Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

Abstract

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.

Role of specialized pro-resolving lipid mediators and their receptors in virus infection: a promising therapeutic strategy for SARS-CoV-2 cytokine storm

“…Respiratory syncytial virus (RSV), also known as human respiratory cell fusion virus (HRSV) and human orthopneumovirus, is a virus that causes respiratory infections in which infected mucosal cells fuse to form a syncytium (Schweitzer and Justice 2020 ). It is the leading cause of lower respiratory tract infections and hospital visits in infancy and childhood (Read and Bosco 2020 ). RSV infection results in bronchiolitis, which is classically caused by activated macrophages and eventually resolved by alternatively activated macrophages (Shirey et al 2010 ).…”

Topic Sessions

“…Transcriptomics is able to investigate in an in vivo situation the gene regulation changes associated with viral‐induced asthma in children (6). This approach has given insight into the way in which viruses cause airway inflammation and asthma exacerbations and the way the immune system responds either driven by the virus according to its agenda or in host defense both for respiratory viruses in general (1) and for COVID‐19 (7).…”

Editorial: Type I and Type III Interferon Immune Responses in Asthma

“…Air pollution is one of the greatest environmental risks to health in general and to respiratory diseases in particular ( 4 ). Virus infections, especially rhinovirus (RV) infections, on the other hand, are significant triggers of asthma attacks ( 5 , 6 ).…”

“…In addition, an association between RV-induced early wheezing episodes and subsequent development of school-age asthma has been reported (odds ratio up to 45 in subjects with aeroallergen sensitization). Altogether these findings have led to the hypothesis that impaired IFN responses may actually have an important role in the development of asthma ( 6 – 8 ). In agreement, knockout mouse models have demonstrated the importance of IFN-α/β in controlling virus replication ( 9 ), while studies with IFN-λs report that they suppress both virus replication ( 10 ) and allergic airway inflammation ( 11 ).…”

“…Bronchiolitis is usually defined as a virus-induced inflammation of small bronchioles and their surrounding tissue in infants. The airway inflammation consequently causes airway edema, mucus hyper-production and bronchial smooth muscle contraction, making it more difficult to breathe ( 5 , 6 ). In this issue, Makrinioti et al.…”