Porcine Circovirus Type 2 Suppresses IL-12p40 Induction via Capsid/gC1qR-Mediated MicroRNAs and Signalings

Abstract

Porcine circovirus (PCV) type 2 (PCV2), an immunosuppression pathogen, is often found to increase the risk of other pathogenic infections. Yet the relative immune mechanisms determining the susceptibility of PCV2-infected animals remain unclear. In this study, we confirmed that PCV2 infection suppressed IL-12p40 expression and host Th1 immune response, leading to a weakened pathogenic clearance upon porcine reproductive respiratory syndrome virus (PRRSV) or infection. PCV2 infection suppressed pathogens, LPS/IFN-γ, or LPS/R848-induced IL-12p40 expression in porcine alveolar macrophages. PCV2 capsid (Cap) was the major component to suppress IL-12p40 induction by LPS/IFN-γ, LPS/R848, PRRSV, or Either wild-type PCV2 or mutants PCV2-replicase 1 and PCV type 1-Cap2, which contained PCV2 Cap, significantly decreased IL-12p40 levels and increased the replication of PRRSV and in the lung tissues relative to mock or PCV type 1 infection. gC1qR, a Cap binding protein, was not involved in IL-12p40 induction but mediated the inhibitory effect of PCV2 Cap on IL-12p40 induction. PCV2 also activated PI3K/Akt1 and p38 MAPK signalings to inhibit IL-12p40 expression via inhibition of NF-κB p65 binding to promoter and upregulation of miR-23a and miR-29b. Knockdown of Akt1 and p38 MAPK downregulated miR-23a and miR-29b and increased IL-12p40 expression. Inhibition of miR-23a and miR-29b attenuated the inhibitory effect of PCV2 on IL-12p40 induction, resulting in an increased IL-12p40 expression and Th1 cell population and reduced susceptibility to PRRSV or Taken together, these results demonstrate that PCV2 infection suppresses IL-12p40 expression to lower host Th1 immunity to increase the risk of other pathogenic infection via gC1qR-mediated PI3K/Akt1 and p38 MAPK signaling activation.

Interleukin-10 Promotes Porcine Circovirus Type 2 Persistent Infection in Mice and Aggravates the Tissue Lesions by Suppression of T Cell Infiltration

“…We found that IL-10 deficiency significantly inhibited the PCV2-induced reduction of CD4 + CD8 + T cells in spleens of mice. Combined with the results we previously found that PCV2 infection suppressed the host Th1 cells’ responses to other pathogens (Du et al, 2018), we infer that PCV2 infection leads to dysfunction of T cells through IL-10 production in mice.…”

“…The PCVD symptoms are characterized by weight loss, interstitial pneumonia, lymphocytes depletion, and multisystemic wasting in pigs (Segalés, 2012). PCV2 is considered to mainly affect the immune system and cause immunosuppression, which lead the piglets to become susceptible to other pathogens, such as porcine reproductive respiratory syndrome virus (PRRSV), porcine parvovirus (PPV), Haemophilus parasuis , or Mycoplasma hyopneumoniae (Afghah et al, 2017; Niederwerder, 2017; Du et al, 2018). The coinfection with other pathogens results in severe clinical diseases and leads to serious economic losses in world pig industry (Denner and Mankertz, 2017).…”

Porcine Circovirus Type 2 Rep Enhances IL-10 Production in Macrophages via Activation of p38-MAPK Pathway

“…In addition, it has been reported that the p38-MAPK and ERK pathways are involved in regulating IL-10 expression [34][35][36]. Previous studies have also shown that the p38-MAPK pathway not only plays important roles in the PCV2 replication and contributes to virus-mediated changes in PK-15 cells, but is also mediated via gC1qR to suppress IL-12p40 expression to increase the risk of other pathogenic infection after PCV2 infection [37,38]. Simultaneously, it has been reported that the ERK signaling pathway is involved in PCV2 infection and is beneficial to PCV2 replication in cultured cells [39].…”

Chlorogenic Acid Promotes Autophagy and Alleviates Salmonella Typhimurium Infection Through the lncRNAGAS5/miR-23a/PTEN Axis and the p38 MAPK Pathway

“…Reduction in miR-23a markedly inhibits the levels of TNF-α and IL-6 in lipopolysaccharide-induced macrophages (Peng et al, 2015). Inhibition of miR-23a results in increases in IL-12 levels (Du et al, 2018). Briefly, low expression of miR-23a reversed the promoting effect of GAS5 knockdown on ST invasion to intestinal epithelial cells.…”