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African swine fever virus MGF_110-3L and MGF_110-4L signal TLR2-mediated lethal inflammation
Yue Wang1,2, Tian Xia1,2, Yu Huan Shao2,3
1State Key Laboratory of Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China.
Abstract:
African swine fever virus (ASFV) is a lethal pathogen that triggers uncontrolled cytokine storms and severe immunopathology. However, the viral factors responsible for systemic inflammation remain unclear. Here, we show that the ASFV-encoded proteins MGF_110-3L and MGF_110-4L are secreted via the conventional ER-Golgi pathway. Single-cell RNA sequencing of porcine PBMCs revealed that MGF_110-3L preferentially activates inflammatory responses in monocytic cells. Mechanistically, both proteins bind Toll-like receptor 2 (TLR2) and signal through TLR2/TLR1 and TLR2/TLR6 heterocomplexes, with the co-receptor CD14 enhancing ligand recognition and signal amplification. These interactions activate MyD88-dependent NF-κB signaling, leading to robust induction of proinflammatory cytokines. ASFV strains lacking either MGF_110-3L or MGF_110-4L cause attenuated cytokine responses in vitro and impaired inflammatory pathology in pigs. Together, these findings establish MGF_110-3L and MGF_110-4L as secreted virulence factors that subvert innate immune recognition and drive lethal inflammation, highlighting their potential as targets for antiviral and vaccine development.
Insights
African swine fever virus (ASFV) proteins MGF_110-3L and MGF_110-4L trigger lethal inflammation by activating TLR2 signaling. Removing these viral factors reduces ASFV-induced cytokine storms and pathology in pigs.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- African swine fever virus (ASFV) causes severe disease through uncontrolled cytokine storms.
- The specific viral components driving ASFV-induced inflammation are not fully understood.
Purpose of the Study:
- To identify ASFV proteins responsible for triggering systemic inflammation.
- To elucidate the molecular mechanisms by which ASFV proteins activate innate immune responses.
Main Methods:
- Single-cell RNA sequencing of porcine peripheral blood mononuclear cells (PBMCs).
- Protein localization studies using the ER-Golgi pathway.
- Toll-like receptor (TLR) binding assays and signaling pathway analysis (MyD88-dependent NF-κB).
- In vitro and in vivo studies using ASFV strains with and without specific MGF proteins.
Main Results:
- ASFV proteins MGF_110-3L and MGF_110-4L are secreted and activate inflammatory responses, particularly in monocytic cells.
- These proteins bind to Toll-like receptor 2 (TLR2), forming heterocomplexes with TLR1/TLR6, with CD14 enhancing the interaction.
- Activation of MyD88-dependent NF-κB signaling leads to significant proinflammatory cytokine production.
- ASFV strains lacking MGF_110-3L or MGF_110-4L exhibit reduced cytokine responses and attenuated pathology in pigs.
Conclusions:
- MGF_110-3L and MGF_110-4L are secreted ASFV virulence factors that drive lethal inflammation by subverting innate immune recognition via TLR2.
- These proteins represent potential therapeutic targets for developing antivirals and vaccines against African swine fever.
