Microbes are associated with host innate immune response in idiopathic pulmonary fibrosis

Yong Huang, Shwu Fan Ma, Milena S. Espindola, Rekha Vij, Justin M. Oldham, Gary B. Huffnagle, John R. Erb-Downward, Kevin R. Flaherty, Beth B. Moore, Eric S. White, Tong Zhou, Jianrong Li, Yves A Lussier, Meilan K. Han, Naftali Kaminski, Joe GN Garcia, Cory M. Hogaboam, Fernando J. Martinez, Imre Noth

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)208-219
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume196
Issue number2
DOIs
StatePublished - Jul 15 2017

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Idiopathic Pulmonary Fibrosis
Innate Immunity
Fibroblasts
Disease-Free Survival
Oligodeoxyribonucleotides
Microbiota
Prevotella
Lung
Leukocytes
Nucleotides
Microbial Interactions
Toll-Like Receptor 9
16S Ribosomal RNA
RNA Sequence Analysis
Phenotype
Gene Expression
CXC Chemokines
Chemokine Receptors
Toll-Like Receptors
Bronchoalveolar Lavage

Keywords

  • Bronchoalveolar lavage microbiome
  • CpG-oligodeoxynucleotide response
  • Host immune response and microbial interaction
  • Pattern recognition receptors
  • Peripheral blood mononuclear cell transcriptome

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Microbes are associated with host innate immune response in idiopathic pulmonary fibrosis. / Huang, Yong; Ma, Shwu Fan; Espindola, Milena S.; Vij, Rekha; Oldham, Justin M.; Huffnagle, Gary B.; Erb-Downward, John R.; Flaherty, Kevin R.; Moore, Beth B.; White, Eric S.; Zhou, Tong; Li, Jianrong; Lussier, Yves A; Han, Meilan K.; Kaminski, Naftali; Garcia, Joe GN; Hogaboam, Cory M.; Martinez, Fernando J.; Noth, Imre.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 196, No. 2, 15.07.2017, p. 208-219.

Research output: Contribution to journalArticle

Huang, Y, Ma, SF, Espindola, MS, Vij, R, Oldham, JM, Huffnagle, GB, Erb-Downward, JR, Flaherty, KR, Moore, BB, White, ES, Zhou, T, Li, J, Lussier, YA, Han, MK, Kaminski, N, Garcia, JGN, Hogaboam, CM, Martinez, FJ & Noth, I 2017, 'Microbes are associated with host innate immune response in idiopathic pulmonary fibrosis', American Journal of Respiratory and Critical Care Medicine, vol. 196, no. 2, pp. 208-219. https://doi.org/10.1164/rccm.201607-1525OC
Huang, Yong ; Ma, Shwu Fan ; Espindola, Milena S. ; Vij, Rekha ; Oldham, Justin M. ; Huffnagle, Gary B. ; Erb-Downward, John R. ; Flaherty, Kevin R. ; Moore, Beth B. ; White, Eric S. ; Zhou, Tong ; Li, Jianrong ; Lussier, Yves A ; Han, Meilan K. ; Kaminski, Naftali ; Garcia, Joe GN ; Hogaboam, Cory M. ; Martinez, Fernando J. ; Noth, Imre. / Microbes are associated with host innate immune response in idiopathic pulmonary fibrosis. In: American Journal of Respiratory and Critical Care Medicine. 2017 ; Vol. 196, No. 2. pp. 208-219.
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abstract = "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.",
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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 GN

AU - Hogaboam, Cory M.

AU - Martinez, Fernando J.

AU - Noth, Imre

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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.

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KW - CpG-oligodeoxynucleotide response

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KW - Peripheral blood mononuclear cell transcriptome

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