Microbes Are Associated with Host Innate Immune Response in Idiopathic Pulmonary Fibrosis

被引：110

作者：

Huang, Yong ^{[1
]}

Ma, Shwu-Fan ^{[1
]}

Espindola, Milena S. ^{[2
]}

Vij, Rekha ^{[1
]}

Oldham, Justin M. ^{[3
]}

Huffnagle, Gary B. ^{[4
]}

Erb-Downward, John R. ^{[4
]}

Flaherty, Kevin R. ^{[4
]}

Moore, Beth B. ^{[4
]}

White, Eric S. ^{[4
]}

Zhou, Tong ^{[5
]}

Li, Jianrong ^{[6
]}

Lussier, Yves A. ^{[6
]}

Han, MeiLan K. ^{[4
]}

Kaminski, Naftali ^{[7
]}

Garcia, Joe G. N. ^{[6
]}

Hogaboam, Cory M. ^{[2
]}

Martinez, Fernando J. ^{[8
]}

Noth, Imre ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, Sect Pulm & Crit Care Med, 5841 South Maryland Ave,MC6076, Chicago, IL 60637 USA

[2] Cedars Sinai Med Ctr, Pulm & Crit Care Med, Los Angeles, CA 90048 USA

[3] Univ Calif Davis, Pulm & Crit Care Med, Sacramento, CA 95817 USA

[4] Univ Michigan Hlth Syst, Div Pulm & Crit Care Med, Ann Arbor, MI USA

[5] Univ Nevada, Sch Med, Dept Physiol & Cell Biol, Reno, NV 89557 USA

[6] Univ Arizona, Univ Arizona Hlth Sci, Tucson, AZ USA

[7] Yale Univ, Sch Med, Sect Pulm Crit Care & Sleep Med, New Haven, CT USA

[8] Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA

来源：

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE | 2017年 / 196卷 / 02期

关键词：

host immune response and microbial interaction; peripheral blood mononuclear cell transcriptome; bronchoalveolar lavage microbiome; CpG-oligodeoxynucleotide response; pattern recognition receptors; TGF-BETA ACTIVATION; DISEASE PROGRESSION; LUNG MICROBIOME; T-CELLS; SUSCEPTIBILITY; PATHOGENESIS; EXPRESSION; POLYMORPHISM; INHIBITION; PROGNOSIS;

D O I：

10.1164/rccm.201607-1525OC

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

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 oligomerization domain (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.

引用

页码：208 / 219

页数：12

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