African swine fever virus (ASFV) inflicts severe economic losses on the global pig industry, yet the mechanisms underlying its lethal inflammation have remained obscure. Researchers have now identified two ASFV-encoded proteins, MGF_110-3L and MGF_110-4L, as secreted virulence factors that are recognized by the host innate immune system. Unlike typical viral proteins that function inside infected cells, these molecules are released via the ER–Golgi secretory pathway and act on neighboring immune cells, revealing a previously unrecognized route of immune activation.
Key findings from the study include:
Identification of Secreted Viral Virulence Factors
MGF_110-3L and MGF_110-4L are secreted from infected macrophages through the classical ER–Golgi pathway. This extracellular release enables them to reach and influence uninfected immune cells, distinguishing them from proteins confined to the infected cell.
Potent Inflammatory Cytokine Induction
Single-cell RNA sequencing of porcine immune cells demonstrated that MGF_110-3L strongly activates monocytes. Together with MGF_110-4L, it triggers the production of key inflammatory cytokines such as TNF-α, IL-1β, and IL-6, mirroring the cytokine storm observed in severe ASF.
TLR2-Mediated Host Recognition and NF-kB Activation
These secreted proteins are sensed by host Toll-like receptor 2 (TLR2), involving both TLR2/TLR1 and TLR2/TLR6 complexes. Recognition depends on the co-receptor CD14 and activates the MyD88–NF-kB signaling pathway, a central driver of innate inflammatory responses, resulting in excessive cytokine release.
Attenuated Disease with Deletion Mutants
ASFV mutants lacking MGF_110-3L or MGF_110-4L induced markedly lower inflammatory responses and caused significantly milder disease. Infected animals survived, whereas wild-type virus led to severe inflammation and uniform lethality, confirming the contribution of these proteins to virulence.
This study establishes that lethal ASFV inflammation originates from host recognition of secreted viral proteins via the TLR2/TLR1 and TLR2/TLR6 axis. The findings highlight the interaction between these viral proteins and TLR2 as a promising therapeutic target for vaccine design and antiviral development. The work, entitled “African swine fever virus MGF_110-3L and MGF_110-4L signal TLR2-mediated lethal inflammation,” has been published in Protein & Cell.
DOI: 10.1093/procel/pwag047