An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic

ÁCAROS TROMBICULÍDEOS: REVISÃO DE UMA PARASITOSE NEGLIGENCIADA EM ANIMAIS DE COMPANHIA

A trombiculose é uma parasitose causada por ácaros trombiculídeos (Acari: Trombiculidae) que afeta vertebrados, incluindo cães, gatos e o ser humano. É a fase larvar dos ácaros trombiculídeos que se caracteriza por ser parasita obrigatório e responsável pelo aparecimento de sinais clínicos. Estes incluem prurido, várias lesões cutâneas, podendo, em alguns casos, surgir distúrbios gastrointestinais, neurológicos ou mesmo a morte do animal quando as infestações são massivas. Apesar da sua distribuição mundial, incluindo em Portugal, esta é uma parasitose negligenciada, sobretudo no contexto da medicina veterinária de animais de companhia. Os estudos existentes são escassos, contribuindo para o seu desconhecimento, e a sua verdadeira prevalência nestes animais é pouco conhecida a nível mundial. Apesar do seu papel enquanto vetores de agentes patogénicos não ser claro, alguns estudos já demonstraram a presença de ADN de Anaplasma spp., Bartonella spp., Borrelia spp. e Rickettsia spp., em trombiculídeos. O facto de os ácaros trombiculídeos afetarem várias espécies animais, incluindo os animais de companhia e o ser humano, bem como o seu potencial papel no ciclo de manutenção de vários agentes infeciosos, revela a importância de um maior conhecimento acerca desta parasitose, tanto ao nível da comunidade científica como da comunidade médico veterinária. Assim, esta revisão pretende reunir os dados disponíveis à data quanto à epidemiologia, características clínicas e tratamento desta parasitose, com especial enfoque em Portugal

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events

Bacterial Signatures of Paediatric Respiratory Disease : An Individual Participant Data Meta-Analysis

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies.Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses.Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus. Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively.Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis.Peer reviewe

Telemetry and genetics reveal asymmetric dispersal of a lake-feeding salmonid between inflow and outflow spawning streams at a microgeographic scale

The degree of natal philopatry relative to natal dispersal in animal populations has important demographic and genetic consequences and often varies substantially within species. In salmonid fishes, lakes have been shown to have a strong influence on dispersal and gene flow within catchments; for example, populations spawning in inflow streams are often reproductively isolated and genetically distinct from those spawning in relatively distant outflow streams. Less is known, however, regarding the level of philopatry and genetic differentiation occurring at microgeographic scales, for example, where inflow and outflow streams are separated by very small expanses of lake habitat. Here, we investigated the interplay between genetic differentiation and fine-scale spawning movements of brown trout between their lake-feeding habitat and two spawning streams (one inflow, one outflow, separated by <100 m of lake habitat). Most (69.2%) of the lake-tagged trout subsequently detected during the spawning period were recorded in just one of the two streams, consistent with natal fidelity, while the remainder were detected in both streams, creating an opportunity for these individuals to spawn in both natal and non-natal streams. The latter behavior was supported by genetic sibship analysis, which revealed several half-sibling dyads containing one individual that was sampled as a fry in the outflow and another that was sampled as fry in the inflow. Genetic clustering analyses in conjunction with telemetry data suggested that asymmetrical dispersal patterns were occurring, with natal fidelity being more common among individuals originating from the outflow than the inflow stream. This was corroborated by Bayesian analysis of gene flow, which indicated significantly higher rates of gene flow from the inflow into the outflow than vice versa. Collectively, these results reveal how a combination of telemetry and genetics can identify distinct reproductive behaviors and associated asymmetries in natal dispersal that produce subtle, but nonetheless biologically relevant, population structuring at microgeographic scales

Gene Expression Signatures of Radiation Response Are Specific, Durable and Accurate in Mice and Humans

Background: Previous work has demonstrated the potential for peripheral blood (PB) gene expression profiling for the detection of disease or environmental exposures. Methods and Findings: We have sought to determine the impact of several variables on the PB gene expression profile of an environmental exposure, ionizing radiation, and to determine the specificity of the PB signature of radiation versus other genotoxic stresses. Neither genotype differences nor the time of PB sampling caused any lessening of the accuracy of PB signatures to predict radiation exposure, but sex difference did influence the accuracy of the prediction of radiation exposure at the lowest level (50 cGy). A PB signature of sepsis was also generated and both the PB signature of radiation and the PB signature of sepsis were found to be 100 % specific at distinguishing irradiated from septic animals. We also identified human PB signatures of radiation exposure and chemotherapy treatment which distinguished irradiated patients and chemotherapy-treated individuals within a heterogeneous population with accuracies of 90 % and 81%, respectively. Conclusions: We conclude that PB gene expression profiles can be identified in mice and humans that are accurate i

Systems Biology Approaches Reveal a Specific Interferon-Inducible Signature in HTLV-1 Associated Myelopathy

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP

Distinct Peripheral Blood RNA Responses to Salmonella in Pigs Differing in Salmonella Shedding Levels: Intersection of IFNG, TLR and miRNA Pathways

Transcriptomic analysis of the response to bacterial pathogens has been reported for several species, yet few studies have investigated the transcriptional differences in whole blood in subjects that differ in their disease response phenotypes. Salmonella species infect many vertebrate species, and pigs colonized with Salmonella enterica serovar Typhimurium (ST) are usually asymptomatic, making detection of these Salmonella-carrier pigs difficult. The variable fecal shedding of Salmonella is an important cause of foodborne illness and zoonotic disease. To investigate gene pathways and biomarkers associated with the variance in Salmonella shedding following experimental inoculation, we initiated the first analysis of the whole blood transcriptional response induced by Salmonella. A population of pigs (n = 40) was inoculated with ST and peripheral blood and fecal Salmonella counts were collected between 2 and 20 days post-inoculation (dpi). Two groups of pigs with either low shedding (LS) or persistent shedding (PS) phenotypes were identified. Global transcriptional changes in response to ST inoculation were identified by Affymetrix Genechip® analysis of peripheral blood RNA at day 0 and 2 dpi. ST inoculation triggered substantial gene expression changes in the pigs and there was differential expression of many genes between LS and PS pigs. Analysis of the differential profiles of gene expression within and between PS and LS phenotypic classes identified distinct regulatory pathways mediated by IFN-γ, TNF, NF-κB, or one of several miRNAs. We confirmed the activation of two regulatory factors, SPI1 and CEBPB, and demonstrated that expression of miR-155 was decreased specifically in the PS animals. These data provide insight into specific pathways associated with extremes in Salmonella fecal shedding that can be targeted for further exploration on why some animals develop a carrier state. This knowledge can also be used to develop rational manipulations of genetics, pharmaceuticals, nutrition or husbandry methods to decrease Salmonella colonization, shedding and spread

A predictive assessment of genetic correlations between traits in chickens using markers

International audienceAbstractBackgroundGenomic selection has been successfully implemented in plant and animal breeding programs to shorten generation intervals and accelerate genetic progress per unit of time. In practice, genomic selection can be used to improve several correlated traits simultaneously via multiple-trait prediction, which exploits correlations between traits. However, few studies have explored multiple-trait genomic selection. Our aim was to infer genetic correlations between three traits measured in broiler chickens by exploring kinship matrices based on a linear combination of measures of pedigree and marker-based relatedness. A predictive assessment was used to gauge genetic correlations.MethodsA multivariate genomic best linear unbiased prediction model was designed to combine information from pedigree and genome-wide markers in order to assess genetic correlations between three complex traits in chickens, i.e. body weight at 35 days of age (BW), ultrasound area of breast meat (BM) and hen-house egg production (HHP). A dataset with 1351 birds that were genotyped with the 600 K Affymetrix platform was used. A kinship kernel (K) was constructed as K = λG + (1 − λ)A, where A is the numerator relationship matrix, measuring pedigree-based relatedness, and G is a genomic relationship matrix. The weight (λ) assigned to each source of information varied over the grid λ = (0, 0.2, 0.4, 0.6, 0.8, 1). Maximum likelihood estimates of heritability and genetic correlations were obtained at each λ, and the “optimum” λ was determined using cross-validation.ResultsEstimates of genetic correlations were affected by the weight placed on the source of information used to build K. For example, the genetic correlation between BW–HHP and BM–HHP changed markedly when λ varied from 0 (only A used for measuring relatedness) to 1 (only genomic information used). As λ increased, predictive correlations (correlation between observed phenotypes and predicted breeding values) increased and mean-squared predictive error decreased. However, the improvement in predictive ability was not monotonic, with an optimum found at some 0 < λ < 1, i.e., when both sources of information were used together.ConclusionsOur findings indicate that multiple-trait prediction may benefit from combining pedigree and marker information. Also, it appeared that expected correlated responses to selection computed from standard theory may differ from realized responses. The predictive assessment provided a metric for performance evaluation as well as a means for expressing uncertainty of outcomes of multiple-trait selection

Uso de tratamento hidrotérmico e ácido clorídrico na qualidade de lichia 'Bengal'

Um dos maiores problemas na pós-colheita da lichia é o escurecimento do pericarpo, cuja cor vermelha se torna totalmente escurecida em 48 horas, sob 25 ºC. Tecnologias que possam controlar o escurecimento do pericarpo são valiosas, e é o foco principal da pesquisa na área de pós-colheita. O objetivo deste trabalho foi avaliar a vida útil de lichias 'Bengal', armazenadas a 20 ºC e 82 %UR após o tratamento hidrotérmico e/ou imersão em solução de HCl. O delineamento experimental foi o inteiramente casualizado, em esquema fatorial 4 x 7, com 3 repetições, onde o primeiro fator correspondeu aos tratamentos: testemunha; imersão em HCl a 1%, por 6 minutos; tratamento hidrotérmico, com imersão em água a 52 ºC por 1 minuto, seguido de resfriamento em água a 10 ºC, por 6 minutos; e tratamento hidrotérmico, seguido de resfriamento em HCl a 1%, a 10 ºC, por 6 minutos. O segundo fator foram os períodos de armazenamento: 0; 1; 2; 3;6; 9 e 12 dias. A combinação entre tratamento hidrotérmico (52 ºC por 1 minuto) e resfriamento em HCl a 1% permite conservar a coloração das lichias 'Bengal' por até dois dias. Mesmo assim há escurecimento em 25% da superfície.One of the biggest problems in postharvest litchi pericarp browning is, the color red becomes totally dark in 48 hours at 25 º C. Technologies that can control the browning of the pericarp are valuable, and is the main focus of research in post-harvest. The aim of this study was to evaluate the shelf life of lychee 'Bengal', stored at 20 ° C and 82% RH after the hydrothermal treatment and/or immersion in HCl solution. The experimental design was completely randomized in a 4 x 7, with three replications, where the first factor was the treatment: control, immersion in HCl 1%, for 6 minutes; hydrothermal treatment, soaking in water at 52 ° C for 1 minutes, followed by immersion in water at 10 º C for 6 minutes, and hydrothermal treatment and subsequent cooling in 1% HCl, 10 ° C for 6 minutes. The second factor was the storage periods: 0, 1, 2, 3, 6, 9 and 12 days. The combination of hydrothermal treatment (52 ° C for 1 min) and cooling in HCl 1% allowed to retain the color of lychee 'Bengal' for up to two days. Yet there are browning in 25% of the surface.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)UNESP FCAV Departamento de TecnologiaUNESP FCAV Departamento de Tecnologi