Biology subjects

Feeney, M.

Publications and source records attributed to Feeney, M..

5 recordsLinked to original sources

bioRxiv2026

Repeated malaria exposure reprograms Vδ2+ γδT cell chromatin accessibility and immune function toward a reversible hyporesponsive state

V{delta}2+ {gamma}{delta} T cells contribute to antimalarial immunity via pro-inflammatory and cytotoxic mechanisms. Among children who have experienced repeated episodes of malaria, V{delta}2+ T cells develop reduced pro-inflammatory function through mechanisms that remain unknown. We hypothesized that recurrent malaria drives coordinated epigenetic and transcriptional remodeling of these semi-innate cells. Using PBMC from Ugandan children in cohorts spanning high and low transmission (10 children) and longitudinally across a marked decline in transmission (20 children, 3 timepoints), we profiled the epigenome and transcriptome of V{delta}2+ T cells by paired bulk ATAC-seq and RNA-seq and by CITE-seq. Higher malaria exposure was associated with reduced V{delta}2+ T cell TNF and IFN{gamma} production and with thousands of differentially accessible chromatin regions. Immunoregulatory genes including LYN, PLCG2, and HAVCR2 (Tim-3) showed increased chromatin accessibility and/or expression at high exposure, whereas pro-inflammatory gene (IFNG, GZMK, IL7R) and AP-1 (JUN/FOS) motif accessibility were increased at low exposure; linkage of regulatory elements with target genes corroborated these associations. Single-cell transcriptional analysis identified a cytotoxic CD8+CD16+CD57+ V{delta}2+ T cell subset. In our in vitro model, repeated stimulation with malaria-infected red blood cells or the phosphoantigen HMBPP was similarly associated with reduced V{delta}2+ T cell degranulation and cytokine production. Diminished responsiveness was predominantly TCR-dependent, accompanied by heightened p38 signaling, and was partially reversed by rest induced by the tyrosine kinase inhibitor dasatinib. Together these data reveal how repeated malaria may reshape cellular immunity by reprogramming V{delta}2+ T cells toward a reversible, hyporesponsive state and highlight targets for therapeutically restoring their function.

immunology↗

bioRxiv2026

Stability of phoneme-related potentials across testing sessions and stimulus presentation conditions

ObjectivesObjective and ecologically valid measures of speech processing can complement conventional audiologic assessments. Phoneme-related potentials (PRPs), derived by averaging listeners electroencephalography (EEG) responses time-locked to phonemes in continuous speech, have emerged as a promising approach for capturing cortical processing of speech in naturalistic listening conditions. Importantly, PRPs reveal speech perception challenges even when conventional audiograms are clinically normal, positioning them as a promising neural marker for suprathreshold listening difficulties that standard audiometry often misses. As a critical step toward clinical translation, this study examined the extent to which PRP-derived measures remain stable across real-world contexts relevant to clinical implementation, including monaural versus binaural presentation, stimulus intensity level, and repeated testing sessions. The study also assessed cortical tracking of lower-level speech acoustics to determine whether the PRP findings could be attributed to acoustic processing. DesignEEG was recorded from 18 young adults with normal hearing as they listened to audiobook speech presented monaurally or binaurally at 60 or 75 dB across two sessions separated by approximately one week. Neural differentiation of phoneme manner-of-articulation classes (vowels, nasals/approximants, fricatives, and stops) in PRPs was quantified using two measures: an F-statistic reflecting between-manner relative to within-manner variability, and classification accuracy from a machine-learning model trained to predict manner class from PRPs. Temporal response function modeling assessed neural tracking of continuous acoustic envelope and onset features of the audiobook speech. ResultsNeither PRP-derived measure of manner differentiation showed significant effects of session, presentation modality, intensity level, or their interactions. Intraclass correlation analyses further indicated moderate-to-good reliability across all three factors. In contrast, neural tracking of the acoustic envelope and acoustic onsets was stronger under binaural than monaural presentation, with binaural presentation eliciting more pronounced cortical responses to the envelope. ConclusionsPRP-derived measures remained relatively stable across modest procedural variations that are common in clinical testing contexts, positioning PRPs as a potent objective index of naturalistic speech processing. This stability may reflect cortical processing of abstract, linguistically relevant speech categories and suggest that PRPs provide complementary information beyond audiologic assessments of peripheral auditory functions and EEG measures that primarily capture lower-level acoustic processing.

neuroscience↗

bioRxiv2025

Hallmarks and metabolic regulation of type 2 activated human lung macrophages

Although human lung macrophages are heterogenous and play key roles during health and disease, the mechanisms that govern their activation and function are unclear, particularly in type 2 settings. Our understanding of how human lung macrophages respond to inflammatory signals have predominantly relied on cell lines or peripheral blood derived cells, which have a limited capacity to reflect the complexity of tissue macrophage responses. Therefore, we isolated macrophages from resected human lung tissue and stimulated them ex vivo under type 2 (IL-4, IL-13, or IL-4 + IL-13) or type 1 (IFN{gamma} + LPS) conditions. Human lung macrophages stimulated with IL-4/13, alone or in combination, significantly upregulated expression of the chemokines CCL17, CCL18 and CCL22, along with the transglutaminase TGM2 and the lipoxygenase ALOX15. This type 2 activation profile was distinct from LPS + IFN{gamma} activated human lung macrophages, which upregulated IL6, IL8, IL1{beta}, TNF and CHI3L1 (YKL-40). Further, type 2 activated human lung macrophage products showed differential metabolic reliance for their induction, with IL-4/13 induced CCL22 being glycolytically controlled, while ALOX15 was regulated by fatty acid oxidation. These data clarify hallmarks of human lung macrophage activation and polarisation in addition to revealing novel metabolic regulation of type 2 markers.

immunology↗

bioRxiv2023

Fractal complexity of Escherichia coli nutrient transport channels is influenced by cell shape and growth environment

Recent mesoscopic characterisation of nutrient-transporting channels in E. coli has allowed the identification and measurement of individual channels in whole mature biofilms. However, their complexity under different physiological and environmental conditions remains unknown. Analysis of confocal micrographs of biofilms formed by cell shape mutants of E. coli shows that channels have a high fractal complexity, regardless of cell phenotype or growth medium. In particular, biofilms formed by the mutant strain {Delta}ompR, which has a wide-cell phenotype, have a higher fractal dimension when grown on rich medium than when grown on minimal medium, with channel complexity affected by glucose and agar concentration in the medium. Osmotic stress leads to a dramatic reduction in {Delta}ompR cell size, but has a limited effect on channel morphology. This work shows that fractal image analysis is a powerful tool to quantify the effect of phenotypic mutations and growth environment on the morphological complexity of internal E. coli biofilm structures. If applied to a wider range of mutant strains, this approach could help elucidate the genetic determinants of channel formation in E. coli biofilms.

microbiology↗

bioRxiv2021

Age dependent changes in circulating Tfh cells influence the development of functional antibodies to malaria in children.

T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies were boosted in children with current infection, and were higher in females. The children with the very highest antibody levels had increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.

immunology↗