It revealed a distinct transition from an early robust immune response to a devastating, late-stage collapse of core cellular functions.
The findings, published by researchers from Chungnam National University and the National Institute of Animal Science in South Korea, as well as the National Institute of Veterinary Research in Vietnam, pinpointed four key hub genes — CMPK2, ZBP1, EPRS1, and USP7 — that orchestrate the host’s reaction to the virus.
This discovery offers new potential targets for both diagnostic and therapeutic strategies against a disease that continues to devastate the global pork industry.
Fierce anti-viral counter-attack in early infection
The study re-analysed publicly available RNA sequencing data from the spleen tissue of pigs infected with a virulent ASFV strain, focusing on three time points: pre-infection, early infection, and late infection. Acute ASFV infection is typically fatal within seven days, making the late infection time point critical for understanding the final, lethal phase.
At the early infection stage, the scientists observed a strong, coordinated activation of immune-related genes, described as a “macrophage-driven antiviral burst”. Their analysis showed that at the early infection stage, the host rapidly recognised the virus and initiated a fierce counter-attack.
The researchers saw two groups of genes, which they called the ‘pink’ and ‘cyan’ modules, switch on strongly. The pink group was full of genes that manage the pig’s innate immune system. These genes use pathways like Toll-like receptor signalling to spot the virus and immediately launch a defence.
Two key genes
Two important control genes, CMPK2 and ZBP1, took centre-stage during this early battle. CMPK2 is a gene the immune system uses against viruses. It sits inside the cell’s power source, the mitochondria, and acts as a vital link, connecting the virus-sensing systems to a process that drives serious swelling and cell death in immune cells.
ZBP1 is a powerful cell death gene that senses unusual genetic material from the virus, then triggers a specific type of programmed cell death called necroptosis. Other studies show that the ASFV infection helps build the death complex that ZBP1 drives. This suggests the pig’s body uses this system to stop the virus from spreading.
The rise in CMPK2 and ZBP1 at two days showed the host’s urgent plan. It coordinated stress signals and programmed cell death to contain the infection. This early stage happens right before the pig starts showing the severe bleeding and blood clotting problems associated with acute ASFV.
A short pause in inflammation
The study also made an interesting observation: a separate gene group, the ‘red’ module, which contained genes related to a major inflammatory protein called TNF, actually switched down at two days.
The team said this did not mean the immune system was failing, instead calling it a “pre-haemorrhagic regulatory phase”. They suggested that the spleen tried to balance the urgent need for defence with the need to control inflammation. This delay helps stop the widespread tissue damage that usually follows.
Late infection physical failure
By five days after infection, the gene activity changes dramatically for the worse, signalling the pig’s body has lost control. This time point matches the severe sickness and high levels of virus that lead to death.
At this late stage, the scientists saw a widespread, coordinated shutdown of the pig’s most vital cell processes. Two main gene groups, the ‘blue’ and the ‘pink’ modules, crashed. The blue module’s genes were severely suppressed.
This group handles basic cellular housework — the genes in this module are essential for oxidative phosphorylation (the main process cells use to make energy) and ribosome function (the machinery cells need to build proteins).
This simultaneous crash of energy production and protein-building showed a state the researchers call “immuno-metabolic collapse”. This severe failure stopped the host from fighting back or repairing tissue damage.
Taken over by the virus
The two other control genes, EPRS1 and USP7, became central players in this late-stage failure. They switched down sharply at five days, after only a small increase earlier on.
USP7 is an enzyme that helps regulate important immune and cell-cycle pathways. Many DNA viruses are known to take control of USP7 to help them multiply. USP7’s drop at five days suggested ASFV could re-wire the host’s regulatory systems to suppress immune function.
EPRS1 is part of a complex that normally keeps inflammation in check by silencing specific inflammatory signals. Its suppression suggested that the pig lost this key control, likely contributing to the massive inflammation and tissue damage seen in late-stage ASFV.
In addition, two other gene groups, the brown and turquoise modules, switched up at five days. These groups control signalling pathways and ribosome function. This proves that while the host’s core systems shut down, the virus actively took over the remaining protein-building machinery to multiply fast and spread.
Translational relevance for the swine industry
This time-resolved network view of ASFV pathogenesis moves beyond simple lists of differentially expressed genes, providing a systems-level understanding of how the host response unfolds over time.
The four identified hub genes — CMPK2 and ZBP1 for early defence, and EPRS1 and USP7 for late-stage collapse — represent high-priority candidates for future functional validation.
Targeting early hub genes like CMPK2 or ZBP1 could enhance the host’s initial, protective innate immune response. Targeting late hub genes like EPRS1 or USP7, on the other hand, could help prevent the devastating immuno-metabolic collapse that ultimately leads to mortality.
The study’s authors concluded: “These findings delineate dynamic spleen transcriptional responses to ASFV infection and suggest coordinated shifts in mitochondrial–innate and translational/ubiquitin pathways across infection stages. Further experimental and protein-level validation in independent and field-infected populations will be required to confirm mechanistic roles and assess potential translational relevance.”
Source: Life “Dynamic Gene Network Alterations and Identification of Key Genes in the Spleen During African Swine Fever Virus (ASFV) Infection” https://doi.org/10.3390/life15121844 Authors: Go Jae-Beom, et al.
