Protection against severe infant lower respiratory tract infections by immune training: Mechanistic studies.

Background: Results from recent clinical studies suggest potential efficacy of immune training (IT)-based approaches for protection against severe lower respiratory tract infections in infants, but underlying mechanisms are unclear.

Objective: We used systems-level analyses to elucidate IT mechanisms in infants in a clinical trial setting.

Methods: Pre- and posttreatment peripheral blood mononuclear cells from a placebo-controlled trial in which winter treatment with the IT agent OM85 reduced infant respiratory infection frequency and/or duration were stimulated for 24 hours with the virus/bacteria mimics polyinosinic:polycytidylic acid/lipopolysaccharide.

Airway Epithelial Cell Immunity Is Delayed During Rhinovirus Infection in Asthma and COPD.

Respiratory viral infections, particularly those caused by rhinovirus, exacerbate chronic respiratory inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the primary site of rhinovirus replication and responsible of initiating the host immune response to infection. Numerous studies have reported that the anti-viral innate immune response (including type I and type III interferon) in asthma is less effective or deficient leading to the conclusion that epithelial innate immunity is a key determinant of disease severity during a rhinovirus induced exacerbation.

Rewiring of gene networks underlying mite allergen-induced CD4 + Th-cell responses during immunotherapy.

Background: Multiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate to maintain immunological homeostasis is incomplete.

Objective: To explore the potential for unbiased systems-level gene co-expression network analysis to advance understanding of immunotherapy mechanisms.

Methods: We profiled genome-wide allergen-induced Th-cell responses prospectively during 24 months subcutaneous immunotherapy (SCIT) in 25 rhinitis, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores out to 36 months.

QuantSeq. 3' Sequencing combined with Salmon provides a fast, reliable approach for high throughput RNA expression analysis.

RNA-Seq is increasingly used for the diagnosis of patients, targeting of therapies and for single cell transcriptomics. These applications require cost effective, fast and reliable ways of capturing and analyzing gene expression data. Here we compared Lexogen's QuantSeq which captures only the 3' end of RNA transcripts and Illumina's TruSeq, using both Tophat2 and Salmon for gene quantification.

Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing.

Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7 versus IRF7 molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ.

CD8XCR1 Dendritic Cells Express High Levels of Toll-Like Receptor 5 and a Unique Complement of Endocytic Receptors.

Conventional dendritic cells (cDC) resident in the lymphoid organs of mice have been classically divided into CD8 and CD8 subsets. It is well-established that CD8 dendritic cells (DCs) and their migratory counterparts in the periphery comprise the cross-presenting cDC1 subset. In contrast, CD8 DCs are grouped together in the heterogeneous cDC2 subset.

Airway Microbiota Dynamics Uncover a Critical Window for Interplay of Pathogenic Bacteria and Allergy in Childhood Respiratory Disease.

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera.

Persistent activation of interlinked type 2 airway epithelial gene networks in sputum-derived cells from aeroallergen-sensitized symptomatic asthmatics.

Atopic asthma is a persistent disease characterized by intermittent wheeze and progressive loss of lung function. The disease is thought to be driven primarily by chronic aeroallergen-induced type 2-associated inflammation. However, the vast majority of atopics do not develop asthma despite ongoing aeroallergen exposure, suggesting additional mechanisms operate in conjunction with type 2 immunity to drive asthma pathogenesis.

Critical Role of Plasmacytoid Dendritic Cells in Regulating Gene Expression and Innate Immune Responses to Human Rhinovirus-16.

Though human rhinoviruses (HRVs) are usually innocuous viruses, they can trigger serious consequences in certain individuals, especially in the setting of impaired interferon (IFN) synthesis. Plasmacytoid dendritic cells (pDCs) are key IFN producing cells, though we know little about the role of pDC in HRV-induced immune responses. Herein, we used gene expression microarrays to examine HRV-activated peripheral blood mononuclear cells (PBMCs) from healthy people, in combination with pDC depletion, to assess whether observed gene expression patterns were pDC dependent.

Respiratory viral infections and host responses; insights from genomics.

Respiratory viral infections are a leading cause of disease and mortality. The severity of these illnesses can vary markedly from mild or asymptomatic upper airway infections to severe wheezing, bronchiolitis or pneumonia. In this article, we review the viral sensing pathways and organizing principles that govern the innate immune response to infection.

Effect of human rhinovirus infection on airway epithelium tight junction protein disassembly and transepithelial permeability.

Rationale: No studies have assessed the effects of human rhinovirus (HRV) infection on epithelial tight junctions (TJs) and resultant barrier function.

Aim Of The Study: To correlate viral infection with TJ disassembly, epithelial barrier integrity, and function.

Materials And Methods: Human airway epithelial cells were infected with HRV minor serotype 1B (HRV-1B) at various 50% tissue culture infectivity doses (TCID) over 72 hours.

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease.

Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function.

Differential gene network analysis for the identification of asthma-associated therapeutic targets in allergen-specific T-helper memory responses.

Background: Asthma is strongly associated with allergic sensitization, but the mechanisms that determine why only a subset of atopics develop asthma are not well understood. The aim of this study was to test the hypothesis that variations in allergen-driven CD4 T cell responses are associated with susceptibility to expression of asthma symptoms.

Methods: The study population consisted of house dust mite (HDM) sensitized atopics with current asthma (n = 22), HDM-sensitized atopics without current asthma (n = 26), and HDM-nonsensitized controls (n = 24).

The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.

The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs.

Pre-exposure of Galleria mellonella larvae to different doses of Aspergillus fumigatus conidia causes differential activation of cellular and humoral immune responses.

Larvae of Galleria mellonella are useful models for studying the virulence of microbial pathogens or for evaluating the potency of antimicrobial agents. In this work we demonstrated that prior exposure of larvae to non-lethal doses of Aspergillus fumigatus conidia increases the resistance of larvae to a lethal dose (1 x 10⁷ 20 μl⁻¹) 24 h later. Exposure of larvae to a conidia concentration of 1 x 10⁴ 20 μl⁻¹ leads to an increase in haemocyte density but an inoculum of 1 x 10⁵ conidia leads to enhanced expression of antimicrobial peptides, increased binding of proteins (e.