877. Th17 Downstream Signaling is Associated with Disease Severity in Children with Rhinovirus (HRV) Bronchiolitis
Session: Oral Abstract Session: Microbiome and Susceptibility to Infection
Saturday, October 22, 2011: 10:30 AM
Room: 156ABC
Background: HRV are one of the most frequent viral etiologic agents of bronchiolitis and wheezing in children. The mechanisms involved in HRV wheezing are not well characterized and might be driven by a disregulated immune response. We sought to define which immune pathways are activated by HRV infection and, to determine whether those pathways and/or immune markers correlate with disease severity in children with HRV wheezing (bronchiolitis).

Methods: Blood transcriptional profiles from 83 previously healthy children < 2 years, with a first episode of HRV-wheezing and 13 age- and sex- healthy matched controls were analyzed using Illumina arrays, GeneSpring and Ingenuity Pathway Analysis (IPA) software.  Children with HRV bronchiolitis were grouped into (a) mild, and (b) moderate-severe disease using a clinical disease severity score (CDSS). Non-parametric tests (p<0.01) and 1.25 fold-change filter were used to: 1) identify the distinct HRV transcriptional profile and, 2) correlate the distinct immune profiles and a genomic score (MDTH; molecular distance to health) with the CDSS.

Results: Statistical group comparisons identified 1,457 significantly expressed genes (HRV profile) between children with HRV (n= 25; 14.5 [7.6-17.5] months) and healthy controls, which was validated in two independent cohorts of 28 and 30 children each. The HRV profile was characterized by under expression of Th1 and Th2-cytokine related genes (IL-18 and IL9R) and over expression of Th17 related genes. IPA revealed stronger activation of Th17 cytokine downstream signaling (IL-17A, IL-17F, IL-17R, STAT-3 and IL-22) in children with moderate-severe HRV disease [n=32; CDSS ≥ 5] vs those with mild HRV bronchiolitis [n=21; CDSS ≤ 4]. MDTH scores were higher in children with moderate-severe vs mild disease [1131 (347-2171) vs 336 (58-458) respectively; p<0.0001]. MDTH scores and the expression of Th-17 related genes (IL-17R and STAT-3) significantly correlated with the CDSS (r =0.4;p <0.01).

Conclusion: We found a strong activation of Th17 cytokine signaling in infants with HRV-bronchiolitis that correlated with clinical disease severity. These results indicate that Th17 immune responses may play a significant role in the pathogenesis of HRV-induced wheezing.


Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

Blerta Dimo, M.D, PhD1, Tuomas Jartti2, Olli Ruuskanen2, T Vuorinen2, Damien Chaussabel, PhD3, Octavio Ramilo, MD4 and Asuncion Mejias, MD, PhD5, (1)Vaccines and Immunity, Nationwide Children's Hospital , Columbus, OH, (2)Turku university hospital, Turku, Finland, (3)Benaroya Research Institute, Seattle, WA, (4)Pediatrics, Infectious Diseases, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, (5)Pediatrics, Infectious Diseases, Nationwide Children's Hospital, Columbus, OH

Disclosures:

B. Dimo, None

T. Jartti, None

O. Ruuskanen, None

T. Vuorinen, None

D. Chaussabel, None

O. Ramilo, Medimmune: Grant Investigator, Grant recipient
Qudeil: Scientific Advisor, Consulting fee
Abbott Labs: Consultant, Speaker honorarium
Abbott Molecular: Grant Investigator, Grant recipient
Merck: Consultant, Consulting fee

A. Mejias, Abbott: Grant Investigator, Grant recipient
Mead-Johnson: Grant Investigator, Grant recipient

Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.