Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells

Liu, Yiping; Bochkov, Yury A.; Eickhoff, Jens; Hu, Tianchen; Zumwalde, Nicholas A.; Tan, Jin; Lopez, Christopher; Fichtinger, Paul S.; Reddy, Thiruchelvi R.; Overmyer, Katherine A.; Gumperz, Jennifer E; Coon, Joshua J.; Mathur, Sameer K.; Gern, James E.; Smith, Judith A.

doi:10.1165/rcmb.2019-0237oc

Cited by 22 publications

(20 citation statements)

References 44 publications

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“…Consistent with our observations, research reported that sphingolipid metabolism is associated with bronchiolitis severity 16 and childhood asthma (eg, ORMDL3 within the 17q21 locus regulating de novo sphingolipid synthesis) 25 . A recent study using human epithelial cell models showed that a ORMDL3 knockdown inhibits RV‐A16 replication, endoplasmic reticulum stress, and IFN‐β expression 26 . Furthermore, previous research using newborn screening data also reported associations of acylcarnitines—metabolites that play critical role in fatty acid metabolism—with risks of wheezing by age of 3 years 27 .…”

Section: Discussionsupporting

confidence: 90%

Respiratory viruses are associated with serum metabolome among infants hospitalized for bronchiolitis: A multicenter study

Fujiogi

Camargo

Raita

et al. 2020

Pediatric Allergy Immunology

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Background: Bronchiolitis is the leading cause of infant hospitalizations in the United States. Growing evidence supports the heterogeneity of bronchiolitis. However, little is known about the interrelationships between major respiratory viruses (and their species), host systemic metabolism, and disease pathobiology. Methods: In an ongoing multicenter prospective cohort study, we profiled the serum metabolome in 113 infants (63 RSV-only, 21 RV-A, and 29 RV-C) hospitalized with bronchiolitis. We identified serum metabolites that are most discriminatory in the RSV-RV-A and RSV-RV-C comparisons using sparse partial least squares discriminant analysis. We then investigated the association between discriminatory metabolites with acute and chronic outcomes. Results: In 113 infants with bronchiolitis, we measured 639 metabolites. Serum metabolomic profiles differed in both comparisons (P permutation < 0.05). In the RSV-RV-A comparison, we identified 30 discriminatory metabolites, predominantly in lipid metabolism pathways (eg, sphingolipids and carnitines). In multivariable models, these metabolites were significantly associated with the risk of clinical outcomes (eg, tricosanoyl sphingomyelin, OR for recurrent wheezing at age of 3 years = 1.50; 95% CI: 1.05-2.15). In the RSV-RV-C comparison, the discriminatory metabolites were also primarily involved in lipid metabolism (eg, glycerophosphocholines [GPCs], 12,13-diHome). These metabolites were also significantly associated with the risk of outcomes (eg, 1-stearoyl-2-linoleoyl-GPC, OR for positive pressure ventilation use during hospitalization = 0.47; 95% CI: 0.28-0.78). Conclusion: Respiratory viruses and their species had distinct serum metabolomic signatures that are associated with differential risks of acute and chronic morbidities of bronchiolitis. Our findings advance research into the complex interrelations between viruses, host systemic response, and bronchiolitis pathobiology.

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Section: Discussionsupporting

confidence: 90%

Respiratory viruses are associated with serum metabolome among infants hospitalized for bronchiolitis: A multicenter study

Fujiogi

Camargo

Raita

et al. 2020

Pediatric Allergy Immunology

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“…43 Moreover, the ORMDL3 gene product was recently shown to support RV replication in epithelia cells. 81 Finally, GSDMB encodes gasdermin B, which is a member of the gasdermin-domain containing protein family linked to epithelial apoptosis. Recently, it has been shown that GSDMB is elevated in the airway epithelium in asthma.…”

Section: G Ene Ti C Fac Tor S and The Epithelial Barrier In A S Thmamentioning

confidence: 99%

Epithelial cell dysfunction, a major driver of asthma development

Heijink

Kuchibhotla

Roffel

et al. 2020

Allergy

186

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Asthma is a chronic inflammatory airway disease characterized by coughing, wheezing, chest tightness, variable airflow limitation and airway hyper-responsiveness (AHR) 1 to environmental specific (allergens such as house dust mite (HDM), pollen and animal dander) and nonspecific (eg tobacco smoke, air pollution) stimuli. Asthma is a heterogeneous disease with a complex aetiology. Allergen-induced asthma is the most common form, with atopy and allergic sensitization being identified as major risk factors. 2 Other risk factors include increased viral infections during early childhood, exposure to tobacco smoke and air pollution. 3 In

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“…Knockdown of ORMDL3 in airway epithelial cells resulted in a marked reduction in expression of ICAM1, which is the main receptor exploited by some HRV-A and HRV-B species for host cell entry, demonstrating a plausible functional link between ORMDL3 and HRV wheezing [ 34 ]. Liu et al [ 35 ] demonstrated that silencing ORMDL3 reduced replication of HRV-16 in airway epithelial and HeLa cells following in vitro infection. Unlike the previous report, however, ICAM1 was not reduced following ORMDL3 knockdown which may suggest the influence of ORMDL3 occurs after viral binding [ 34 , 35 ].…”

Section: Geneticsmentioning

confidence: 99%

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

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Bosco

2020

IJMS

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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.

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Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells

Cited by 22 publications

References 44 publications

Respiratory viruses are associated with serum metabolome among infants hospitalized for bronchiolitis: A multicenter study

Respiratory viruses are associated with serum metabolome among infants hospitalized for bronchiolitis: A multicenter study

Epithelial cell dysfunction, a major driver of asthma development

Decoding Susceptibility to Respiratory Viral Infections and Asthma Inception in Children

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