PorSignDB: a database of in vivo perturbation signatures for dissecting clinical outcome of PCV2 infection

Abstract

Porcine Circovirus Type 2 (PCV2) is a pathogen that has the ability to cause often devastating disease manifestations in pig populations with major economic implications. How PCV2 establishes subclinical persistence and why certain individuals progress to lethal lymphoid depletion remain to be elucidated. Here we present PorSignDB, a gene signature database describing in vivo porcine tissue physiology that we generated from a large compendium of in vivo transcriptional profiles and that we subsequently leveraged for deciphering the distinct physiological states underlying PCV2-affected lymph nodes. This systems biology approach indicated that subclinical PCV2 infections shut down the immune system. A robust signature of PCV2 disease emphasized that immune activation is dysfunctional in subclinical infections, however, in contrast it is promoted in PCV2 patients with clinical manifestations. Functional genomics further uncovered IL-2 as a driver of PCV2-mediated disease and we identified STAT3 as a druggable PCV2 host factor candidate. Our systematic dissection of the mechanistic basis of PCV2 reveals that subclinical and clinical PCV2 display two diametrically opposed immunotranscriptomic recalibrations that represent distinct physiological states in vivo, which suggests a paradigm shift in this field. Finally, our PorSignDB signature database is publicly available as a community resource (http://www.vetvirology.ugent.be/PorSignDB/, included in Gene Sets from Community Contributors http://software.broadinstitute.org/gsea/msigdb/contributed_genesets.jsp) and provides systems biologists with a valuable tool for catalyzing studies of human and veterinary disease.\n\nAuthor SummaryPorcine Circovirus Type 2 (PCV2) is a small but economically important pathogen circulating endemically in pig populations. Although PCV2 causes mostly chronic subclinical infections, many individuals develop a lethal form of circoviral disease consisting of a collapse of lymphoid tissue. In order to provide a fresh look at how PCV2 reprograms host tissue, we created PorSignDB, a compendium of hundreds of transcriptomic gene-expression signatures derived from primary porcine tissue specimens of well over 1500 patients or lab animals. By leveraging PorSignDB on transcriptomic data of PCV2 patients, we uncover that subclinical PCV2 reprograms the host into a striking state of non-infection, which explains its failure to respond to an initial phase of circoviral presence. A PCV2 disease signature further demonstrates that the silenced immune system associated with subclinical PCV2 becomes fully activate in PCV2 patients, triggering severe circoviral disease. Further genomic and functional analysis demonstrate STAT3 as a druggable host factor and IL-2 as a disease driver. Together, this study demonstrates the mechanistic underpinnings of clinical outcome of PCV2 infections: subclinical and clinical PCV2 display two entirely opposing transcriptomic recalibrations of lymphoid tissue.