title: Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection.
abstract: Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g. neutrophils), but the underlying mechanisms remain unclear.
  
  
  
  The major goal was to determine the role of genetic variation [e.g. single nucleotide polymorphisms (SNPs)] of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu.
  
  
  
  DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and antiviral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and antiviral response.
  
  
  
  Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (vs. AA) produced more IL-8 and expressed less antiviral genes, which was coupled with increased NF-κB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co-localized and interacted with LC3. Inhibition of autophagy decreased antiviral genes in IL-13- and RV16-treated cells. Upon HDM and RV1B, Tollip knockout (vs. wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of antiviral gene expression.
  
  
  
  Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma.
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: C
authors: C
authors: Huang
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: D
authors: D
authors: Jiang
authors: Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: D
authors: D
authors: Francisco
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: R
authors: R
authors: Berman
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: Q
authors: Q
authors: Wu
authors: Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: J G
authors: JG
authors: Ledford
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: C M
authors: CM
authors: Moore
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: Y
authors: Y
authors: Ito
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: C
authors: C
authors: Stevenson
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: D
authors: D
authors: Munson
authors: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
authors: L
authors: L
authors: Li
authors: Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.
authors: M
authors: M
authors: Kraft
authors: Department of Medicine, National Jewish Health, Denver, CO, USA.
authors: H W
authors: HW
authors: Chu
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D005838:Genotype; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010850:Picornaviridae Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology*; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000821:virology*; D012229:Rhinovirus / Q000276:immunology*; D019562:Viral Load
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C410602:TOLLIP protein, human
keywords: Tollip; airway epithelial cells; autophagy; inflammation; rhinovirus