23Porcine Circovirus Type 2 (PCV2) is a pathogen that has the ability to cause often devastating 24 disease manifestations in pig populations with major economic implications. How PCV2 25 establishes subclinical persistence and why certain individuals progress to lethal lymphoid 26 depletion remain to be elucidated. Here we present PorSignDB, a gene signature database 27 describing in vivo porcine tissue physiology that we generated from a large compendium of in 28 vivo transcriptional profiles and that we subsequently leveraged for deciphering the distinct 29 physiological states underlying PCV2-affected lymph nodes. This systems biology approach 30 indicated that subclinical PCV2 infections shut down the immune system. A robust signature 31 of PCV2 disease emphasized that immune activation is dysfunctional in subclinical infections, 32 however, in contrast it is promoted in PCV2 patients with clinical manifestations. Functional 33 genomics further uncovered IL-2 as a driver of PCV2-mediated disease and we identified 34 STAT3 as a druggable PCV2 host factor candidate. Our systematic dissection of the 35 mechanistic basis of PCV2 reveals that subclinical and clinical PCV2 display two diametrically 36 opposed immunotranscriptomic recalibrations that represent distinct physiological states in 37 vivo, which suggests a paradigm shift in this field. Finally, our PorSignDB signature database 38 is publicly available as a community resource