Biology subjects

Mair, I.

Publications and source records attributed to Mair, I..

4 recordsLinked to original sources

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↗

bioRxiv2020

Cell-intrinsic IL4R alpha independence of large intestinal RELMα+ Ym1+ macrophages

The balance of pro-inflammatory and anti-inflammatory macrophages is critically important in enabling the development and resolution of inflammatory responses. Anti-inflammatory macrophages have been shown to be activated by IL4 and/or IL13 via the IL4R. In the context of type 2 immunity, anti-inflammatory macrophages have been defined by the expression of the signature markers RELM, CD206 and Ym1, associated with activation of macrophages via the IL4R. Despite a breadth of inflammatory pathologies associated with the large intestine, many of which feature unbalanced macrophage activation states, little is known about how large intestinal macrophages are activated. Here, we address this important knowledge gap by using a Trichuris muris infection model of resolving type 2 intestinal inflammation, in combination with transgenic mice (IL4Rfl/fl.CX3CR1Cre) and IL4R-deficient/wild-type mixed bone marrow chimaeras. These models allowed us to interrogate the role of IL4/IL13 in macrophage activation driven by inflammation of the large intestine. We make the unexpected finding that education of large intestinal macrophages towards a RELM and Ym1 expressing cell type during type 2 inflammation, does not require IL4R expression on macrophages. Thus, upregulation of RELM and Ym1 post infection is independent of macrophage IL4R expression. Further, this independence is maintained even when the mice are treated with anti-IFN{gamma} antibody to create a strongly polarised Th2 environment. In contrast to RELM and Ym1, PD-L2 expression on macrophages post infection was dependent on IL4R signalling in the macrophages. These data challenge existing paradigms, evidencing that expression of RELM and Ym1 by macrophages, typically regarded as having anti-inflammatory functions, do not always rely on IL4/IL13.

immunology↗

bioRxiv2019

In silico design of a T-cell epitope vaccine candidate for parasitic helminth infection

Trichuris trichiura is a parasite that infects 500 million people worldwide, leading to colitis, growth retardation and Trichuris dysentery syndrome. There are no licensed vaccines available to prevent Trichuris infection and current treatments are of limited efficacy. Trichuris infections are linked to poverty, reducing childrens educational performance and the economic productivity of adults. We employed a systematic, multi-stage process to identify a candidate vaccine against trichuriasis based on the incorporation of selected T cell epitopes into virus-like particles. We conducted a systematic review to identify the most appropriate in silico prediction tools to predict histocompatibility complex class II (MHC-II) molecule T-cell epitopes. These tools were used to identify candidate MHC-II epitopes from predicted ORFs in the Trichuris genome, selected using inclusion and exclusion criteria. Selected epitopes were incorporated into Hepatitis B core antigen virus-like particles (VLPs). A combined VLP vaccine containing four Trichuris MHC-II T-cell epitopes stimulated dendritic cells and macrophages to produce pro-inflammatory and anti-inflammatory cytokines. The VLPs were internalized and co-localized in the antigen presenting cell lysosomes. Upon challenge infection, mice vaccinated with the VLPs+T-cell epitopes showed a significantly reduced worm burden, and mounted Trichuris-specific IgM and IgG2c antibody responses. The protection of mice by VLPs+T-cell epitopes was characterised by the production of mesenteric lymph node (MLN)-derived Th2 cytokines and goblet cell hyperplasia. Collectively our data establishes that a combination of in silico genome-based CD4+ T cell epitope prediction, combined with VLP delivery, offers a promising pipeline for the development of an effective, safe and affordable helminth vaccine. Author SummaryThe soil transmitted helminth Trichuris trichiura is a major parasite in developing countries; development of a comprehensive vaccine has been elusive. Here we used a systematic approach based on in silico identification of MHC-II T cell epitopes from genome sequences, their incorporation into a virus-like particle (VLP), characterization of the assemblies and testing in an in vivo murine infection model. Animals vaccinated with a preparation of four different VLP-antigen fusions showed significant reductions in intestinal worm burdens and associated antibody responses consistent with protection. The results suggest that a pipeline based on in silico prediction of potent MHC-II T cell epitopes, followed by incorporation into VLPs, could be a strategy which enables rapid translation into a vaccine against Trichuris trichiura.

immunology↗

bioRxiv2019

Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

BackgroundEosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings.\n\nObjectivesTo investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI.\n\nMethodsBlood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice ({Delta}dblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests.\n\nResultsBlood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0{+/-}2.2cm2 v 21.6{+/-}1.6cm2; p=0.02) and reduced ejection fraction (22.0{+/-}3.6% v 34.3{+/-}4.0% in p=0.04,) in {Delta}dblGATA v WT following MI (n=8-9/group), an outcome reproduced by pharmacological depletion. {Delta}dblGATA mice had increased scar size with disrupted collagen deposition and altered expression of the collagen cross-linking genes plod2 and lox. CD206+pro-repair macrophages were less prevalent in the infarct zone of {Delta}dblGATA mice (27.0{+/-}2.3% v WT: 39.2.4{+/-}3.5%; p=0.01, n=9-11/group) but were restored by replenishment with bone marrow-derived eosinophils. Anti-inflammatory cytokine concentrations were reduced in {Delta}dblGATA mice and IL-4 complex administration 24h after MI rescued adverse remodelling.\n\nConclusionsEosinophils are recruited to the heart following MI and are required for effective repair and to prevent adverse remodelling. IL-4 therapy has potential to limit detrimental outcomes when eosinophil availability is low.\n\nHIGHLIGHTSA drop in eosinophil blood count is associated with recruitment of eosinophils to the heart during repair following clinical and experimental myocardial infarction.\n\nGenetic & pharmacological eosinophil depletion leads to increased adverse remodelling in experimental MI.\n\nEosinophils are required for aquisition of an anti-inflammatory macrophage phenotype and a shift to resolution of inflammation during infarct repair.\n\nInterleukin-4 therapy is able to rescue the adverse remodelling phenotype in conditions of eosinophil deficiency.\n\nCondensed abstractIn ST-segment elevation myocardial infarction (STEMI) of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory pro-repair macrophage polarization, enhanced myocardial inflammation, increased scar size and deterioration of myocardial structure and function. Adverse cardiac remodelling in the setting of eosinophil deficiency was prevented by IL-4 therapy.

immunology↗