Domain fusion TLR2-4 enhances the autophagy-dependent clearance of Staphylococcus aureus in the genetic engineering goat

  • Elife. 2022 Jun 28;11:e78044. doi: 10.7554/eLife.78044.
Mengyao Wang   #  1  2  3 ,  Yu Qi   #  1  2  3 ,  Yutao Cao  1  2  3 ,  Xiaosheng Zhang  4 ,  Yongsheng Wang  5 ,  Qingyou Liu  6 ,  Jinlong Zhang  4 ,  Guangbin Zhou  7 ,  Yue Ai  1  2  3 ,  Shao Wei  1  2  3 ,  Linli Wang  1  2  3 ,  Guoshi Liu  1  2  3 ,  Zhengxing Lian  1  2  3 ,  Hongbing Han  1  2  3
Affiliations
  • 1. Beijing Key Laboratory of Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 2. National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 3. Key Laboratory of Animal Genetics, Breeding and Reproduction of the Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 4. Tianjin Academy of Agricultural Sciences, Tianjin, China.
  • 5. Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest Agriculture and Forest University, Shaanxi, China.
  • 6. State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, China.
  • 7. Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, China.
  • # Contributed equally.
PMID: 35762728 DOI: 10.7554/eLife.78044
Abstract

Staphylococcus aureus infections pose a potential threat to livestock production and public health. A novel strategy is needed to control S. aureus infections due to its adaptive evolution to Antibiotics. Autophagy plays a key role in degrading bacteria for innate immune cells. In order to promote S. aureus clearance via Toll-like Receptor (TLR)-induced Autophagy pathway, the domain fusion TLR2-4 with the extracellular domain of TLR2, specific recognizing S. aureus, and transmembrane and intracellular domains of TLR4 is assembled, then the goat expressing TLR2-4 is generated. TLR2-4 substantially augments the removal of S. aureus within macrophages by elevating Autophagy level. Phosphorylated JNK and ERK1/2 promote LC3-puncta in TLR2-4 macrophages during S. aureus-induced Autophagy via MyD88 mediated the TAK1 signaling cascade. Meantime, the TRIF-dependent TBK1-TFEB-OPTN signaling is involved in TLR2-4-triggered Autophagy after S. aureus challenge. Moreover, the transcript of ATG5 and ATG12 is significantly increased via cAMP-PKA-NF-κB signaling, which facilitates S. aureus-induced Autophagy in TLR2-4 macrophages. Overall, the novel receptor TLR2-4 enhances the autophagy-dependent clearance of S. aureus in macrophages via TAK1/TBK1-JNK/ERK, TBK1-TFEB-OPTN, and cAMP-PKA-NF-κB-ATGs signaling pathways, which provide an alternative approach for resistant against S. aureus Infection.

Keywords
Staphylococcus aureus; Toll-like receptor 2-4; autophagy; goat; immunology; infectious disease; inflammation; macrophages; microbiology.
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