UBC Theses and Dissertations
Multi ’omics integration of the HIV airway epithelium : integration of the microbiome, transcriptome and methylome Jude, Marcia Smiti
RATIONALE: People living with HIV (PLWH) appear to have increased proneness to chronic obstructive pulmonary disease (COPD) independent of their cigarette smoke exposure. Previous studies have shown that HIV infection is associated with changes in the airway microbiome and host response, however, the exact mechanism of disease progression is still unknown. We hypothesize that airway epithelial dysbiosis in PLWH increases the susceptibility to COPD in this group. METHODS: Airway epithelial cell brushings were obtained from 18 COPD+HIV+,16 COPD-HIV+, 22 COPD+HIV- and 20 COPD-HIV- subjects. Microbiome, methylation, and transcriptome profiles were measured using 16s amplicon sequencing (Illumina Miseq®), Illumina Infinium Methylation EPIC chip®, and RNA sequencing (NovaSeq6000®), respectively. Microbiome analysis was performed using QIIME 2™, and transcriptome and methylation analyses were performed using R language. The three datasets were integrated using Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) implemented in the mixOmics R package. Fifty repeats of 10-fold cross-validations and a correlation threshold of 0.7 were set to determine key interactions between bacterial ASVs, CpG methylation sites, and gene transcripts amongst the subjects based on their COPD, HIV, and combined COPD and HIV statuses. RESULTS: The microbiome analysis identified that the groups most associated with disease (COPD+, HIV+, and COPD+HIV+ groups) had reduced alpha diversity (Shannon Diversity Index p=0.0013, p=0023, and p=0.0002, respectively), and significantly disrupted microbial communities (Bray Curtis PERMANOVA p=0.001, p=0.007 and p=0.001, respectively) compared to their relatively ”healthy” counterparts. This was accompanied by changes in the host transcriptome and epigenome, our analysis of which identified top genes and CpG sites that were differentially regulated in patients with COPD and/or HIV. Integration of the three -omes identified features that were correlated with one another at a threshold>0.70. On combining the COPD and HIV statuses of subjects, the multiomic integration identified correlations between the bacterial ASV Bacteroidetes Prevotella and transcriptomic features FUZ, FASTKD3, and ACVR1B, and epigenetic features CpG-FUZ and CpG-PHLDB3. It may be that these features together influence host pathways regulating mucociliary clearance, respiration and energy, cell cycle, and immunity.
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