Salmonella Typhimurium reprograms macrophage metabolism via T3SS effector SopE2 to promote intracellular replication and virulence

Jiang, Lingyan; Wang, Peisheng; Song, Xiaorui; Zhang, Huan; Ma, Shuangshuang; Wang, Jingting; Li, Wanwu; Lv, Runxia; Liu, Xiaoqian; Ma, Shuai; Yan, Jiaqi; Zhou, Haiyan; Huang, Di; Cheng, Zhihui; Yang, Chen; Feng, Lu; Wang, Lei

doi:10.1038/s41467-021-21186-4

Cited by 99 publications

(103 citation statements)

References 71 publications

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“…ProQ suppresses growth in succinate-containing media Succinate has been identified as an important carbon source for Salmonella during colonization of the murine gastrointestinal tract (Spiga et al, 2017), and plays an important role during macrophage infection (Jiang et al, 2021;Rosenberg et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

Scanning mutagenesis of RNA-binding protein ProQ reveals a quality control role for the Lon protease

Mouali

Ponath

Scharrer

et al. 2021

RNA

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The FinO-domain protein ProQ belongs to a widespread family of RNA-binding proteins (RBPs) involved in gene regulation in bacterial chromosomes and mobile elements. Whilst the cellular RNA targets of ProQ have been established in diverse bacteria, the functionally crucial ProQ residues remain to be identified under physiological conditions. Following our discovery that ProQ deficiency alleviates growth suppression of Salmonella with succinate as the sole carbon source, an experimental evolution approach was devised to exploit this phenotype. By coupling mutational scanning with loss-of-function selection, we identified multiple ProQ residues in both the N-terminal FinO domain and the variable C-terminal region that are required for ProQ activity. Two C-terminal mutations abrogated ProQ function and mildly impaired binding of a model RNA target. By contrast, several mutations in the FinO domain rendered ProQ both functionally inactive and unable to interact with target RNA in vivo. Alteration of the FinO domain stimulated the rapid turnover of ProQ by Lon-mediated proteolysis, suggesting a quality control mechanism that prevents the accumulation of non-functional ProQ molecules. We extend this observation to Hfq, the other major sRNA chaperone of enteric bacteria. The Hfq Y55A mutant protein, defective in RNA-binding and oligomerization, proved to be labile and susceptible to degradation by Lon. Taken together, our findings connect the major AAA+ family protease Lon with RNA-dependent quality control of Hfq and ProQ, the two major sRNA chaperones of Gram-negative bacteria.

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Section: Resultsmentioning

confidence: 99%

Scanning mutagenesis of RNA-binding protein ProQ reveals a quality control role for the Lon protease

Mouali

Ponath

Scharrer

et al. 2021

RNA

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“…Typhimurium infection of murine macrophages also induces a Warburg-like metabolism. Moreover, S. Typhimurium suppressed serine synthesis in the host via the type III secretion system (T3SS) effector, SopE2, promoting the accumulation of glycolytic intermediates, especially 3-phosphoglycerate (3PG), pyruvate, and lactate [ 22 ]. Of these, S. Typhimurium used 3PG as an intracellular growth nutrient, whereas pyruvate and lactate were used as signals to induce SPI-2 gene expression [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, S. Typhimurium suppressed serine synthesis in the host via the type III secretion system (T3SS) effector, SopE2, promoting the accumulation of glycolytic intermediates, especially 3-phosphoglycerate (3PG), pyruvate, and lactate [ 22 ]. Of these, S. Typhimurium used 3PG as an intracellular growth nutrient, whereas pyruvate and lactate were used as signals to induce SPI-2 gene expression [ 22 ]. Although S. Typhi and S. Typhimurium share many virulence factors, they also exhibit distinct features in association with specific hosts.…”

Section: Introductionmentioning

confidence: 99%

Salmonella enterica Serovar Typhi Induces Host Metabolic Reprogramming to Increase Glucose Availability for Intracellular Replication

Wang

et al. 2021

IJMS

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Salmonella enterica serovar Typhi (S. Typhi) is a human-limited intracellular pathogen and the cause of typhoid fever, a severe systemic disease. Pathogen–host interaction at the metabolic level affects the pathogenicity of intracellular pathogens, but it remains unclear how S. Typhi infection influences host metabolism for its own benefit. Herein, using metabolomics and transcriptomics analyses, combined with in vitro and in vivo infection assays, we investigated metabolic responses in human macrophages during S. Typhi infection, and the impact of these responses on S. Typhi intracellular replication and systemic pathogenicity. We observed increased glucose content, higher rates of glucose uptake and glycolysis, and decreased oxidative phosphorylation in S. Typhi-infected human primary macrophages. Replication in human macrophages and the bacterial burden in systemic organs of humanized mice were reduced by either the inhibition of host glucose uptake or a mutation of the bacterial glucose uptake system, indicating that S. Typhi utilizes host-derived glucose to enhance intracellular replication and virulence. Thus, S. Typhi promotes its pathogenicity by inducing metabolic changes in host macrophages and utilizing the glucose that subsequently accumulates as a nutrient for intracellular replication. Our findings provide the first metabolic signature of S. Typhi-infected host cells and identifies a new strategy utilized by S. Typhi for intracellular replication.

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“…However, we did not detect marked changes in core mitochondrial and glycolytic enzymes in butyrate treated macrophages after Legionella infections. This may relate to our observation that Legionella infections only marginally affected the expression of core metabolic enzymes (Fig 2b), in stark contrast to other infections which upregulate the expression of metabolic genes (49,50).…”

Section: Discussionmentioning

confidence: 69%

The short chain fatty acid butyrate prevents intracellular replication of Legionella by regulating cysteine levels in macrophages

Abraham

Swaminathan

Barlow

et al. 2021

Preprint

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Macrophages can prevent infections from intracellular pathogens by restricting access to essential nutrients, termed nutritional immunity. With the exception of tryptophan depletion, it is unclear if other amino acids are similarly regulated in infected macrophages. Here, we show that the expression of nutrient transporters in Legionella-infected macrophages is modulated by the short chain fatty acid butyrate. Butyrate prevented the upregulation of the cystine/glutamate exchanger, Slc7a11, in macrophages infected with L. pneumophila, which decreased cellular cysteine levels. Butyrate and the Slc7a11 inhibitor erastin impaired intracellular Legionella replication in macrophages in vitro, with these being restored by exogenous supplementation with cysteine. Butyrate caused increased histone acetylation in infected macrophages, and pan- and class II HDAC inhibitors also restricted intracellular Legionella growth in a cysteine-dependent manner. Intranasal administration of butyrate reduced L. pneumophila lung burdens in mice. Our data suggest that butyrate alters the metabolism of macrophages to promote nutritional immunity by decreasing cysteine levels and that this can be harnessed to treat bacterial lung infections.

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Salmonella Typhimurium reprograms macrophage metabolism via T3SS effector SopE2 to promote intracellular replication and virulence

Cited by 99 publications

References 71 publications

Scanning mutagenesis of RNA-binding protein ProQ reveals a quality control role for the Lon protease

Scanning mutagenesis of RNA-binding protein ProQ reveals a quality control role for the Lon protease

Salmonella enterica Serovar Typhi Induces Host Metabolic Reprogramming to Increase Glucose Availability for Intracellular Replication

The short chain fatty acid butyrate prevents intracellular replication of Legionella by regulating cysteine levels in macrophages

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