Type 2 immunity is a stereotyped host response to allergens and parasitic helminths that is sustained in large part by the cytokines IL-4 and IL-13. Recent advances have called attention to the contributions by innate cells in initiating adaptive immunity, including a novel lineage-negative population of cells that secretes IL-13 and IL-5 in response to the epithelial cytokines IL-25 and IL-33. Here, we use IL-4 and IL-13 reporter mice to track lineage-negative innate cells that arise during type 2 immunity or in response to IL-25 and IL-33 in vivo. Unexpectedly, lineage-negative IL-25 (and IL-33) responsive cells are widely distributed in tissues of the mouse and are particularly prevalent in mesenteric lymph nodes, spleen, and liver. These cells expand robustly in response to exogenous IL-25 or IL-33 and after infection with the helminth Nippostrongylus brasiliensis, and they are the major innate IL-13-expressing cells under these conditions. Activation of these cells using IL-25 is sufficient for worm clearance, even in the absence of adaptive immunity. Widely dispersed innate type 2 helper cells, which we designate Ih2 cells, play an integral role in type 2 immune responses.T ype 2 immune responses are important for the control of infections at mucosal barriers and the development of allergic inflammation. These responses are characterized by eosinophilia, elevated IgE, goblet cell metaplasia with enhanced mucus production, and smooth muscle hyperreactivity, all of which rely critically on production of the canonical type 2-associated cytokines IL-4, IL-5, and IL-13 (1, 2). Although adaptive Th2 cells and follicular T cells are important sources of these cytokines (3), various innate cells, including eosinophils, basophils, and mast cells, have also been implicated as producers of these cytokines in various model systems (1, 2, 4, 5). More recently, the cytokines IL-25 and IL-33, members of the IL-17 and IL-1 cytokine families, respectively, were found to induce type 2 cytokine production when administered to mice, implicating these cytokines in the initiation of type 2 immune responses (6, 7). IL-25 and IL-33 are expressed by epithelial cells, macrophages, and possibly other cell types (8), and they are expressed at elevated levels during infection with parasitic helminths (9, 10) or after challenge with allergens (9, 11). Administration of exogenous IL-25 or IL-33 to mice leads to markedly enhanced levels of IL-4, IL-5, and IL-13 and many of the tissue features of a type 2 immune response (6, 7). Conversely, deficiency in IL-25 leads to diminished IL-4, IL-5, and IL-13 production and variable delays in worm clearance in different helminth models (12, 13). Similarly, mice unable to respond to IL-33 because of deficiency in the T1-ST2 subunit of the IL-33 receptor display diminished Th2-associated cytokines and decreased granuloma formation after injection of Schistosoma mansoni eggs (14).Some of the original descriptions of these cytokines as well as more recent reports have noted the capacity of exogenous ...

CD4+ T cell activation–induced Argonaute degradation and global miRNA downregulation promotes acquisition of helper T cell effector functions.

BackgroundAcute respiratory illness is the leading cause of asthma exacerbations yet the mechanisms underlying this association remain unclear. To address the deficiencies in our understanding of the molecular events characterizing acute respiratory illness-induced asthma exacerbations, we undertook a transcriptional profiling study of the nasal mucosa over the course of acute respiratory illness amongst individuals with a history of asthma, allergic rhinitis and no underlying respiratory disease.MethodsTranscriptional profiling experiments were performed using the Agilent Whole Human Genome 4X44K array platform. Time point-based microarray and principal component analyses were conducted to identify and distinguish acute respiratory illness-associated transcriptional profiles over the course of our study. Gene enrichment analysis was conducted to identify biological processes over-represented within each acute respiratory illness-associated profile, and gene expression was subsequently confirmed by quantitative polymerase chain reaction.ResultsWe found that acute respiratory illness is characterized by dynamic, time-specific transcriptional profiles whose magnitudes of expression are influenced by underlying respiratory disease and the mucosal repair signature evoked during acute respiratory illness. Most strikingly, we report that people with asthma who experience acute respiratory illness-induced exacerbations are characterized by a reduced but prolonged inflammatory immune response, inadequate activation of mucosal repair, and the expression of a newly described exacerbation-specific transcriptional signature.ConclusionFindings from our study represent a significant contribution towards clarifying the complex molecular interactions that typify acute respiratory illness-induced asthma exacerbations.

No abstract

BackgroundPreviously, we identified a major quantitative trait locus (QTL) for host response to Porcine Respiratory and Reproductive Syndrome virus (PRRSV) infection in high linkage disequilibrium (LD) with SNP rs80800372 on Sus scrofa chromosome 4 (SSC4).ResultsWithin this QTL, guanylate binding protein 5 (GBP5) was differentially expressed (DE) (p < 0.05) in blood from AA versus AB rs80800372 genotyped pigs at 7,11, and 14 days post PRRSV infection. All variants within the GBP5 transcript in LD with rs80800372 exhibited allele specific expression (ASE) in AB individuals (p < 0.0001). A transcript re-assembly revealed three alternatively spliced transcripts for GBP5. An intronic SNP in GBP5, rs340943904, introduces a splice acceptor site that inserts five nucleotides into the transcript. Individuals homozygous for the unfavorable AA genotype predominantly produced this transcript, with a shifted reading frame and early stop codon that truncates the 88 C-terminal amino acids of the protein. RNA-seq analysis confirmed this SNP was associated with differential splicing by QTL genotype (p < 0.0001) and this was validated by quantitative capillary electrophoresis (p < 0.0001). The wild-type transcript was expressed at a higher level in AB versus AA individuals, whereas the five-nucleotide insertion transcript was the dominant form in AA individuals. Splicing and ASE results are consistent with the observed dominant nature of the favorable QTL allele. The rs340943904 SNP was also 100 % concordant with rs80800372 in a validation population that possessed an alternate form of the favorable B QTL haplotype.ConclusionsGBP5 is known to play a role in inflammasome assembly during immune response. However, the role of GBP5 host genetic variation in viral immunity is novel. These findings demonstrate that rs340943904 is a strong candidate causal mutation for the SSC4 QTL that controls variation in host response to PRRSV.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1635-9) contains supplementary material, which is available to authorized users.

Increasing Foxa2 expression reduced mucous metaplasia in an allergic mouse model. Subjects with asthma had decreased FOXA2 expression, suggesting that therapeutic approaches that increase FOXA2 expression or function could be beneficial for reducing mucus production in asthma. Unlike FOXA2, FOXA3 did not regulate mucous metaplasia.

It has been shown that inter-individual variation in host response to porcine reproductive and respiratory syndrome (PRRS) has a heritable component, yet little is known about the underlying genetic architecture of gene expression in response to PRRS virus (PRRSV) infection. Here, we integrated genome-wide genotype, gene expression, viremia level, and weight gain data to identify genetic polymorphisms that are associated with variation in inter-individual gene expression and response to PRRSV infection in pigs. RNA-seq analysis of peripheral blood samples collected just prior to experimental challenge (day 0) and at 4, 7, 11 and 14 days post infection from 44 pigs revealed 6,430 differentially expressed genes at one or more time points post infection compared to the day 0 baseline. We mapped genetic polymorphisms that were associated with inter-individual differences in expression at each day and found evidence of cis-acting expression quantitative trait loci (cis-eQTL) for 869 expressed genes (qval < 0.05). Associations between cis-eQTL markers and host response phenotypes using 383 pigs suggest that host genotype-dependent differences in expression of GBP5, GBP6, CCHCR1 and CMPK2 affect viremia levels or weight gain in response to PRRSV infection.

BackgroundThe presence of variability in the response of pigs to Porcine Reproductive and Respiratory Syndrome virus (PRRSv) infection, and recent demonstration of significant genetic control of such responses, leads us to believe that selection towards more disease resistant pigs could be a valid strategy to reduce its economic impact on the swine industry. To find underlying molecular differences in PRRS susceptible versus more resistant pigs, 100 animals with extremely different growth rates and viremia levels after PRRSv infection were selected from a total of 600 infected pigs. A microarray experiment was conducted on whole blood RNA samples taken at 0, 4 and 7 days post infection (dpi) from these pigs. From these data, we examined associations of gene expression with weight gain and viral load phenotypes. The single nucleotide polymorphism (SNP) marker WUR10000125 (WUR) on the porcine 60 K SNP chip was shown to be associated with viral load and weight gain after PRRSv infection, and so the effect of the WUR10000125 (WUR) genotype on expression in whole blood was also examined.ResultsLimited information was obtained through linear modeling of blood gene differential expression (DE) that contrasted pigs with extreme phenotypes, for growth or viral load or between animals with different WUR genotype. However, using network-based approaches, molecular pathway differences between extreme phenotypic classes could be identified. Several gene clusters of interest were found when Weighted Gene Co-expression Network Analysis (WGCNA) was applied to 4dpi contrasted with 0dpi data. The expression pattern of one such cluster of genes correlated with weight gain and WUR genotype, contained numerous immune response genes such as cytokines, chemokines, interferon type I stimulated genes, apoptotic genes and genes regulating complement activation. In addition, Partial Correlation and Information Theory (PCIT) identified differentially hubbed (DH) genes between the phenotypically divergent groups. GO enrichment revealed that the target genes of these DH genes are enriched in adaptive immune pathways.ConclusionThere are molecular differences in blood RNA patterns between pigs with extreme phenotypes or with a different WUR genotype in early responses to PRRSv infection, though they can be quite subtle and more difficult to discover with conventional DE expression analyses. Co-expression analyses such as WGCNA and PCIT can be used to reveal network differences between such extreme response groups.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1741-8) contains supplementary material, which is available to authorized users.