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Title: The role of ORF3 Protein in the Molecular Pathogenesis of Porcine circovirus 2 infection
Keywords: PCV2, ORF3, Apoptosis, p53, Pirh2, live attenuated vaccine
Issue Date: 11-Aug-2011
Citation: ANBU KUMAR KARUPPANNAN (2011-08-11). The role of ORF3 Protein in the Molecular Pathogenesis of Porcine circovirus 2 infection. ScholarBank@NUS Repository.
Abstract: Porcine circovirus 2 (PCV2) of the Circoviridae family is a nonenveloped, single stranded DNA virus with a circular genome of 1.7 kilobases. It is a major pathogen of porcine species causing growth retardation, lymphadenopathy, multi-organ inflammation and immune suppression, especially affecting weanling piglets. The PCV2 open reading frame 3 (ORF3) codes a 104 amino acid protein that causes apoptosis of PCV2 infected cells, and is not essential for virus replication. This thesis describes the characterisation of the role of ORF3 in the molecular and the systemic pathogenesis during the PCV2 infection in cell culture, mice model and in natural infection in piglets. Mutant PCV2 lacking the expression of ORF3 are infectious and replicate in cells in vitro, but do not cause apoptosis of the infected cells. The ORF3 of PCV2 has been shown to be involved in the pathogenesis of the virus in mice model. In PCV2 infected piglets, B and CD4 T lymphocyte depletion and lymphoid organ destruction are generally observed; however, the ORF3 deficient PCV2 is attenuated in its pathogenicity in infected piglets. The mutant virus does not cause any observable disease or perturbation of the lymphocyte count in the inoculated piglets and elicits an efficient immune response. When compared with the wildtype virus infection, the ORF3 mutant PCV2 infection is characterized by mild viremia and absence of pathological lesions. In infected cells, the ORF3 protein interacts with the porcine homologue of Pirh2 (pPirh2), a p53-induced ubiquitin-protein E3 ligase and causes the accumulation of p53 by disrupting the physiological association of p53 and pPirh2. The ORF3 protein competes with p53 in binding to pPirh2. The amino acid residues 20 to 65 of the ORF3 protein are essential in this interaction of ORF3 protein with pPirh2, which leads to an alteration in the cellular localization and a significant reduction in the stability of pPirh2. These events contribute to the deregulation of p53 by pPirh2, leading to increased p53 levels and apoptosis of the infected cells. In addition to its role in causing the apoptosis of the immune cells, characteristic of the PCV2 infection associated disease conditions, the ORF3 also plays a role in the systemic dissemination of the PCV2 infection. The ORF3 expedites the spread of the virus by inducing the early release of the virus from the infected cells. Further, in PCV2 infected mice, the ORF3 induced apoptosis also aids in recruiting macrophages to phagocytise the infected apoptotic cells leading to the systemic dissemination of the infection. The apoptotic activity of the ORF3 of PCV2 hence lends advantage to the spread of the virus.
Appears in Collections:Ph.D Theses (Open)

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