ABSTRACT As an essential component of host defense against infection, necroptosis is a novel highly regulated mode of cell death that is mediated by signaling complexes containing receptor-interacting protein kinase 1 (RIPK1) and RIPK3. Lymphocyte depletion and immunosuppression are typical clinical features of pigs infected with classical swine fever virus (CSFV). Here, we provide the first evidence for the involvement of necroptosis in the necrosis of T lymphocytes in the spleen and peripheral blood of pigs infected in vivo with CSFV. However, it is true for some viruses with non-cytopathic effects, including CSFV, to balance host defense against infection. In vitro, the induction of autophagy by CSFV at a later stage of infection clearly restricts necroptosis. Mechanistic studies revealed that CSFV NS4A protein promoted tripartite motif-containing 25 expression, synergistically induced the occurrence of mitophagy, targeted the autophagic degradation of RIPK3 to block the progression of necroptosis occurrence, and achieved persistent viral infection. Interestingly, we found that RIPK3 was able to specifically localize at the outer mitochondrial membrane, and the autophagy receptor NDP52 was most likely involved in the autophagic degradation of RIPK3 during CSFV infection. Our findings provide evidence supporting that the CSFV-induced autophagy pathway plays an important role in counteracting host cell necrosis, enriching our knowledge of pathogens that may subvert and evade necroptosis this host defense, and shedding new light on understanding the mechanisms of T lymphocyte exhaustion and immunosuppression during CSFV infection. IMPORTANCE CSFV infection in pigs causes persistent high fever, hemorrhagic necrotizing multi-organ inflammation, and high mortality, which seriously threatens the global swine industry. Cell death is an essential immune response of the host against pathogen invasion, and lymphopenia is the most typical clinical feature in the acute phase of CSFV infection, which affects the initial host antiviral immunity. As an “old” virus, CSFV has evolved mechanisms to evade host immune response after a long genetic evolution. Here, we show that necroptosis is a limiting host factor for CSFV infection and that CSFV-induced autophagy can subvert this host defense mechanism to promote its sustained replication. Our findings reveal a complex link between necroptosis and autophagy in the process of cell death, provide evidence supporting the important role for CSFV in counteracting host cell necrosis, and enrich our knowledge of pathogens that may subvert and evade this host defense.
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