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Review
. 2017 Aug 25;9(9):241.
doi: 10.3390/v9090241.

Investigations of Pro- and Anti-Apoptotic Factors Affecting African Swine Fever Virus Replication and Pathogenesis

Linda K Dixon  1 , Pedro J Sánchez-Cordón  2 , Inmaculada Galindo  3 , Covadonga Alonso  4
Affiliations
Review

Investigations of Pro- and Anti-Apoptotic Factors Affecting African Swine Fever Virus Replication and Pathogenesis

Linda K Dixon et al. Viruses. .

Abstract

African swine fever virus (ASFV) is a large DNA virus that replicates predominantly in the cell cytoplasm and is the only member of the Asfarviridae family. The virus causes an acute haemorrhagic fever, African swine fever (ASF), in domestic pigs and wild boar resulting in the death of most infected animals. Apoptosis is induced at an early stage during virus entry or uncoating. However, ASFV encodes anti-apoptotic proteins which facilitate production of progeny virions. These anti-apoptotic proteins include A179L, a Bcl-2 family member; A224L, an inhibitor of apoptosis proteins (IAP) family member; EP153R a C-type lectin; and DP71L. The latter acts by inhibiting activation of the stress activated pro-apoptotic pathways pro-apoptotic pathways. The mechanisms by which these proteins act is summarised. ASF disease is characterised by massive apoptosis of uninfected lymphocytes which reduces the effectiveness of the immune response, contributing to virus pathogenesis. Mechanisms by which this apoptosis is induced are discussed.

Keywords: A179L; A224L pathogenesis; African swine fever virus; apoptosis.

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Conflict of interest statement

The authors have no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanisms of apoptosis inhibition by African swine fever virus (ASFV). Pathways by which ASFV inhibits induction of apoptosis in infected cells and ASFV proteins are shown as red hexagons with the name of the protein inside. The ASFV A179L Bcl-2 family protein binds to and inhibits several BH3 only domain pro-apoptotic proteins. The A224L IAP-family protein binds to and inhibits caspase 3 and activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, thus increasing expression of anti-apoptotic genes including cFLIP, cIAP2 and c-rel. The DP71L protein recruits protein phosphatase 1 to dephosphorylate eIF2a, restoring global protein synthesis and inhibiting transcriptional activation of pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP). The EP153R protein inhibits activation of the p53 protein.
Figure 2
Figure 2
Sequence comparison of ASFV A179L protein with other Bcl-2 family proteins. The ASFV A179L (Interpro annotation P42485) protein sequence was compared with those from EBV BHRF1 (P03182), human Bcl-xL (Q07817) and Bcl-2 (P10415). BH domains are shown as coloured backgrounds. The BH4 domain is shown in yellow, BH3 in grey, BH1 in green and BH2 in turquoise. Amino acid identities between the sequences are shown as asterisks * and similarities as double (:) or single (.) dots. Amended from [30] http://jvi.asm.org/content/91/6/e02228-16.full?sid=d5398579-2b8b-47c3-8fbc-c68ac6dc3ddf.
Figure 3
Figure 3
Comparison of ASFV A224L and opIAP protein sequences. The sequences of the ASFV BA71V isolate A224L protein (AOAOCAZXO) and Baculovirus opIAP (P41437) were aligned using Clustal Omega. The positions of domains in the proteins are indicated as coloured backgrounds. The BIR1 repeat (yellow) is present only in the opIAP protein. The BIR2 repeat is in both A224L and OpIAP sequences. At the C-terminus, A224L has a predicted C4 Zn binding domain (grey). The OpIAP protein contains a RING finger domain (turquoise). Identical amino acids are shown as asterisks (*) and similarities as double (:) or single (.) dots.
Figure 4
Figure 4
Alignment of ASFV DP71L with GADD34 and ICP34.5 of HSV-1. The long and short forms of DP71L share significant homology with the C-terminal domain of ICP34.5 of HSV-1 and GADD34. Within the C-terminal region of ICP34.5, residues 233–248 (shaded green) have been identified as the eIF2α binding domain [55]. The LSAVL motif within this was identified as critical for function [48]. The eIF2α binding motif described [56] in GADD34 is highlighted in blue. Identical amino acid residues shard between the sequences are shown with an asterisk (*) and similarities are shown as double (:) or single (.) dots.
Figure 5
Figure 5
Immunohistochemical detection of ASFV protein P30 on wax-embedded tissue sections from pigs inoculated with the highly virulent ASFV isolate OURT88/1 and euthanized at day 5 post-infection. (A) Tonsil, Bar 40 μm. Lymphoid follicle with severe lymphoid depletion. Observe the presence of infected macrophages (arrows) close to areas where lymphocytes show characteristic features of apoptosis such as reduced size and hyperchromatic nuclei. Cell debris and apoptotic bodies, many of them immunolabeled, are also observed; (B) spleen, Bar 80 μm. Note the presence of infected cells, mainly macrophages (arrows), along with pyknotic cells, cell debris and apoptotic bodies immunolabeled against P30 in white pulp areas (WP) with severe lymphoid depletion.
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