Mechanisms of African Swine Fever Virus Pathogenesis and Immune Evasion Inferred from Gene Expression Changes in Infected Swine Macrophages

Authors: Zhu, James; RAMANATHAN, PALANIAPPAN - University Of Texas Medical Branch; Bishop, Elizabeth; O'DONNELL, VIVIAN - Animal And Plant Health Inspection Service (APHIS); Gladue, Douglas; Borca, Manuel

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/10/2019
Publication Date: N/A
Citation: N/A

Interpretive Summary: African swine fever (ASF) is a devastating disease of pigs caused by a virus (ASFV). ASFV is currently responsible for outbreaks in Europe and Asia causing great losses to the swine industry. There is no vaccine against ASF, and very little is known in how ASFV interacts with the pigs to cause disease. We performed an analysis of pig immune cells (called macrophages) at different timed after infection with ASF virus using microarray analysis to determine what pig genes were being expressed in response to the virus infecting the cells. Using this approach, we detected cellular pathways being activated or repressed in response to ASFV infection. We determined that ASFV causes disruption in several immune response pathways that are normally responsible for detecting and destroying viruses when they infect cells. This work will help us develop better vaccines against ASF.

Technical Abstract: African swine fever (ASF) is a swine disease caused by a large, structurally complex, double-stranded DNA virus, African swine fever virus (ASFV). In domestic pigs, acute infection by highly virulent ASF viruses causes hemorrhagic fever and death. Previous work has suggested that ASFV pathogenesis is primarily mediated by host cytokines produced by infected monocytes and macrophages. To better understand molecular mechanisms mediating virus pathogenesis and immune evasion, we used transcriptome analysis to identify gene expression changes after ASFV infection in ex vivo swine macrophages. Our results suggest that the cytokines of TNF family including FASLG, LTA, LTB, TNF, TNFSF4, TNFSF10, TNFSF13B and TNFSF18 are the major causative cytokine factors in ASF pathogenesis via inducing apoptosis. Other up-regulated proinflammatory cytokines (IL17F and interferons) and down-regulated anti-inflammatory cytokine (IL10) may also significantly contribute to ASF pathogenesis and cause excessive tissue inflammatory responses. The differential expression of genes also indicates that ASFV could evade both the innate and adaptive immune responses by (i) inhibiting MHC Class II antigen processing and presentation, (ii) avoiding CD8+ T effector cells and neutrophil extracellular traps via decreasing expression of neutrophil/CD8+ T effector cell-recruiting chemokines, (iii) suppressing M1 activation of macrophages, (iv) inducing immune suppressive cytokines, and (v) inhibiting the processes of macrophage autophagy and apoptosis. These results provide novel information to further investigate and better understand the mechanism of pathogenesis and immune evasion of this devastating swine disease.