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. Then, we reconstruct the molecular networks that differentiate symptomatic from asymptomatic respiratory viral infections, and identify the underlying molecular drivers of these networks. Finally, we discuss unique aspects of the biology and pathogenesis of infections with respiratory syncytial virus, rhinovirus and influenza, drawing on insights from genomics.
Human Respiratory Syncytial Virus and Human Rhinovirus are the most frequent cause of respiratory tract infections in infants and children and are major triggers of acute viral bronchiolitis, ...wheezing and asthma exacerbations. Here, we will discuss the application of the powerful tools of systems biology to decode the molecular mechanisms that determine risk for infection and subsequent asthma. An important conceptual advance is the understanding that the innate immune system is governed by a Bow-tie architecture, where diverse input signals converge onto a few core pathways (e.g., IRF7), which in turn generate diverse outputs that orchestrate effector and regulatory functions. Molecular profiling studies in children with severe exacerbations of asthma/wheeze have identified two major immunological phenotypes. The IRF7hi phenotype is characterised by robust upregulation of antiviral response networks, and the IRF7lo phenotype is characterised by upregulation of markers of TGFβ signalling and type 2 inflammation. Similar phenotypes have been identified in infants and children with severe viral bronchiolitis. Notably, genome-wide association studies supported by experimental validation have identified key pathways that increase susceptibility to HRV infection (ORMDL3 and CHDR3) and modulate TGFβ signalling (GSDMB, TGFBR1, and SMAD3). Moreover, functional deficiencies in the activation of type I and III interferon responses are already evident at birth in children at risk of developing febrile lower respiratory tract infections and persistent asthma/wheeze, suggesting that the trajectory to asthma begins at birth or in utero. Finally, exposure to microbes and their products reprograms innate immunity and provides protection from the development of allergies and asthma in children, and therefore microbial products are logical candidates for the primary prevention of asthma.
Gasdermin B (GSDMB) is a gene located in the 17q12-21 region, which is strongly associated with childhood asthma. Previous studies have focused on ORMDL3, another gene in the same region, but recent ...research suggests that GSDMB may play a more significant role in asthma pathogenesis. Gasdermin B is a lipid-binding protein that forms pores in biological membranes. Activation of Gasdermin B can lead to epithelial cell death, release of cytokines, and killing of bacteria. Severe rhinovirus infections in early life are a major risk factor for asthma development. The airway epithelium is the primary site of virus infection, and studies have shown that interferon responses are deficient in subjects with asthma. However, recent research has identified two distinct immune pathways driving childhood asthma exacerbations: one involving impaired interferon responses and the release of alarmins, and the other involving robust interferon responses and the infiltration of cytotoxic cells into the airways. A recent study found that high mucosal expression of GSDMB is associated with upregulation of an IFN-gamma-mediated inflammatory response and downregulation of type I and III interferon responses. These findings highlight a novel role for the GSDMB/IFN-gamma axis in susceptibility to rhinovirus infections and childhood asthma.
Background Exacerbations are responsible for a substantial burden of morbidity and health care use in children with asthma. Most asthma exacerbations are triggered by viral infections; however, the ...underlying mechanisms have not been systematically investigated. Objective The objective of this study was to elucidate the molecular networks that underpin virus-induced exacerbations in asthmatic children in vivo. Methods We followed exacerbation-prone asthmatic children prospectively and profiled global patterns of gene expression in nasal lavage samples obtained during an acute, moderate, picornavirus-induced exacerbation and 7 to 14 days later. Coexpression network analysis and prior knowledge was used to reconstruct the underlying gene networks. Results The data showed that an intricate modular program consisting of more than 1000 genes was upregulated during acute exacerbations in comparison with 7 to 14 days later. The modules were enriched for coherent cellular processes, including interferon-induced antiviral responses, innate pathogen sensing, response to wounding, small nucleolar RNAs, and the ubiquitin-proteosome and lysosome degradation pathways. Reconstruction of the wiring diagram of the modules revealed the presence of hyperconnected hub nodes, most notably interferon regulatory factor 7, which was identified as a major hub linking interferon-mediated antiviral responses. Conclusions This study provides an integrated view of the inflammatory networks that are upregulated during virus-induced asthma exacerbations in vivo . A series of innate signaling hubs were identified that could be novel therapeutic targets for asthma attacks.
Background Activated TH 2 cells and eosinophils are hallmarks of the allergic inflammation seen in patients with allergic rhinitis (AR). However, which cells activate and attract T cells and ...eosinophils to the inflammatory lesion has not been determined. Objective We wanted to assess the role of mucosal mononuclear phagocytes, consisting of monocytes, macrophages, and dendritic cells, in the local allergic inflammatory reaction. Methods Patients with AR and nonatopic control subjects were challenged with pollen extract, and nasal symptoms were recorded. Mucosal biopsy specimens obtained at different time points before and after challenge were used for immunostaining in situ and flow cytometric cell sorting. Sorted mononuclear phagocytes were subjected to RNA extraction and gene expression profiling. Results In an in vivo model of AR, we found that CD14+ monocytes were recruited to the nasal mucosa within hours after local allergen challenge, whereas conventional dendritic cells accumulated after several days of continued provocation. Transcriptomic profiling of mucosal mononuclear phagocytes sorted after 1 week of continued allergen challenge showed an activated phenotype at least partially driven by IL-4 signaling, IL-13 signaling, or both. Importantly, gene expression of several TH 2-related chemokines was significantly upregulated by the mononuclear phagocyte population concomitant with an increased recruitment of CD4+ T cells and eosinophils. Conclusion Our findings suggest that the mononuclear phagocyte population is directly involved in the production of proinflammatory chemokines that attract other immune cells. Rapid recruitment of CD14+ monocytes to the challenged site indicates that these proinflammatory mononuclear phagocytes have a central role in orchestrating local allergic inflammation.
Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in ...asthma inception. Objective We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study n = 30 and the Childhood Origins of Asthma Study n = 28) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell–derived IL-1β levels were measured by means of ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3 , the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.
Abstract
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin ...therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C
+
/CD11b
+
inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Background Atopy and asthma are commonly initiated during early life, and there is increasing interest in the development of preventive treatments for at-risk children. However, effective methods for ...assessing the level of risk in individual children are lacking. Objective We sought to identify clinical and laboratory biomarkers in 2-year-olds that are predictive of the risk for persistent atopy and wheeze at age 5 years. Methods We prospectively studied 198 atopic family history–positive children to age 5 years. Clinical and laboratory assessments related to asthma history and atopy status were undertaken annually; episodes of acute respiratory illness were assessed and classified throughout and graded by severity. Results Aeroallergen-specific IgE titers cycled continuously within the low range in nonatopic subjects. Atopic subjects displayed similar cycling in infancy but eventually locked into a stable pattern of upwardly trending antibody production and TH 2-polarized cellular immunity. The latter was associated with stable expression of IL-4 receptor in allergen-specific TH 2 memory responses, which was absent from responses during infancy. Risk for persistent wheeze was strongly linked to early sensitization and in turn to early infection. Integration of these data by means of logistic regression revealed that attaining mite-specific IgE titers of greater than 0.20 kU/L by age 2 years was associated with a 12.7% risk of persistent wheeze, increasing progressively to an 87.2% risk with increasing numbers of severe lower respiratory tract illnesses experienced. Conclusion The risk for development of persistent wheeze in children can be quantified by means of integration of measures related to early sensitization and early infections. Follow-up studies along similar lines in larger unselected populations to refine this approach are warranted.
PDF
