Journal
VIRULENCE
Volume 12, Issue 1, Pages 298-311Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/21505594.2020.1870331
Keywords
Salmonella Typhimurium; transcriptional regulator; asir; flagellar gene expression; acidic pH
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Funding
- National Natural Science Foundation of China [81871624, 31800126]
- National Key R&D Program of China [2018YFA0901000]
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Salmonella enterica serovar Typhimurium utilizes host macrophages as a niche for survival and replication, controlling the expression of flagellar genes to minimize host immune response. The transcriptional regulator AsiR positively regulates flagellar gene expression and its downregulation contributes to S. Typhimurium replication and systemic infection. Acidic pH in macrophages serves as a signal for AsiR and flagellar gene downregulation.
The intracellular pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits host macrophage as a crucial survival and replicative niche. To minimize host immune response stimulated by flagellin, the expression of flagellar genes is downregulated during S. Typhimurium growth within host macrophages. However, the underlying mechanisms are largely unknown. In this study, we show that STM14_1285 (named AsiR), a putative RpiR-family transcriptional regulator, which is downregulated within macrophages as previously reported and also confirmed here, positively regulates the expression of flagellar genes by directly binding to the promoter of flhDC. By generating an asiR mutant strain and a strain that persistently expresses asiR gene within macrophages, we confirmed that the downregulation of asiR contributes positively to S. Typhimurium replication in macrophages and systemic infection in mice, which could be attributed to decreased flagellar gene expression and therefore reduced flagellin-stimulated secretion of pro-inflammatory cytokines IL-1 beta and TNF-alpha. Furthermore, the acidic pH in macrophages is identified as a signal for the downregulation of asiR and therefore flagellar genes. Collectively, our results reveal a novel acidic pH signal-mediated regulatory pathway that is utilized by S. Typhimurium to promote intracellular replication and systemic pathogenesis by repressing flagellar gene expression.
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