UNLABELLED: 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 peripheral 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 immunopathological processes associated with severe inflammation disease and a blunted lymphocyte proliferation. IMPORTANCE: Field observations show that the severity of PPR is highly dependent on the viral (PPRV) strains and the host infected, but the mechanisms behind these variations are not well understood. Here we compare immune response in Saanen goats infected with high (MA08) and low (IC89) virulent PPRV strains. Analyses revealed a differential immune response: early activation of IFN-I responses only with MA08 but comparable IFN-I expression levels with MA08 and IC89 at later stages. Additionally, MA08 strain triggered inflammatory and myeloid cell-related responses in the tonsils and marked suppression of lymphocyte proliferation evidenced by cell cycle arrest. CD4 T cells were found to be most affected in terms of depletion in the peripheral blood. Massive infection of the tonsils seems to induce epithelial lesions that promote the inflammatory responses. These results underscore the need to understand strain-specific differences for PPR surveillance and control.