures in a simple, field-ready, and non-destructive approach that when combined with a simple, extraction-free PCR on individual mosquito legs provides potentially unlimited marking information. ResultsThis marking, first tested in the laboratory with Anopheles gambiae s.l. mosquitoes, did not affect survival (median ages 24-28 days, p-adj > 0.25), oviposition (median eggs/female of 28.8, 32.5, 33.3 for water, green, red dyes, respectively, p-adj > 0.44), or Plasmodium competence (mean oocysts 5.56 to 10.6, p-adj > 0.95). DNA and fluorescence had 100% retention up to 3 weeks (longest time point tested) with high intensity, indicating marks would persist longer. ConclusionsWe describe a novel, simple, no/low-impact, and long-lasting marking method that allows separation of multiple insect subpopulations by combining unlimited length and sequence variation in the synthetic DNA tags. This method can be readily deployed in the field for marking multiple groups of mosquitoes or other insects.

ecology↗

bioRxiv2018

NK cells inhibit Plasmodium falciparum growth in red blood cells via antibody dependent cellular cytotoxicity

Antibodies acquired naturally through repeated exposure to Plasmodium falciparum are essential in the control of blood-stage malaria. Antibody-dependent functions may include neutralization of parasite-host interactions, complement activation, and activation of Fc receptor functions. A role of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in protection from malaria has not been established. Here we show that IgG isolated from adults living in a malaria-endemic region activated ADCC by primary human NK cells, which lysed infected red blood cells (RBCs) and inhibited parasite growth in an in vitro assay for ADCC-dependent growth inhibition. RBC lysis by NK cells was highly selective for infected RBCs in a mixed culture with uninfected RBCs. Human antibodies to P. falciparum antigens PfEMP1 and RIFIN were sufficient to promote NK-dependent growth inhibition. As these results implicate acquired immunity through NK-mediated ADCC, antibody-based vaccines that target bloodstream parasites should consider this new mechanism of action.

immunology↗