2. Academic Validation
  3. Overexpression of Toll-like receptor 4 contributes to the internalization and elimination of Escherichia coli in sheep by enhancing caveolae-dependent endocytosis

Overexpression of Toll-like receptor 4 contributes to the internalization and elimination of Escherichia coli in sheep by enhancing caveolae-dependent endocytosis

  • J Anim Sci Biotechnol. 2021 May 10;12(1):63. doi: 10.1186/s40104-021-00585-z.
Yao Li 1,  Yue Zhao 1,  Xueling Xu 1,  Rui Zhang 1,  Jinlong Zhang 2,  Xiaosheng Zhang 2,  Yan Li 3 4,  Shoulong Deng 5,  Zhengxing Lian 6
Affiliations

Affiliations

  • 1 Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China.
  • 2 Tianjin Institute of Animal Sciences, Tianjin, China.
  • 3 Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China. scauly@cau.edu.cn.
  • 4 State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China. scauly@cau.edu.cn.
  • 5 Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China. popo84350746@163.com.
  • 6 Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing, China. lianzhx@cau.edu.cn.
PMID: 33966642 DOI: 10.1186/s40104-021-00585-z
Abstract

Background: Gram-negative Bacterial infections have a major economic impact on both the livestock industry and public health. Toll-like Receptor 4 (TLR4) plays a crucial role in host defence against Gram-negative bacteria. Exploring the defence mechanism regulated by TLR4 may provide new targets for treatment of inflammation and control of Bacterial infections. In a previous study, we generated transgenic sheep overexpressing TLR4 by microinjection to improve disease resistance. The defence mechanism through which TLR4 overexpression protected these sheep against pathogens is still not fully understood.

Results: In the present study, we used Escherichia coli to infect monocytes isolated from peripheral blood of the animal model. The overexpression of TLR4 strongly enhanced the percentage of endocytosis and capacity of elimination in monocytes during the early stages of Infection. This phenomenon was mainly due to overexpression of TLR4 promoting caveolae-mediated endocytosis. Pretreatment of the transgenic sheep monocytes with inhibitors of TLR4, Src signalling, or the caveolae-mediated endocytosis pathway reduced the internalization of bacteria, weakened the ability of the monocytes to eliminate the bacteria, and increased the pH of the endosomes.

Conclusion: Together, our results reveal the effects of TLR4 on the control of E. coli Infection in the innate immunity of sheep and provide crucial evidence of the caveolae-mediated endocytosis pathway required for host resistance to invading bacteria in a large animal model, providing theoretical support for breeding disease resistance in the future. Furthermore, Src and caveolin 1 (CAV1) could be potentially valuable targets for the control of infectious diseases.

Keywords

Caveolae-dependent endocytosis; Host defence infection; Inflammatory responses; Monocytes; Toll-like receptor 4.

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