Biology subjects

Fife, M.

Publications and source records attributed to Fife, M..

3 recordsLinked to original sources

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗

bioRxiv2020

Genetic control of Campylobacter colonisation in broiler chickens: genomic and transcriptomic characterisation

Campylobacter is the leading cause of bacterial foodborne gastroenteritis in many countries. Source attribution studies unequivocally identify the handling or consumption of contaminated poultry meat as the primary risk factor. One potential strategy to control Campylobacter is to select poultry with increased resistance to colonisation. We conducted genomic and transcriptomic analyses of commercial pedigree broilers exposed to Campylobacter to examine persistent colonisation of the caecum as a quantitative trait. 3,000 broilers were genotyped using a 50K single nucleotide polymorphism (SNP) array and imputed to 600K SNPs. Genotypes were analysed for associations with the number of viable Campylobacter in the caeca. Heritability of the trait was modest but significantly greater than zero (h2=0.11 {+/-} 0.03). Genome-wide association analyses confirmed quantitative trait loci (QTL) on chromosomes 14 and 16 previously identified using the progeny of crosses of inbred lines differing in resistance, and detected two additional genome-wide significant QTLs on chromosomes 19 and 26. RNA-Seq analysis of the transcriptome of caecal tonsils from birds at the low and high extremes of C. jejuni colonisation phenotype identified differentially transcribed genes, mainly located within the QTL on chromosome 16 and proximal to the major histocompatibility complex (MHC) locus. We also identified strong cis-QTLs located within the MHC suggesting the presence of cis-acting variation in both MHC class I, class II and BG genes. Multiple other cis-acting variants were identified in association with key immune genes (COPS3, CCL4, CR1L, C4BP, PLGR) in the other QTLs. Pathway and network analysis implicated cooperative functional pathways and networks in colonisation, including those related to antigen presentation, innate and adaptive immune responses, calcium, and renin-angiotensin signalling. While co-selection for enhanced resistance and other breeding goal traits is feasible, the frequency of resistance-associated alleles was high in the population studied and non-genetic factors significantly influence Campylobacter colonisation in poultry. Author summaryCampylobacter infection is estimated to cause 95 million illnesses in people worldwide each year. Human infections mostly involve gastroenteritis, but can have severe complications. The handling or consumption of contaminated poultry meat is a key risk factor for human campylobacteriosis. The bacteria reach high numbers in the intestines of chickens reared for meat (broilers) and are frequently found on carcasses after slaughter. Effective vaccines against Campylobacter are not yet available, and treatments to reduce carcass contamination (e.g. chlorination) are not acceptable in some markets. One alternative is to breed for chickens with improved resistance to Campylobacter colonisation. To test the feasibility of this option in commercial birds, we analysed the genetic make-up of 3,000 pedigree broilers and determined the number of Campylobacter in their gut. There were associations between specific regions of the chicken genome and resistance to Campylobacter. Within some of these regions, expression of certain genes differed between birds at the low and high extremes of Campylobacter colonisation, providing a potential explanation for genetic variation in resistance. Selection of poultry with increased resistance to Campylobacter colonisation may be a complementary strategy to improved biosecurity, management, handling and processing procedures to reduce the burden of Campylobacter on human health.

genomics↗

bioRxiv2018

The genome of the biting midge Culicoides sonorensis and gene expression analyses of vector competence for Bluetongue virus

BackgroundThe use of the new genomic technologies has led to major advances in control of several arboviruses of medical importance such as Dengue. However, the development of tools and resources available for vectors of non-zoonotic arboviruses remains neglected. Biting midges of the genus Culicoides transmit some of the most important arboviruses of wildlife and livestock worldwide, with a global impact on economic productivity, health and welfare. The absence of a suitable reference genome has hindered genomic analyses to date in this important genus of vectors. In the present study, the genome of Culicoides sonorensis, a vector of bluetongue virus (BTV) in the USA, has been sequenced to provide the first reference genome for these vectors. In this study, we also report the use of the reference genome to perform initial transcriptomic analyses of vector competence for BTV.\n\nResultsOur analyses reveal that the genome is 197.4 Mb, assembled in 7,974 scaffolds. Its annotation using the transcriptomic data generated in this study and in a previous study has identified 15,629 genes. Gene expression analyses of C. sonorensis females infected with BTV performed in this study revealed 165 genes that were differentially expressed between vector competent and refractory females. Two candidate genes, glutathione S-transferase (gst) and the antiviral helicase ski2, previously recognized as involved in vector competence for BTV in C. sonorensis (gst) and repressing dsRNA virus propagation (ski2), were confirmed in this study.\n\nConclusionsThe reference genome of C. sonorensis has enabled preliminary analyses of the gene expression profiles of vector competent and refractory individuals. The genome and transcriptomes generated in this study provide suitable tools for future research on arbovirus transmission. These provide a significant resource for these vector lineage, which diverged from other major Dipteran vector families over 200 million years ago. The genome will be a valuable source of comparative data for other important Dipteran vector families including mosquitoes (Culicidae) and sandflies (Psychodidae), and yield potential targets for transgenic modification in vector control and functional studies.

genomics↗