Acute induction of cell death-related IFN stimulated genes (ISG) differentiates highly from moderately virulent CSFV strains

Abstract

Classical swine fever (CSF) severity is dependent on the virulence of the CSF virus (CSFV) strain. The earliest event detected following CSFV infection is a decrease in lymphocytes number. With some CSFV strains this leads to lymphopenia, the severity varying according to strain virulence. This lymphocyte depletion is attributed to an induction of apoptosis in non-infected bystander cells. We collected peripheral blood mononuclear cells (PBMC) before and during 3 days post-infection with either a highly or moderately virulent CSFV strain and subjected them to comparative microarray analysis to decipher the transcriptomic modulations induced in these cells in relation to strain virulence. The results revealed that the main difference between strains resided in the kinetics of host response to the infection: strong and immediate with the highly virulent strain, progressive and delayed with the moderately virulent one. Also although cell death/apoptosis-related IFN stimulated genes (ISG) were strongly up-regulated by both strains, significant differences in their regulation were apparent from the observed differences in onset and extent of lymphopenia induced by the two strains. Furthermore, the death receptors apoptotic pathways (TRAIL-DR4, FASL-FAS and TNFa-TNFR1) were also differently regulated. Our results suggest that CSFV strains might exacerbate the interferon alpha response, leading to bystander killing of lymphocytes and lymphopenia, the severity of which might be due to the host’s loss of control of IFN production and downstream effectors regulation.

Classical Swine Fever—An Updated Review

“…High IFN-α concentrations are found as early as two days post infection, prior to the onset of clinical symptoms [112]. These findings are confirmed by microarray analyses of peripheral blood monocytic cells derived from CSFV-infected pigs [142]. …”

Treatment with interferon-alpha delays disease in swine infected with a highly virulent CSFV strain

“…Virulence studies using recombinant CSFV harboring modified forms of N pro , which should alter IFN induction/production rendered controversial results (Mayer et al, 2004;Ruggli et al, 2009;Tamura et al, 2014). Interestingly, a direct correlation between the virulence of a CSFV strain and the amount of IFN produced during the infection in swine has been reported (Renson et al, 2010;Summerfield et al, 1998;Tarradas et al, 2014), challenging the hypothesis that inhibition of host IFN is a critical step during infection, particularly with highly virulent CSFV strains. More recently, Tamura et al (2014) have shown that functional N pro influences the innate immune response at local sites of virus replication in pigs thus contributing to pathogenicity in synergy with viral replication.…”

Partial Activation of Natural Killer and γδ T Cells by Classical Swine Fever Viruses Is Associated with Type I Interferon Elicited from Plasmacytoid Dendritic Cells

“…Moreover, it has recently been shown that the interaction of pDCs with CSFV-infected cells induces greater IFN-␣ production than that from direct infection of pDCs (45); therefore, the ability of virulent CSFV strains to rapidly replicate in macrophages and mDCs may potentiate the IFN-␣ response by pDCs in the lymphoid tissues. This exacerbated type I IFN response to CSFV mediated by pDCs has been hypothesized as a key driver of the pathogenesis of CSF, including the hallmark trait of leukopenia (46,47). A novel subset of porcine NK cells expressing high levels of NKp46 and low levels of CD8␣ has recently been described in the spleen, with a highly activated status (18); future analyses should assess whether this population resides in other secondary lymphoid tissues, such as the tonsils, and determine if they show evidence of activation following infection with C-strain and/or virulent CSFV.…”