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Comparative Study
. 2018 Jun;102(6):986-993.
doi: 10.1097/TP.0000000000002058.

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft

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Free PMC article
Comparative Study

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft

S Samuel Weigt et al. Transplantation. .
Free PMC article

Abstract

Background: Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis.

Methods: We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant.

Results: Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD.

Conclusions: Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD.

Conflict of interest statement

Disclosures: The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Bronchoalveolar lavage percent leukocyte differentials
(A) Percentage of neutrophils among the BAL cells by sample. (B) Percent neutrophils analysis (Mann-Whitney test) by Aspergillus vs No Aspergillus group. (C) Percent neutrophils analysis (Mann-Whitney test) by Aspergillus/CLAD vs Aspergillus/No CLAD group. (D.) Percentage of lymphocytes among the BAL cells by sample. (E) Percent lymphocytes analysis (Mann-Whitney test) by Aspergillus vs No Aspergillus group. (F) Percent lymphocytes analysis (Mann-Whitney test) by Aspergillus/CLAD vs Aspergillus/No CLAD group.
Figure 2
Figure 2
Volcano Plot visualization of DAE results. DAE generated a candidate list of 489 probe sets in the Aspergillus colonized cases as compared to the infection free controls, based on an unadjusted P-value <0.05 and absolute FDR >2.0.
Figure 3
Figure 3
Volcano Plot visualization of DAE results. DAE generated a candidate list of 69 probe sets in the Aspergillus colonization cases who progressed to CLAD as compared to those who remained CLAD free for at least 3 years, based on an unadjusted P-value <0.05 and absolute FDR >2.0.

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