2. Academic Validation
  3. Streptococcus suis employs the Ihk/Irr-PepO axis to subvert macrophage actin polymerization: A novel anti-phagocytic strategy enhancing bacterial virulence

Streptococcus suis employs the Ihk/Irr-PepO axis to subvert macrophage actin polymerization: A novel anti-phagocytic strategy enhancing bacterial virulence

  • Vet Microbiol. 2025 Sep 11:310:110726. doi: 10.1016/j.vetmic.2025.110726.
Kaiyue Yang 1,  Qiancheng Wang 1,  Mingxing Liu 1,  Dong Wei 1,  Jinsheng Tang 1,  Hong Zhou 1,  Huixing Lin 1,  Zhe Ma 2,  Fei Pan 3,  Hongjie Fan 4
Affiliations

Affiliations

  • 1 MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
  • 2 MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China.
  • 3 MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China. Electronic address: pf@njau.edu.cn.
  • 4 MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; College of Animal Science, Anhui Science and Technology University, Chuzhou 233100, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China. Electronic address: fhj@njau.edu.cn.
PMID: 40946614 DOI: 10.1016/j.vetmic.2025.110726
Abstract

Streptococcus suis serotype 2 (SS2), a significant zoonotic pathogen, causes streptococcal toxic shock-like syndrome (STSLS) in humans and acute septicemia in pigs, highlighting its ability to evade host immune clearance during early Infection. Evasion of macrophage phagocytosis is a critical strategy for Bacterial immune escape. However, the mechanisms by which SS2 subverts cytoskeletal remodeling to inhibit phagocytosis remain elusive. Here, we identified a TCS named Ihk/Irr as a key regulator of SS2 resistance to macrophage phagocytosis through screening SS2 TnYLB-1 mutant library. Phosphorylation of histidine at position 246 (H246) in Ihk and aspartate at position 52 (D52) in Irr enhances SS2 anti-phagocytic capacity and virulence. EMSA revealed that Irr directly binds to the pepO promoter; however, the phosphorylation-site inactivation protein Irr-D52A loses this binding ability. Interestingly, SS2 directly regulates PepO expression by sensing extracellular stimuli through Ihk/Irr phosphorylation. PepO subsequently activates the p38 and ERK1/2 pathways via TLR2, leading to enhanced phosphorylation of p38 and ERK1/2. This phosphorylation ultimately inhibits actin polymerization, impairing phagocytosis and thereby enhancing SS2's phagocytosis resistance. Our study elucidates a novel immune evasion mechanism that SS2 exploits Ihk/Irr-PepO axis to resist macrophage phagocytosis, providing new insights into SS2 pathogenesis and potential therapeutic targets for combating Bacterial infections.

Keywords

Actin polymerization; PepO; Phagocytosis resistence; Streptococcus suis serotype 2 (SS2); Two-component systems (TCSs).

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