Biology subjects

Little, F.

Publications and source records attributed to Little, F..

4 recordsLinked to original sources

bioRxiv2025

Maternal and early-life longitudinal cytokine profiles in a South African birth cohort: the impact of HIV

BackgroundDuring pregnancy, exposure to maternal HIV and a disrupted cytokine environment may impact foetal immune development and health outcomes through cytokine-mediated mechanisms. We evaluated (i) peripheral blood cytokine differences in pregnant women with and without HIV, (ii) longitudinal differences in HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) children, and (iii) latent cytokine groupings. Additionally, we explored the impact of maternal antiretroviral treatment (ART) initiation timing on cytokine levels. MethodsWe assessed 399 mother-child pairs in the Drakenstein Child Health Study (DCHS), in pregnancy (n=179 mothers with HIV and n=220 without HIV) and their children at 6 weeks, 2-, 3-, and 5-years. Eighteen serum immune markers were quantified with ELISA and multiplex assays. Group differences were assessed with linear regression, and longitudinal analysis of child immune trajectories was evaluated with linear mixed models. Latent cytokine groupings were assessed using an integrated ANOVA framework with principal component analysis. ResultsPregnant women living with HIV had lower GM-CSF, IL-10, IL-12p70, IL-13, IL-2, IL-4, IL-6, IL-7, NGAL, and MMP-9 levels, and higher TNF-, IFN-{gamma}, and sCD14 levels compared to women without HIV. HEU children had lower GM-CSF, IL-10, IL-12p70, IL-1{beta}, IL-2, and IL-4 and higher sCD14 levels over time compared to HUU children and revealed distinct immunoregulatory profiles. ART initiation during compared to before pregnancy was associated with higher immune marker levels in mothers but not in their children. ConclusionsAltered immune responses are present in mothers with HIV that persist longitudinally in their HEU children, potentially contributing to their health outcomes.

immunology↗

bioRxiv2024

Using short-read 16S rRNA sequencing of multiple variable regions to generate high-quality results to a species level.

IntroductionShort-read amplicon sequencing studies have typically focused on 1-2 variable regions of the 16S rRNA gene. Species-level resolution is limited in these studies, as each variable region enables the characterisation of a different subsection of the microbiome. Although long-read sequencing techniques take advantage of all 9 variable regions by sequencing the entire 16S rRNA gene, they are substantially more expensive. This work assessed the feasibility of accurate species-level resolution and reproducibility using a relatively new sequencing kit and bioinformatics pipeline developed for short-read sequencing of multiple variable regions of the 16S rRNA gene. In addition, we evaluated the potential impact of different sample collection methods on our outcomes. MethodsUsing xGenTM 16S Amplicon Panel v2 kits, sequencing of all 9 variable regions of the 16S rRNA gene was carried out on an Illumina MiSeq platform. Mock cells and mock DNA for 8 bacterial species were included as extraction and sequencing controls respectively. Within-run and between-run replicate samples, and pairs of stool and rectal swabs collected at 0-5 weeks from the same participants, were incorporated. Observed relative abundances of each species were compared to theoretical abundances provided by ZymoBIOMICS. Paired Wilcoxon rank sum tests and distance-based intraclass correlation coefficients were used to statistically compare alpha and beta diversity measures, respectively, for pairs of replicates and stool/rectal swab sample pairs. ResultsUsing multiple variable regions of the 16S ribosomal Ribonucleic Acid (rRNA) gene, we found that we could accurately identify taxa to a species level and obtain highly reproducible results at a species level. Yet, the microbial profiles of stool and rectal swab sample pairs differed substantially despite being collected concurrently from the same infants. ConclusionThis protocol provides an effective means for studying infant gut microbial samples at a species level. However, sample collection approaches need to be accounted for in any downstream analysis.

microbiology↗

bioRxiv2024

Distinct alterations in white matter properties and organization related to maternal treatment initiation in neonates exposed to HIV but uninfected

HIV exposed-uninfected (HEU) infants and children are at risk of developmental delays as compared to uninfected unexposed (HUU) populations. The effects of exposure to in utero HIV and ART regimens on the HEU the developing brain are not well understood. In a cohort of 2-week-old newborns, we used diffusion tensor imaging (DTI) tractography and graph theory to examine the influence of HIV and ART exposure in utero on neonate white matter integrity and organisation. The cohort included HEU infants born to mothers who started ART before conception (HEUpre) and after conception (HEUpost), as well as HUU infants from the same community. We investigated HIV exposure and ART duration group differences in DTI metrics (fractional anisotropy (FA) and mean diffusivity (MD)) and graph measures across white matter. We found increased MD in white matter connections involving the thalamus and limbic system in the HEUpre group compared to HUU. We further identified reduced nodal efficiency in the basal ganglia. Within the HEUpost group, we observed reduced FA in cortical-subcortical and cerebellar connections as well as decreased transitivity in the hindbrain area compared to HUU. Overall, our analysis demonstrated distinct alterations in white matter integrity related to the timing of maternal ART initiation that influence regional brain network properties.

neuroscience↗

bioRxiv2018

A comparison of antigen-specific T cell responses induced by six novel tuberculosis vaccine candidates

Eradication of tuberculosis (TB), the worlds leading cause of death due to infectious disease, requires a highly efficacious TB vaccine. Many TB vaccine candidates are in preclinical and clinical development but only a few can be advanced to large-scale efficacy trials due to limited global resources. We aimed to perform a statistically rigorous comparison of the antigen-specific T cell responses induced by six novel TB vaccine candidates and the only licensed TB vaccine, Bacillus Calmette-Guerin (BCG). We propose that the antigen-specific immune response induced by such vaccines provides an objective, data-driven basis for prioritisation of vaccine candidates for efficacy testing. We analyzed frequencies of antigen-specific CD4 and CD8 T cells expressing IFN{gamma}, IL-2, TNF and/or IL-17 from adolescents or adults, with or without Mycobacterium tuberculosis (M.tb) infection, who received MVA85A, AERAS-402, H1:IC31, H56:IC31, M72/AS01E, ID93+GLA-SE or BCG. Two key response characteristics were analyzed, namely response magnitude and cytokine co-expression profile of the memory T cell response that persisted above the pre-vaccination response to the final study visit in each trial. All vaccines preferentially induced antigen-specific CD4 T cell responses expressing Th1 cytokines; levels of IL-17-expressing cells were low or not detected. In M.tb-uninfected and -infected individuals, M72/AS01E induced higher memory Th1 cytokine-expressing CD4 T cell responses than other novel vaccine candidates. Cytokine co-expression profiles of memory CD4 T cells induced by different novel vaccine candidates were alike. Our study suggests that the T cell response feature which most differentiated between the TB vaccine candidates was response magnitude, whilst functional profiles suggested a lack of response diversity. Since M72/AS01E induced the highest memory CD4 T cell response it demonstrated the best vaccine take. In the absence of immunological correlates of protection the likelihood of finding a protective vaccine by empirical testing of candidates may be increased by the addition of candidates that induce distinct immune characteristics.\n\nAuthor summaryTuberculosis (TB) causes more deaths than any other single infectious disease, and a new, improved vaccine is needed to control the epidemic. Many new TB vaccine candidates are in clinical development, but only one or two can be advanced to expensive efficacy trials. In this study, we compared magnitude and functional attributes of memory T cell responses induced in recently conducted clinical trials by six TB vaccine candidates, as well as BCG. The results suggest that these vaccines induced CD4 and CD8 T cell responses with similar functional attributes, but that one vaccine, M72/AS01E, induced the largest responses. This finding may indicate a lack of diversity in T cell responses induced by different TB vaccine candidates. A repertoire of vaccine candidates that induces more diverse immune response characteristics may increase the chances of finding a protective vaccine against TB.

immunology↗