Biology subjects

Serralha, M.

Publications and source records attributed to Serralha, M..

4 recordsLinked to original sources

bioRxiv2023

Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years.

Human perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution. In this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)). We found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and IFN-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation. Additionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life.

immunology↗

bioRxiv2020

Mapping the landscape of chromatin dynamics during naïve CD4+ T-cell activation.

T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naive CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naive T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of individual chromatin accessibility peaks that are associated with T-cell activation. The majority of these were localized to intronic and intergenic enhancer regions, marked by active histone modifications whilst quiescence was maintained by repressive histone marks. Regions of activation-associated gains in chromatin accessibility were enriched for well-known pioneer transcription factor motifs, and super-enhancer regions associated with distinct gene regulatory networks. These cis-regulatory elements together brought about distinct transcriptional signatures in activated cells including TNFa-NFkB signaling, hormone-responsive genes, inflammatory response genes and IL2-STAT5 signaling. Our data provides novel insights into the chromatin dynamics and motif usage of T-cell receptor signaling events in early life. The characterized pathways demonstrate the utility of chromatin profiling techniques applied to bio-banked samples for characterizing gene regulatory elements.

immunology↗

bioRxiv2018

Rewiring of Th-memory-associated gene co-expression networks underlie immunotherapy-induced changes in symptom expression in mite-sensitised atopics

BackgroundMultiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate to maintain immunological homeostasis is incomplete. ObjectiveTo explore the potential for unbiased systems-level gene co-expression network analysis to advance understanding of immunotherapy mechanisms. MethodsWe profiled genome-wide allergen-specific Th-memory responses prospectively across 24mths of subcutaneous immunotherapy (SCIT) in 25 rhinitics, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores to 36mths. ResultsPrior to immunotherapy, mite-specific Th-memory response networks involved multiple discrete co-expression modules including those related to Th2-, Type1-IFN-, Inflammation-, and FOXP3/IL2-associated signalling. A signature comprising 109 genes correlated with symptom scores, and these mapped to cytokine signalling/T-cell activation-associated pathways, with upstream drivers including hallmark Th1/Th2-and inflammation-associated genes. Reanalysis after 3.5mths SCIT updosing detected minimal changes to pathway/upstream regulator profiles despite 32.5% reduction in symptoms, however network analysis revealed underlying merging of FOXP3/IL2-with Inflammation-and Th2-associated modules. By 12mths on SCIT, symptoms had reduced by 41% without further significant changes to pathway/upstream regulator or network profiles. Continuing SCIT to 24mths stabilised symptoms at 47% of baseline, accompanied by upregulation of the Type1-IFN-associated network module and its merging into the Th2/FOXP3/IL2/Inflammation module. ConclusionsSCIT stimulates progressive integration of Th-memory-associated Th2-,FOXP3/IL2-, Inflammation-, and Type1-IFN-signalling subnetworks, forming a single highly integrated co-expression network module, maximising potential for stable homeostatic control of allergen-specific Th2 responses via cross-regulation. Th2-anatogonistic Type1-IFN signalling may play a key role in stabilising clinical effects of SCIT. Clinical ImplicationStabilisation of the clinical effectiveness of SCIT involves recruitment of Th2-antagonistic Type 1 IFN-dependent signalling into the overall gene co-expression network underlying the allergen-specific Th-memory response, and this does not occur until the 2nd year of treatment. Capsule summarySCIT-induced rewiring of the gene network governing allergen-specific Th2-memory, as opposed to selective upregulation of genes associated with regulatory functions, underlies the clinical effectiveness of immunotherapy.

immunology↗

bioRxiv2017

Dynamics of the upper airway microbiome in the pathogenesis of asthma-associated persistent wheeze in preschool children

Repeated cycles of infection-associated lower airway inflammation drives the pathogenesis of persistent wheezing disease in children. Tracking these events across a birth cohort during their first five years, we demonstrate that >80% of infectious events indeed involve viral pathogens, but are accompanied by a shift in the nasopharyngeal microbiome (NPM) towards dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change in NPM frequently precedes the appearance of viral pathogens and acute symptoms. In non-sensitized children these events are associated only with \"transient wheeze\" that resolves after age three. In contrast, in children developing early allergic sensitization, they are associated with ensuing development of persistent wheeze, which is the hallmark of the asthma phenotype. This suggests underlying pathogenic interactions between allergic sensitization and antibacterial mechanisms.

genetics↗