Interaction between host cell proteins and open reading frames of porcine circovirus type 2

Abstract

Postweaning multisystemic wasting syndrome (PMWS) is caused by a systemic inflammation after porcine circovirus type 2 (PCV2) infection. It was one of the most economically important pathogens affecting pig production worldwide before PCV2 vaccine was first introduced in 2006. After the development of a vaccine against PCV2a type, pig farms gradually restored enormous economic losses from PMWS. However, vaccine against PCV2a type could not be fully effective against several different PCV2 genotypes (PCV2b - PCV2h). In addition, PCV2a vaccine itself could generate antigenic drift of PCV2 capsid. Therefore, PCV2 infection still threats pig industry worldwide. PCV2 infection was initially found in local tissues including reproductive, respiratory, and digestive tracks. However, PCV2 infection often leads to a systemic inflammation which can cause severe immunosuppression by depleting peripheral lymphocytes in secondary lymphoid tissues. Subsequently, a secondary infection with other microorganisms can cause PMWS. Eleven putative open reading frames (ORFs) have been predicted to encode PCV2 genome. Among them, gene products of six ORFs from ORF1 to ORF6 have been identified and characterized to estimate its functional role during PCV2 infection. Acquiring knowledge about the specific interaction between each PCV2 ORF protein and host protein might be a key to develop preventive or therapeutic tools to control PCV2 infection. In this article, we reviewed current understanding of how each ORF of PCV2 manipulates host cell signaling related to immune suppression caused by PCV2.

Keywords: Host cell protein; Open reading frame; Pathogenesis; Pig; Porcine circovirus type 2.

Fig. 1.. Schematic diagram of PCV2 genome.

The circular genome of PCV2 is enlarged with each linearized open reading frame (ORF) [32-39]. Each ORF is illustrated as different colors of lines with arrow indicating the transcriptional orientation of each ORF. Predicted molecular weight of each ORF-encoded protein is denoted with the unit of kDa. ORFs 1, 2, and 4-encoded proteins contain putative glycosylation sites indicated by an asterisk. An arrow of stem loop structures marks the replication origin and used as a starting point for numbering of nucleotide sequences. PCV2, porcine circovirus type 2.

Fig. 2.. PCV2 ORF3-mediated apoptosis and inflammatory responses.

(A) PCV2 ORF3-mediated apoptosis [127,128]. In the steady state, Pirh2, an E3 ubiquitin ligase, can downregulate p53 expression via ubiquitin-dependent proteasomal degradation. During PCV2 infection, ORF3 can interfere with Pirh2 function by binding to Pirh2. As a result, apoptosis is induced by p53 target gene expression via increased half-life of p53. (B) PCV2 ORF3-mediated inflammatory responses [133-135]. In the steady state, RGS16 can block nuclear entry of NFκB. During PCV2 infection, ORF3 can cause proteasomal degradation of RGS16 by increasing ubiquitination. Subsequently, NFκB can migrate into the nucleus and initiate mRNA transcription of IL-6 and IL-8. PCV2, porcine circovirus type 2; ORF, open reading frame; RGS16, regulator of G protein signaling 16.

Fig. 3.. PCV2 ORF4 facilitates host cell apoptosis by inducing mitochondrial damage.

During PCV2 infection, PCV2 ORF4 can directly bind to ANT3 through its N-terminus amphipathic α-helix region. By assistance of ANT3, mitochondria anchored PCV2 ORF4 can damage mitochondria. Subsequently, cytochrome c is released from mitochondria which triggers caspase pathway and leads to host cell apoptosis [139]. PCV2, porcine circovirus type 2; ORF, open reading frame; ANT3, adenine nucleotide translocase 3.

Fig. 4.. Mechanism of PCV2 ORF5-mediated autophagy induction.

During PCV2 infection, PCV2 ORF5 can cause ER stress. Subsequently, PERK-eIF2α-ATF4 pathway can induce autophagosome formation [146]. ER stress can also lead to activation of AMPK pathway which can enhance autophagy by inhibiting phosphorylation of mTOR [146]. PCV2, porcine circovirus type 2; ORF, open reading frame; ER, endoplasmic reticulum; AMPK, AMP-activated protein kinas.