Using a systems immunology approach, this study comprehensively explored the immunopathogenesis of peste des petits ruminants (PPR) focussing on strain-dependent differences in virulence. Saanen goats were infected either with the highly virulent (Morocco 2008 [MA08]) or the low-virulent (Ivory Coast 1989 [IC89]) strain of the PPR virus (PPRV). As expected, MA08-infected goats exhibited higher clinical scores, pronounced lymphocyte depletion, and lesions affecting mucosal and lymphoid tissues. CD4 T cells were more affected in terms of depletion and infection in periph eral blood. Transcriptional analyses of the blood and lymphoid tissue demonstrated activation of interferon type I (IFN-I) responses at 3 days post-infection (dpi) only with MA08, but comparable IFN-I expression levels with MA08 and IC89 at 6 dpi. MA08 strain induced strong inflammatory and myeloid cell-related transcriptional responses observed in tonsils but not in mesenteric lymph node. This inflammatory response in the tonsils was associated with an extensive damage and infection of the tonsillar epithelium in the crypts, pointing to a barrier defect as a possible cause of inflammation. An early and prominent downregulation of cell cycle gene networks was observed in all compartments analyzed in MA08-infected animals. This effect can be interpreted as suppressed lymphocyte proliferation that may cause immunosuppression during the first week following MA08 infection. A proteome analysis confirmed synthesis of IFN-I response proteins during infection with both strains, but only MA08 strain additionally upregulated ribosomal and inflammation-related proteins. In conclusion, the present comprehensive investigation delineates strain-dependent differences in early immuno pathological processes associated with severe inflammation disease and a blunted lymphocyte proliferation.