Dataset Information

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-?, 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-?, 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-?B 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.

SUBMITTER: Du Q

PROVIDER: S-EPMC6039236 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Du Qian Q Wu Xingchen X Wang Tongtong T Yang Xuefeng X Wang Zhenyu Z Niu Yingying Y Zhao Xiaomin X Liu Shan-Lu SL Tong Dewen D Huang Yong Y

Journal of immunology (Baltimore, Md. : 1950) 20180601 2

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 <i>Haemophilus parasuis</i> infection. ...[more]

PMID: 29858268

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Project description:Porcine circovirus type 2 (PCV2) capsid protein (Cap) is a unique structure protein that plays pivotal roles in the process of viral replication and pathogenesis. Herein, we characterized a putative porcine Makorin RING finger protein 1 (pMKRN1) variant, an N-terminal-truncated variant of putative full-size porcine MKRN1 which has a unique expression pattern resulting from the porcine mkrn1 gene and which interacts with PCV2 Cap. A domain mapping assay showed that the C terminus of pMKRN1 and fragments (amino acids 108 to 198) of Cap are required for this interaction. PCV2 transiently upregulated pMKRN1 in PK-15 cells, but persistent viral infection downregulated pMKRN1 in major pathological tissues of PCV2-infected piglets. Overexpression of pMKRN1 significantly inhibited the generation of progeny PCV2 via ubiquitination and degradation of Cap, whereas knockout of pMKRN1 blocked Cap degradation and promoted progeny virus replication. pMKRN1 specifically targeted PCV2 Cap lysine residues 164, 179, and 191 to induce polyubiquitination and subsequent degradation. Mutation of either of the three lysine residues in the Cap protein or mutation of the histidine at residue 243 within the RING finger domain of pMKRN1 abrogated the E3 ligase activity of pMKRN1, rendering cells incapable of inducing Cap ubiquitination and degradation. Consistent with this finding, a Cap ubiquitination-deficient PCV2 strain showed enhanced virus replication and produced severe histological lesions in the lung and lymph node tissues compared with wild-type PCV2. Taken together, the results presented here suggest that PCV2 downregulates the pMKRN1 variant to avoid pMKRN1-mediated Cap ubiquitination and degradation, thus promoting viral replication and pathogenesis in its targeted tissues.IMPORTANCE Porcine circovirus type 2 is the pathogen to which pigs are the most susceptible, causing immense economic losses in the global swine industry, but whether host cells have developed some strategies to prevent viral replication is still unclear. Here, we found that porcine MKRN1 (pMKRN1) was upregulated in the early stage of PCV2 infection and mediated the polyubiquitination and degradation of Cap protein to block PCV2 replication, yet persistent PCV2 infection downregulated pMKRN1 levels to avoid degradation, promoting viral replication and pathogenesis in its targeted tissues. These data present new insight into the molecular mechanisms underlying the antiviral effects of pMKRN1 E3 ligase during PCV2 infection and also suggest potential new control measures for PCV2 outbreaks.

Project description:Porcine circovirus type 3 (PCV3) is an emerging porcine circovirus that has been associated with porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, reproductive failure, cardiac pathologies, and multisystemic inflammation in piglets and sows. Many aspects of PCV3 infection biology and pathogenesis, however, remain unknown. Here, we used a PCV3 virus stock from the rescue of an infectious PCV3 DNA clone to intranasally inoculate 4- and 8-week-old specific-pathogen-free piglets for evaluation of PCV3 pathogenesis. For 4-week-old piglets, typical clinical signs resembling those of PDNS-like disease were observed when piglets were inoculated with PCV3 alone or PCV3 combined with immunostimulation by keyhole limpet hemocyanin, with a mortality of 40% (2/5) for both types of inoculated piglets during a 28-day observation period postinoculation. Both types of inoculated piglets showed similar progressive increases in viral loads in the sera and had seroconverted to PCV3 capsid antibody after inoculation. Pathological lesions and PCV3-specific antigen were detected in various tissues and organs, including the lung, heart, kidney, lymph nodes, spleen, liver, and small intestine, in both types of inoculated piglets. The levels of proinflammatory cytokines and chemokines, including interleukin 1 beta (IL-1?), IL-6, IL-23?, gamma interferon (IFN-?), tumor necrosis factor alpha (TNF-?), and chemokine ligand 5 (CCL5), were significantly upregulated in both groups of inoculated piglets. Eight-week-old piglets also exhibited a similar PDNS-like disease but without death after PCV3 inoculation, as evidenced by pathological lesions and PCV3 antigen in various tissues and organs. These results show for the first time successful reproduction of PDNS-like disease by PCV3 infection and further provide significant information regarding the pathogenesis of PCV3 in piglets.IMPORTANCE Porcine circovirus type 3 (PCV3), an emerging porcine circovirus, is considered the cause of porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs and other systemic diseases in piglets and sows. To evaluate the pathogenesis of PCV3 infection in vivo, we used a PCV3 virus stock from the rescue of an infectious PCV3 DNA clone to intranasally inoculate 4- and 8-week-old specific-pathogen-free piglets and demonstrated successful reproduction of PDNS-like disease in animals that were inoculated with PCV3 alone or PCV3 combined with immunostimulation by keyhole limpet hemocyanin. Both 4- and 8-week-old PCV3-inoculated piglets showed similar increases in viral loads in the sera and had seroconverted to PCV3 capsid antibody. Pathological lesions and PCV3-specific antigen were detected in various tissues and organs, while numerous proinflammatory cytokines and chemokines in the sera were significantly upregulated after PCV3 inoculation. These results will provide significant information regarding the pathogenesis of PCV3 in piglets.

Dataset Information

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

Publications

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

Similar Datasets

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