African swine fever virus (ASFV) poses one of the greatest threats to pig farming worldwide. It is highly infectious and causes rapid haemorrhagic death of domestic pigs and Eurasian wild boar (Sus scrofa). In contrast, native African pig species (bushpigs and warthogs) suffer only a mild, subclinical form of the infection from which they rapidly recover. It is hypothesised that the striking difference in the pathophysiological consequences of ASFV infection may reflect a variable ability of the virus to modulate the host immune response in these species. Alternatively, it may indicate a fundamental evolutionary distinction between the immune responses of these animals. In common with many other DNA viruses, ASFV has evolved a complex strategy for modulating the host-cell immune response. The ASFV-encoded protein, A238L, targets key sites within both the NFκB and NFAT immune-signalling pathways. Furthermore, the ASFV protein, p54, is involved in attachment of virus particles to the microtubule motor complex, cytoplasmic dynein. This may represent a key stage in the infection process. Six host proteins targeted or mimicked by A238L and p54 (light chain dynein, cyclophilin A, calcineurin A, NFAT, p65 (RelA) and IκBα) have been sequenced in the susceptible domestic pig, resistant warthog and phenotypically unknown babirusa. In addition, the ~1.6kbp promoter driving expression of the proinflammatory cytokine, tumour necrosis factor alpha (TNFα), has also been studied. Despite identifying high levels of nucleotide sequence conservation in these genes, polymorphisms have been identified in the NFκB subunit p65 (RelA) and the TNFα promoter. These may be of functional significance in determining the immune response characteristic of the different pig species studied. These polymorphisms have been further explored using in vitro expression and luciferase-reporter analysis. Furthermore, the identification of these sites has enabled the commercial sponsor of this project, Sygen International, to screen their domestic pig lines for ‘warthog-like’ sequence, which may confer some degree of disease resistance. These findings provide a valuable insight into potential mechanisms involved in altered host susceptibility to African swine fever. In addition, this study may have wider-reaching implications for understanding issues of both susceptibility and pathogenesis relating to other infectious diseases of both humans and animals.
|Translated title of the contribution||African swine fever pathogenesis: Comparative analysis of immunoregulatory genes in domestic and wild pigs|
|Number of pages||131|
|Publication status||Published - 2004|