TY - JOUR
T1 - Microbes are associated with host innate immune response in idiopathic pulmonary fibrosis
AU - Huang, Yong
AU - Ma, Shwu Fan
AU - Espindola, Milena S.
AU - Vij, Rekha
AU - Oldham, Justin M.
AU - Huffnagle, Gary B.
AU - Erb-Downward, John R.
AU - Flaherty, Kevin R.
AU - Moore, Beth B.
AU - White, Eric S.
AU - Zhou, Tong
AU - Li, Jianrong
AU - Lussier, Yves A.
AU - Han, Meilan K.
AU - Kaminski, Naftali
AU - Garcia, Joe G.N.
AU - Hogaboam, Cory M.
AU - Martinez, Fernando J.
AU - Noth, Imre
N1 - Publisher Copyright:
© 2017 by the American Thoracic Society.
PY - 2017/7/15
Y1 - 2017/7/15
N2 - Rationale: Differences in the lung microbial community influence idiopathic pulmonary fibrosis (IPF) progression. Whether the lung microbiome influences IPF host defense remains unknown. Objectives: To explore the host immune response and microbial interaction in IPF as they relate to progression-free survival (PFS), fibroblast function, and leukocyte phenotypes. Methods: Paired microarray gene expression data derived from peripheral blood mononuclear cells as well as 16S ribosomal RNA sequencing data from bronchoalveolar lavage obtained as part of the COMET-IPF (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in Idiopathic Pulmonary Fibrosis) study were used to conduct association pathway analyses. The responsiveness of paired lung fibroblasts to Toll-like receptor 9 (TLR9) stimulation by CpG-oligodeoxynucleotide (CpG-ODN) was integrated into microbiome-gene expression association analyses for a subset of individuals. The relationship between associated pathways and circulating leukocyte phenotypes was explored by flow cytometry. Measurements and Main Results: Down-regulation of immune response pathways, including nucleotide-binding oligomerizationdomain (NOD)-, Toll-, and RIG1-like receptor pathways, was associated with worse PFS. Ten of the 11 PFS-associated pathways correlated with microbial diversity and individual genus, with species accumulation curve richness as a hub. Higher species accumulation curve richness was significantly associated with inhibition of NODs and TLRs, whereas increased abundance of Streptococcus correlated with increased NOD-like receptor signaling. In a network analysis, expression of up-regulated signaling pathways was strongly associated with decreased abundance of operational taxonomic unit 1341 (OTU1341; Prevotella) among individuals with fibroblasts responsive to CpG-ODN stimulation. The expression of TLR signaling pathways was also linked to CpG-ODN responsive fibroblasts, OTU1341 (Prevotella), and Shannon index of microbial diversity in a network analysis. Lymphocytes expressing C-X-C chemokine receptor 3 CD8 significantly correlated with OTU1348 (Staphylococcus). Conclusions: These findings suggest that host-microbiome interactions influence PFS and fibroblast responsiveness.
AB - Rationale: Differences in the lung microbial community influence idiopathic pulmonary fibrosis (IPF) progression. Whether the lung microbiome influences IPF host defense remains unknown. Objectives: To explore the host immune response and microbial interaction in IPF as they relate to progression-free survival (PFS), fibroblast function, and leukocyte phenotypes. Methods: Paired microarray gene expression data derived from peripheral blood mononuclear cells as well as 16S ribosomal RNA sequencing data from bronchoalveolar lavage obtained as part of the COMET-IPF (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in Idiopathic Pulmonary Fibrosis) study were used to conduct association pathway analyses. The responsiveness of paired lung fibroblasts to Toll-like receptor 9 (TLR9) stimulation by CpG-oligodeoxynucleotide (CpG-ODN) was integrated into microbiome-gene expression association analyses for a subset of individuals. The relationship between associated pathways and circulating leukocyte phenotypes was explored by flow cytometry. Measurements and Main Results: Down-regulation of immune response pathways, including nucleotide-binding oligomerizationdomain (NOD)-, Toll-, and RIG1-like receptor pathways, was associated with worse PFS. Ten of the 11 PFS-associated pathways correlated with microbial diversity and individual genus, with species accumulation curve richness as a hub. Higher species accumulation curve richness was significantly associated with inhibition of NODs and TLRs, whereas increased abundance of Streptococcus correlated with increased NOD-like receptor signaling. In a network analysis, expression of up-regulated signaling pathways was strongly associated with decreased abundance of operational taxonomic unit 1341 (OTU1341; Prevotella) among individuals with fibroblasts responsive to CpG-ODN stimulation. The expression of TLR signaling pathways was also linked to CpG-ODN responsive fibroblasts, OTU1341 (Prevotella), and Shannon index of microbial diversity in a network analysis. Lymphocytes expressing C-X-C chemokine receptor 3 CD8 significantly correlated with OTU1348 (Staphylococcus). Conclusions: These findings suggest that host-microbiome interactions influence PFS and fibroblast responsiveness.
KW - Bronchoalveolar lavage microbiome
KW - CpG-oligodeoxynucleotide response
KW - Host immune response and microbial interaction
KW - Pattern recognition receptors
KW - Peripheral blood mononuclear cell transcriptome
UR - https://www.scopus.com/pages/publications/85018957747
UR - https://www.scopus.com/pages/publications/85018957747#tab=citedBy
U2 - 10.1164/rccm.201607-1525OC
DO - 10.1164/rccm.201607-1525OC
M3 - Article
C2 - 28157391
AN - SCOPUS:85018957747
SN - 1073-449X
VL - 196
SP - 208
EP - 219
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 2
ER -