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  2. Inhibition of the Extracellular Signal-Regulated Kinase/Ribosomal S6 Kinase Cascade Limits Chlamydia trachomatis Infection

Inhibition of the Extracellular Signal-Regulated Kinase/Ribosomal S6 Kinase Cascade Limits Chlamydia trachomatis Infection

  • J Invest Dermatol. 2021 Apr;141(4):852-862.e6. doi: 10.1016/j.jid.2020.07.033.
Yaohua Xue 1 Wentao Chen 1 Zhida Mai 1 Xueying Yu 1 Qian Wu 1 Chengsong Wan 2 Xin Su 1 Yiquan Wu 1 Zhili Rong 3 Heping Zheng 4
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, Dermatology Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Microbiology, Southern Medical University, Guangzhou, China.
  • 3 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Research Center, Dermatology Hospital, Southern Medical University, Guangzhou, China.
  • 4 Department of Clinical Laboratory, Dermatology Hospital, Southern Medical University, Guangzhou, China. Electronic address: zhhpf@hotmail.com.
Abstract

Chlamydiatrachomatis is the cause of the most common Bacterial sexually transmitted Infection worldwide. Azithromycin is effective in treating chlamydial infection; however, resistance to this Antibiotic is increasing, and it is important that new therapeutic strategies are developed. In this study, we demonstrated that inhibitors targeting each kinase in the extracellular signal-regulated kinase/ribosomal S6 kinase cascade significantly decreased the size and number of inclusions as well as the number of infectious progeny. The suppressive effects of the inhibitors were observed across the Chlamydia serotypes D, E, F, and L1 and across HeLa, McCoy, and Vero host cells. When combined with azithromycin, all the inhibitors exerted a synergistic suppressive effect on chlamydial Infection. Knockdown experiments using small interfering RNA demonstrated that extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase 1 were crucial for chlamydial Infection. Moreover, BVD-523, a first-in-class extracellular signal-regulated kinase 1/2 inhibitor currently undergoing a phase II clinical trial, suppressed chlamydial Infection both in Cell Culture and in a mouse model. These observations demonstrated not only that the extracellular signal-regulated kinase/ribosomal S6 kinase pathway plays a critical role in chlamydial Infection but also that these kinases have potential as targets for host-directed therapy against C. trachomatis.

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