2. Academic Validation
  3. Salmonella Enteritidis T1SS protein SiiD inhibits NLRP3 inflammasome activation via repressing the mtROS-ASC dependent pathway

Salmonella Enteritidis T1SS protein SiiD inhibits NLRP3 inflammasome activation via repressing the mtROS-ASC dependent pathway

  • PLoS Pathog. 2023 May 8;19(5):e1011381. doi: 10.1371/journal.ppat.1011381.
Yaxin Guo 1 2 3 4 5,  Dan Gu 1 2 3 4,  Tingting Huang 1 2 3 4,  Ang Li 1 2 3 4,  Yi Zhou 1 2 3 4,  Xilong Kang 1 2 3 4,  Chuang Meng 1 2 3 4,  Dan Xiong 1 2 3 4,  Li Song 1 2 3 4,  Xinan Jiao 1 2 3 4,  Zhiming Pan 1 2 3 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Zoonosis, Yangzhou University, Yangzhou, Jiangsu, China.
  • 2 Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Jiangsu, China.
  • 3 Key Laboratory of Prevention and Control of Biological Hazard Factors (Animal Origin) for Agrifood Safety and Quality, Ministry of A griculture of China, Yangzhou University, Yangzhou, Jiangsu, China.
  • 4 Joint International Research Laboratory of Agriculture and Agri-product Safety of the Ministry of Education, Yangzhou University, Jiangsu, China.
  • 5 School of Nursing School of Public Health, Yangzhou University, Jiangsu, China.
PMID: 37155697 DOI: 10.1371/journal.ppat.1011381
Abstract

Inflammasome activation is an essential innate immune defense mechanism against Salmonella infections. Salmonella has developed multiple strategies to avoid or delay inflammasome activation, which may be required for long-term Bacterial persistence. However, the mechanisms by which Salmonella evades host immune defenses are still not well understood. In this study, Salmonella Enteritidis (SE) random insertion transposon library was screened to identify the key factors that affect the inflammasome activation. The type I secretion system (T1SS) protein SiiD was demonstrated to repress the NLRP3 inflammasome activation during SE Infection and was the first to reveal the antagonistic role of T1SS in the inflammasome pathway. SiiD was translocated into host cells and localized in the membrane fraction in a T1SS-dependent and partially T3SS-1-dependent way during SE Infection. Subsequently, SiiD was demonstrated to significantly suppress the generation of mitochondrial Reactive Oxygen Species (mtROS), thus repressing ASC oligomerization to form pyroptosomes, and impairing the NLRP3 dependent Caspase-1 activation and IL-1β secretion. Importantly, SiiD-deficient SE induced stronger gut inflammation in mice and displayed NLRP3-dependent attenuation of the virulence. SiiD-mediated inhibition of NLRP3 inflammasome activation significantly contributed to SE colonization in the infected mice. This study links Bacterial T1SS regulation of mtROS-ASC signaling to NLRP3 inflammasome activation and reveals the essential role of T1SS in evading host immune responses.

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