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bioRxiv2025

Correlates of protection against African swine fever virus identified by a systems immunology approach

African swine fever virus (ASFV) causes a fatal hemorrhagic disease in domestic pigs and wild boars, which poses severe threats to the global pork industry. Despite the promise of live attenuated vaccines (LAVs), their narrow margin between efficacy and residual virulence presents major safety challenges. This study bridges a critical knowledge gap in ASF vaccinology by identifying innate and adaptive correlates of protection. This was achieved by using an established model with two groups of pigs differing in baseline immunological status (farm and specific pathogen-free [SPF]). The animals were immunized with an attenuated ASFV strain and subsequently challenged with a related, highly virulent genotype II strain. By applying a systems immunology approach, we correlated kinetic data, including serum cytokines, blood transcription modules (BTMs), T-cell responses, and antibody levels, with clinical outcomes to track protective and detrimental immune responses to the virus over time. Key innate correlates of protection included early and sustained IFN- response, activation of antigen presentation BTMs, and controlled IL-8 levels during immunization. Lower baseline immune activation observed in SPF pigs in steady state was linked to increased protection. Adaptive correlates encompassed cell cycle, plasma cell, and T-cell BTM responses lasting until day 15 post-immunization. Consequently, an effective response from ASFV-specific Th cells prior to challenge indicated protection. After the challenge, an early IFN- response, along with low levels of pro-inflammatory cytokines and a strong induction of memory Th and Tc cells, correlated with improved clinical outcomes. The model highlights the critical role of host-specific factors in vaccine efficacy and provides a valuable framework for optimizing ASFV vaccine design while distinguishing between protective and detrimental immune responses.

immunology↗

bioRxiv2024

Peste des Petits Ruminants virus virulence is associated with an early inflammatory profile in the tonsils and cell cycle arrest in lymphoid tissue

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 Morroco 2008 (MA08) or the low virulent Ivory Coast 1989 (IC89) strain of 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 found to be most affected in terms of depletion and infection in the peripheral blood. Transcriptional analyses of the blood and lymphoid tissue demonstrated activation of interferon type I (IFN-I) responses at three days post infection (dpi) only with MA08, but comparable IFN-I expression levels with MA08 and IC89 at 6 dpi. In contrast, only the MA08 strain induced strong inflammatory and myeloid cell-related transcriptional responses which as observed in tonsils but not in the mesenteric lymph node. This inflammatory response in the tonsil was associated with an extensive damage and infection of the tonsillar epithelium in the crypts, pointing on a barrier defect as a possible cause of inflammation. The other prominent effect induced by MA08, but not IC89, was a strong and early downregulation of cell cycle gene networks in lymphoid tissues. This effect was found in the blood compartment and all analysed lymphoid tissues and can be interpreted as suppressed lymphocyte proliferation that may cause immunosuppression during the first week following MA08 infection. A proteome analysis confirmed elevated synthesis of IFN-I response proteins during infection with both strains, but only the 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. Understanding such strain-specific differences is relevant for effective PPRV surveillance strategies. Author summaryField observations show that the severity of infection with Peste des Petits Ruminants virus (PPRV) is highly dependent on the viral 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 type I interferon (IFN-I) responses only with MA08, but comparable IFN-I expression levels with MA08 and IC89 at later stages. Additionally, only the MA08 strain triggered inflammatory and myeloid cell- related responses in the tonsils, as well as a disseminated early 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, particularly for the highly virulent strains, seems to induce epithelial lesions that promotes the inflammatory responses. These findings underscore the importance of understanding strain- specific differences for appropriate surveillance and control of PPR.

immunology↗