Biology subjects

Bradley, J. E.

Publications and source records attributed to Bradley, J. E..

11 recordsLinked to original sources

bioRxiv2024

Superspreaders have lower gut microbial alpha-diversity and distinct gut microbial composition in a natural rodent population

The microbiome is well-known to drive variation in host states (e.g., behaviour, or immunity) that would be expected to modulate the spread of infectious disease - but the role of microbiotal interactions in promoting superspreading by individuals is poorly understood. Superspreaders are individuals with a strongly disproportionate contribution to pathogen transmission, and they come in two forms. Supershedders transmit infection to more individuals because they shed higher levels of a pathogen. Supercontacters transmit infection to more individuals because they have a larger number of social contacts. We explore associations between the gut microbiota and these two forms of superspreading in a wild rodent model - Bartonella spp. bacteraemia in the field vole (Microtus agrestis). We find evidence that, first, individuals fall into distinct shedding and contacting clusters, and second, that higher-contacters have lower and more variable gut microbial alpha-diversity than lower-contacters. We also show evidence that both higher-shedders and higher-contacters have distinct gut microbial composition, and identify OTUs which are differentially abundant in the gut microbiota of these two classes of individuals when compared to lower-shedders and lower-contacters respectively. We find that the Muribaculaceae are associated with differences in both shedding and contacting, and discuss potential mechanisms by which they may be acting on these host traits.

ecology↗

bioRxiv2024

Density-dependent network structuring within and across wild animal systems

High population density should drive individuals to more frequently share space and interact, producing better-connected spatial and social networks [1-4]. Although this theory is fundamental to our understanding of disease dynamics [2,5-8], it remains unconfirmed how local density generally drives individuals positions within their networks, which reduces our ability to understand and predict density-dependent processes [4,9,10]. Here we provide the first general evidence that density drives greater network connectedness at fine spatiotemporal scales, at the scale of individuals within wild animal populations. We analysed 36 datasets of simultaneous spatial and social behaviour in >58,000 individual animals, spanning 30 species of fish, reptiles, birds, mammals, and insects. 80% of systems exhibited strong positive relationships between local density and network centrality. However, >80% of relationships were nonlinear and 75% became shallower at higher values, signifying that demographic and behavioural processes counteract densitys effects, thereby producing saturating trends [11-15]. Densitys effect was much stronger and less saturating for spatial than social networks, such that individuals become disproportionately spatially connected rather than socially at higher densities. Consequently, ecological processes that depend on spatial connections (e.g. indirect pathogen transmission, resource competition, and territory formation) are likely more density-dependent than those involving social interactions (e.g. direct pathogen transmission, aggression, and social learning). These findings reveal fundamental ecological rules governing societal structuring, with widespread implications. Identifying scaling rules based on processes that generalise across systems, such as these patterns of density dependence, might provide the ability to predict network structures in novel systems.

ecology↗

bioRxiv2023

The adaptive immune response to Trichuris in wild versus laboratory mice: An established model system in context

Laboratory model organisms have provided a window into how the immune system functions. An increasing body of evidence, however, suggests that the immune responses of naive laboratory animals may differ substantially to those of their wild counterparts. Past exposure, environmental challenges and physiological condition may all impact on immune responsiveness. Chronic infections of soil-transmitted helminths impose significant health burdens on humans, livestock and wildlife, with limited treatment success. In laboratory mice, Th1 versus Th2 immune polarisation is the major determinant of helminth infection outcome. Here we compared antigen-specific immune responses to the soil-transmitted whipworm Trichuris muris between controlled laboratory and wild free-ranging populations of house mice (Mus musculus domesticus). Wild mice harbouring chronic, low-level infections produced lower levels of cytokines in response to Trichuris antigen than laboratory-housed C57BL/6 mice. Wild mouse effector/memory CD4+ T cell phenotype reflected the antigen-specific cytokine response across the Th1/Th2 spectrum. Increasing worm burden was associated with body condition loss. However, local Trichuris-specific Th1/Th2 balance was positively associated with worm burden only in older wild mice. Thus, although the fundamental relationships between the CD4+ T helper cell response and resistance to T. muris infection are similar in both laboratory and wild M.m.domesticus, there are quantitative differences and age-specific effects that are analogous to human immune responses. These context-dependent immune responses demonstrate the fundamental importance of understanding the differences between model and natural systems for translating mechanistic models to real world immune function.

immunology↗

bioRxiv2022

Chitinase-3-like 1 regulates TH2 cells, TFH cells and IgE following helminth infection

Data from patient cohorts and mouse models of atopic dermatitis, food allergy and asthma strongly support a role for the chitinase-like protein ChI3L1 in allergic disease. To address whether CHI3L1 also contributes to TH2 responses following nematode infection, we infected Chi3l1-/- mice with Heligmosomoides polygyrus (Hp) and analyzed T cell responses. Not surprisingly, we observed impaired TH2 responses in Hp-infected Chi3l1-/- mice. However, we also found that T cell intrinsic expression of Chi3l1 was required for ICOS upregulation following activation of naive CD4 T cells and was necessary for the development of the IL-4+ TFH subset, which supports germinal center (GC) B cell reactions and IgE responses. The requirement for Chi3l1 in TFH and IgE responses was also seen following alum-adjuvanted vaccination. While Chi3l1 was critical for IgE humoral responses it was not required for vaccine or infection induced IgG1 responses. These results suggest that Chi3l1 specifically modulates IgE responses that are highly dependent on help from IL-4-producing TFH cells.

immunology↗

bioRxiv2021

Early-life immune expression profiles predict later life health and fitness in a wild rodent

Individuals differ in the nature of the immune responses they produce, affecting disease susceptibility and ultimately health and fitness. These differences have been hypothesised to have an origin in events experienced early in life that then affect trajectories of immune development and responsiveness. Here we investigate early life influences on immune expression profiles using a natural population of field voles, Microtus agrestis, in which we are able to monitor variation between and within individuals though time by repeat (longitudinal) sampling of individually marked animals. We analysed the co-expression of 20 immune genes in early life to create a correlational network consisting of three main clusters, one of which (containing Gata3, Il10 and Il17) was associated with later life reproductive success and susceptibility to chronic bacterial (Bartonella) infection. More detailed analyses supported associations between early life expression of Il17 and reproductive success later in life, and of increased Il10 expression early in life and later infection with Bartonella. We also found significant association between an Il17 genotype and the early life expression of Il10. Our results demonstrate that immune expression profiles can be manifested during early life with effects that persist through adulthood and that shape the variability among individuals in susceptibility to infection and fitness widely seen in natural populations.

ecology↗

bioRxiv2021

Critical roles of ICOS in controlling Foxp3-expressing T follicular cell subsets during early-stage germinal center reactions

ICOS is a T cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 upregulation. Further, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.

immunology↗

bioRxiv2020

Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 in mice

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective preventive vaccination to reduce burden and spread of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) in humans. Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry before viral spread to the lung. Although SARS-CoV-2 vaccine development is rapidly progressing, the current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. Here, we show that AdCOVID, an intranasal adenovirus type 5 (Ad5)-vectored vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, elicits a strong and focused immune response against RBD through the induction of mucosal IgA, serum neutralizing antibodies and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. Therefore, AdCOVID, which promotes concomitant systemic and local mucosal immunity, represents a promising COVID-19 vaccine candidate.

immunology↗

bioRxiv2019

IgE receptor polymorphism predicts divergent, sex-specific inflammatory modes and fitness costs in a wild rodent

The genotype of an individual is an important predictor of their immune function, and subsequently, their ability to control or avoid infection and ultimately contribute offspring to the next generation. However, the same genotype, subjected to different intrinsic and/or extrinsic environments can also result in different phenotypic outcomes, which can be missed in controlled laboratory studies. Natural wildlife populations, which capture both genotypic and environmental variability, provide an opportunity to more fully understand the phenotypic expression of genetic variation. We identified a synonymous polymorphism in the high-affinity Immunoglobulin E (IgE) receptor (GC and non-GC haplotypes) that has sex-dependent effects on immune gene expression, susceptibility to infection and reproductive success of individuals in a natural population of field voles (Microtus agrestis). We found that the effect of the GC haplotype on the expression of immune genes differed between sexes. While males with the GC haplotype had upregulated more pro-inflammatory genes, including the cytokine Il33, females had upregulated more anti-inflammatory genes, including the cytokine inhibitor Socs3. Furthermore we found an effect of the GC haplotype on the probability of infection with a common microparasite, Babesia microti, in females - with females carrying the GC haplotype being more likely to be infected. Finally, we found an effect of the GC haplotype on reproductive success in males - with males carrying the GC haplotype having a lower reproductive success. This is a rare example of a polymorphism whose consequences we are able to follow across immunity, infection and reproduction for both males and females in a natural population.

ecology↗

bioRxiv2019

Fcrl5 and T-bet define influenza-specific memory B cells that predict long-lived antibody responses

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific CD27+ memory B cells (Bmem) that differ in expression of T-bet, BACH2 and TCF7. T-bethiBACH2loTCF7lo Bmem are transcriptionally similar to effector-like memory cells while T-betloBACH2+TCF7+ Bmem exhibit stem-like central memory properties. T-bethi Bmem do not express plasma cell-specific transcription factors but do exhibit transcriptional, epigenetic, metabolic and functional changes that poise the cells for antibody production. Consistent with these changes, D7 HA+ T-bethi Bmem express intracellular immunoglobulin and T-bethi Bmem differentiate more rapidly into ASCs in vitro. The T-bethi Bmem response positively correlates with long-lived humoral immunity and clonotypes from T-bethi Bmem are represented in the early secondary ASC response to repeat vaccination, suggesting that this effector-like population can be used to predict vaccine durability and recall potential.

immunology↗

bioRxiv2019

Decomposing variation in immune response in a wild rodent population

Individuals vary in their immune response and, as a result, some are more susceptible to infectious disease than others. Little is known about which components of immune pathways are responsible for this variation, but understanding these underlying processes could allow us to predict the outcome of infection for an individual, and to manage their health more effectively. In this study, we describe transcriptome-wide variation in immune response (to a standardised challenge) in a wild population of field voles (Microtus agrestis). We find that this variation can be categorised into three main types. We also identify markers, across these three categories, which display particularly strong individual variation in response. This work shows how a simple standardised challenge performed on a natural population can reveal complex patterns of natural variation in immune response.

ecology↗

bioRxiv2019

IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation

Although B cells expressing the IFN{gamma}R or the IFN{gamma}-inducible transcription factor T-bet drive autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFN{gamma} signaling in human antibody responses is unknown. We show that elevated levels of IFN{gamma} in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naive B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFN{gamma}, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFN{gamma} or IFN{gamma}-producing T cells. IFN{gamma} promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFN{gamma} signals poise B cells to differentiate by increasing their responsiveness to IL-21.

immunology↗