Abstract Background Respiratory viral infections impact outcomes of COPD patients. In this study, we leveraged Phage ImmunoPrecipitation Sequencing (PhIP-Seq) technology to assess blood samples for antibodies indicative of prior viral infections, and integrated these results with blood RNA-sequencing data from the same subjects in the COPDGene study. We hypothesize blood gene expression signatures will reveal differential host responses to particular viral infections across COPD cases and control subjects, helping to better understand the impact of viral infections in COPD. Methods Using plasma samples from COPDGene subjects at the 5-year study visit, we performed PhIP-Seq profiling to quantify antibody reactivities, focusing here on those targeting viral peptides. We combined the peptide-specific data for each viral species to assess the composite reactivity to particular viruses. Associations between reactivity and genome-wide blood gene expression were tested using limma-voom in stratified analyses of COPD cases and controls. The models included the covariates age, sex, race, smoking status, pack-years of smoking and WBC. We performed pathway analysis using the association results for each virus and the hallmark gene sets from MSigSB. Results The analytical dataset included both blood RNA-seq and PhIP-seq profiling from 245 COPDGene subjects (121 COPD cases and 124 controls). After combining the peptide-specific PhIP-seq data, the human virus reactivity dataset included 117 species and serotypes. In the analysis of virus reactivity and host blood transcriptomic pathways, we observed reactivity for human rhinovirus and influenza species (e.g. HRV16 and Influenza A) associated with increased expression of the oxidative phosphorylation, interferon-alpha and interferon-gamma pathways (FDR0.05), predominantly in COPD cases. Conversely, in COPD cases the reactivity for several human adenoviruses were associated with decreased expression of both interferon pathways. The reactivities for echoviruses and coxsackieviruses in COPD cases were associated with reduced expression of the heme metabolism pathway, associations not observed in control subjects. Also, while Epstein-Barr virus reactivity was associated with increased interferon pathway expression in controls, we observed no association in the COPD cases. Conclusions We sought to identify host blood transcriptomic signatures associated with prior viral infections, hypothesizing this will help reveal the biology unique to viral infections in COPD. We observed differences in the associations between several viral species and host pathways across COPD disease status. This project will help us better understand the biology of host viral responses and the particular viruses impacting COPD outcomes. This abstract is funded by: These efforts were supported by NIH grants: R01 HL168663, R01 HL166231, K25 HL136846, P01 HL114501, U01 HL089897, U01 HL089856, NIH contract 75N92023D00011, an Alpha-1 Foundation Research Grant and a TOPMed Fellowship
Morrow et al. (Fri,) studied this question.