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 Haemophilus parasuis 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 H. parasuis 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 H. parasuis 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 il12B 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 H. parasuis 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.

• Authors: Qian Du, Xingchen Wu, Tongtong Wang, Xuefeng Yang, Zhenyu Wang, Yingying Niu, Xiaomin Zhao, Shan-Lu Liu, Dewen Tong, Yong Huang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 201 Issue 2 Pg. 533-547 (07 15 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 29858268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Capsid Proteins
• Interleukin-12 Subunit p40
• Membrane Glycoproteins
• MicroRNAs
• Receptors, Complement
• complement 1q receptor

Topics

• Animals
• Capsid Proteins (genetics, metabolism)
• Cells, Cultured
• Circoviridae Infections (immunology)
• Circovirus (physiology)
• Haemophilus Infections (immunology)
• Haemophilus parasuis (immunology)
• Immunosuppression Therapy
• Interleukin-12 Subunit p40 (genetics, metabolism)
• Macrophages, Alveolar (immunology, virology)
• Membrane Glycoproteins (genetics, metabolism)
• MicroRNAs (genetics)
• Mutation (genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Porcine Reproductive and Respiratory Syndrome (immunology)
• Porcine respiratory and reproductive syndrome virus (immunology)
• Receptors, Complement (genetics, metabolism)
• Signal Transduction
• Swine (immunology)
• Th1 Cells (immunology)
• Viral Load
• Virus Replication