Recent research led by scholars from Chungnam National University, the National Institute of Animal Science in South Korea, and the National Institute of Veterinary Research in Vietnam has unveiled a critical evolutionary pathway in the immune response to African Swine Fever Virus (ASFV).

The study highlights a dramatic shift from a robust immune reaction during early infection to a catastrophic breakdown in cellular functions during late-stage infection. This discovery identifies four significant hub genes—CMPK2, ZBP1, EPRS1, and USP7—that orchestrate the host’s response to this virulent pathogen.

Early Infection: A Ferocious Immune Counterattack

Utilizing publicly available RNA sequencing data, researchers analyzed spleen tissues from pigs infected with a potent ASFV strain. The focus was on three critical phases: pre-infection, early infection, and late infection. With acute ASFV typically proving fatal within a week, understanding the final stages is paramount.

Initial findings revealed a pronounced activation of immune-related genes, leading to what the scientists termed a “macrophage-driven antiviral burst.” This indicates the host swiftly recognized the virus and mounted a vigorous defense.

Two significant gene groups—the “pink” and “cyan” modules—emerged as key players, with the pink module primarily housing genes involved in the innate immune system. These genes leverage pathways like Toll-like receptor signaling to promptly detect and respond to the viral threat.

Key Players: Genes CMPK2 and ZBP1

A spotlight was placed on CMPK2 and ZBP1, two critical genes that became instrumental in the early battle against ASFV. CMPK2 is found within the cell’s mitochondria and links virus-sensing systems to inflammation and cell death processes essential for immune function.

ZBP1 acts as a guardian against viral invasions, triggering necroptosis, a specific type of programmed cell death upon detecting viral material. This suggests the host’s aggressive strategy to curtail the virus’s spread.

A Temporary Pause in Inflammation

Interestingly, researchers noted that a separate gene group, the “red” module associated with TNF (a key inflammatory marker), downregulated at the two-day mark. The study labeled this phenomenon a “pre-haemorrhagic regulatory phase,” indicating a strategic balance between initiating defense while also moderating inflammation to prevent extensive tissue damage.

Late Infection: A Catastrophic Cellular Collapse

As the infection progressed to five days, gene activity shifted tragically towards a major loss of cellular control, aligning with severe illness and elevated viral levels leading to mortality. This late stage revealed a comprehensive shutdown of essential cellular functions, particularly in the “blue” and “pink” gene modules.

The “blue” module, crucial for energy production and protein synthesis, faced significant suppression, indicating what researchers termed an “immuno-metabolic collapse.” This breakdown significantly impeded the host’s ability to mount a defense or heal tissue damage.

Viral Takeover: The Role of EPRS1 and USP7

Two additional control genes, EPRS1 and USP7, became focal points for understanding the late-stage cellular dysfunction. USP7, known to regulate immune and cell-cycle pathways, showed substantial decline, suggesting that ASFV might manipulate these systems to diminish the immune response.

EPRS1’s role in maintaining control over inflammatory signals was also compromised, culminating in the massive inflammation observed in late-stage ASFV infections. Meanwhile, other gene groups, such as the “brown” and “turquoise” modules, experienced upregulation, indicating that while the host’s core systems faltered, the virus exploited remaining functionalities for rapid multiplication.

Implications for the Swine Industry

This comprehensive analysis of ASFV pathogenesis goes beyond mere identification of gene activity changes. The four hub genes—CMPK2 and ZBP1 in early defense and EPRS1 and USP7 in late-stage collapse—are identified as prime candidates for future research.

Future strategies may target early-phase genes to enhance the animal’s innate immune response, while addressing the late-phase genes could help mitigate the disastrous immuno-metabolic collapse. Researchers concluded that further validation in field-infected populations is crucial to confirm these mechanistic roles and explore their translational relevance for disease control in the swine industry.

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.