It is urgent to develop new approaches to overcome the S. aureus has developed antibiotic resistance mechanisms for most kinds of antibiotics due to the widespread use of antibiotic ( Pantosti et al., 2007). aureus from livestock to dairy products can lead to human food poisoning ( Hennekinne et al., 2012 Mechesso et al., 2021). aureus-induced mastitis is a major disease that poses a potential harm to animal welfare in global dairy industry. aureus usually gives rise to skin and soft tissue infections, pneumonia, device-related infections, severe sepsis, etc. Staphylococcus aureus (S, aureus) is regarded as an important zoonotic pathogen that causes disease in both human and livestock ( Fluit, 2012 Tong et al., 2015). 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. Overall, the novel receptor TLR2-4 enhances the autophagy-dependent clearance of S. aureus-induced autophagy in TLR2-4 macrophages. Moreover, the transcript of ATG5 and ATG12 is significantly increased via cAMP-PKA-NF-κB signaling, which facilitates S. Meantime, the TRIF-dependent TBK1-TFEB-OPTN signaling is involved in TLR2-4-triggered autophagy after S. aureus-induced autophagy via MyD88 mediated the TAK1 signaling cascade. Phosphorylated JNK and ERK1/2 promote LC3-puncta in TLR2-4 macrophages during S. aureus within macrophages by elevating autophagy level. TLR2-4 substantially augments the removal of S. aureus, and transmembrane and intracellular domains of TLR4 is assembled, then the goat expressing TLR2-4 is generated. aureus clearance via Toll-like receptor (TLR)-induced autophagy pathway, the domain fusion TLR2-4 with the extracellular domain of TLR2, specific recognizing S. Autophagy plays a key role in degrading bacteria for innate immune cells. aureus infections due to its adaptive evolution to antibiotics. Staphylococcus aureus infections pose a potential threat to livestock production and public health. Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, China.State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, China.Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Northwest Agriculture and Forest University, China.Tianjin Academy of Agricultural Sciences, China.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, China.National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, China.

Beijing Key Laboratory of Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, China.

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