Downregulation of a novel flagellar synthesis regulator AsiR promotes intracellular replication and systemic pathogenicity of <i>Salmonella</i> Typhimurium

Ma, Shuangshuang; Jiang, Lingyan; Wang, Jingting; Liu, Xiaoqian; Li, Wanwu; Ma, Shuai; Feng, Lu

doi:10.1080/21505594.2020.1870331

Cited by 7 publications

(7 citation statements)

References 54 publications

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“…It is established that environmental signals are critical factors that control the expression of virulence genes [11,38,39]. Although flagellar genes are activated during intestinal infection, they must be repressed during systemic infection due to the strong immunogenicity of flagellar proteins [38]. Various mechanisms related to the inhibition of flagellar genes within macrophages have been characterized, including acid signaling that can inhibit flagellar genes expression via repressing the regulatory protein AsiR as reported in our previous study [38,39].…”

Section: Discussionmentioning

confidence: 84%

“…From these results, we can conclude that S. Typhimurium uses nitrate in different ways during different infection stages, primarily due to the observation that the virulence genes required by the pathogen are different in intestinal and systemic infections. It is established that environmental signals are critical factors that control the expression of virulence genes [11,38,39]. Although flagellar genes are activated during intestinal infection, they must be repressed during systemic infection due to the strong immunogenicity of flagellar proteins [38].…”

Section: Discussionmentioning

confidence: 99%

“…Although flagellar genes are activated during intestinal infection, they must be repressed during systemic infection due to the strong immunogenicity of flagellar proteins [38]. Various mechanisms related to the inhibition of flagellar genes within macrophages have been characterized, including acid signaling that can inhibit flagellar genes expression via repressing the regulatory protein AsiR as reported in our previous study [38,39]. Therefore, although nitrate may also possess the potential to stimulate the expression of flagellar genes in macrophages, flagellar genes are inhibited by various environmental cues in macrophages and regulatory systems.…”

Section: Discussionmentioning

confidence: 99%

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Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Yan

et al. 2022

IJMS

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Salmonella Typhimurium is an invasive enteric pathogen that causes gastroenteritis in humans and life-threatening systemic infections in mice. During infection of the intestine, S. Typhimurium can exploit nitrate as an electron acceptor to enhance its growth. However, the roles of nitrate on S. Typhimurium systemic infection are unknown. In this study, nitrate levels were found to be significantly increased in the liver and spleen of mice systemically infected by S. Typhimurium. Mutations in genes encoding nitrate transmembrane transporter (narK) or nitrate-producing flavohemoprotein (hmpA) decreased the replication of S. Typhimurium in macrophages and reduced systemic infection in vivo, suggesting that nitrate utilization promotes S. Typhimurium systemic virulence. Moreover, nitrate utilization contributes to the acidification of the S. Typhimurium cytoplasm, which can sustain the virulence of S. Typhimurium by increasing the transcription of virulence genes encoding on Salmonella pathogenicity island 2 (SPI-2). Furthermore, the growth advantage of S. Typhimurium conferred by nitrate utilization occurred only under low-oxygen conditions, and the nitrate utilization was activated by both the global regulator Fnr and the nitrate-sensing two-component system NarX-NarL. Collectively, this study revealed a novel mechanism adopted by Salmonella to interact with its host and increase its virulence.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Yan

et al. 2022

IJMS

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“…Through overnight incubation at 37 °C, the CFU number of bacteria could be counted. The intracellular replication fold was calculated as the number of CFU at 20 h hpi divided by the number of CFU at 2 h [ 46 ].…”

Section: Methodsmentioning

confidence: 99%

The LysR-Type Transcription Regulator YhjC Promotes the Systemic Infection of Salmonella Typhimurium in Mice

Yan

et al. 2023

IJMS

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Salmonella Typhimurium is a Gram-negative intestinal pathogen that can infect humans and a variety of animals, causing gastroenteritis or serious systemic infection. Replication within host macrophages is essential for S. Typhimurium to cause systemic infection. By analyzing transcriptome data, the expression of yhjC gene, which encodes a putative regulator in S. Typhimurium, was found to be significantly up-regulated after the internalization of Salmonella by macrophages. Whether yhjC gene is involved in S. Typhimurium systemic infection and the related mechanisms were investigated in this study. The deletion of yhjC reduced the replication ability of S. Typhimurium in macrophages and decreased the colonization of S. Typhimurium in mouse systemic organs (liver and spleen), while increasing the survival rate of the infected mice, suggesting that YhjC protein promotes systemic infection by S. Typhimurium. Furthermore, by using transcriptome sequencing and RT-qPCR assay, the transcription of several virulence genes, including spvD, iroCDE and zraP, was found to be down-regulated after the deletion of yhjC. Electrophoretic mobility shift assay showed that YhjC protein can directly bind to the promoter region of spvD and zraP to promote their transcription. These findings suggest that YhjC contributes to the systemic virulence of S. Typhimurium via the regulation of multiple virulence genes and YhjC could represent a promising target to control S. Typhimurium infection.

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“…The acid signal of the host can suppress flagellar biosynthesis and motility of Salmonella to avoid recognition by the host immune system ( Wang et al., 2022 ). Meanwhile, Salmonella turns off flagellar biosynthesis to promote intracellular replication and cause systemic disease ( Ma et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Response mechanisms to acid stress promote LF82 replication in macrophages

Yao,

Huang,

Huai

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundAdherent–invasive E. coli (AIEC) LF82 is capable of adhering to and invading intestinal epithelial cells, as well as replicating within macrophages without inducing host cell death.MethodsWe compared the transcriptomics of LF82 at pH=7.5 and pH=5.8 by RNA-sequencing, and qRT-PCR verified differentially expressed genes (DEGs). The deletion mutants of DEGs in the treatment group (pH=5.8) compared to the control group (pH=7.5) were constructed by λ recombinant. The replication differences between the mutants and WT infected Raw 264.7 at 24 h.p.i were analyzed by combining LB solid plate count and confocal observation. NH4Cl and chloroquine diphosphate (CQ) were used for acid neutralization to study the effect of pH on the replication of LF82 in macrophages. Na2NO3 was added to RPMI 1640 to study the effect of nitrate on the replication of LF82 in macrophages. 0.3% solid LB was used for flagellar motility assay and Hela was used to study flagellar gene deletion mutants and WT adhesion and invasion ability.ResultsIn this study, we found that infection with LF82 results in acidification of macrophages. Subsequent experiments demonstrated that an intracellular acidic environment is necessary for LF82 replication. Transcriptome and phenotypic analysis showed that high expression of acid shock genes and acid fitness genes promotes LF82 replication in macrophages. Further, we found that the replication of LF82 in macrophages was increased under nitrate treatment, and nitrogen metabolism genes of LF82 were upregulated in acid treatment. The replication in macrophages of ΔnarK, ΔnarXL, ΔnarP, and Δhmp were decreased. In addition, we found that the expression of flagellar genes was downregulated in acidic pH and after LF82 invading macrophages. Motility assay shows that the movement of LF82 on an acidic semisolid agar plate was limited. Further results showed that ΔfliC and ΔfliD decreased in motility, adhesion ability, and invasion of host cells, but no significant effect on replication in macrophages was observed.ConclusionIn this study, we simulated the acidic environment in macrophages, combined with transcriptome technology, and explained from the genetic level that LF82 promotes replication by activating its acid shock and fitness system, enhancing nitrate utilization, and inhibiting flagellar function.

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Downregulation of a novel flagellar synthesis regulator AsiR promotes intracellular replication and systemic pathogenicity of Salmonella Typhimurium

Cited by 7 publications

References 54 publications

Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

The LysR-Type Transcription Regulator YhjC Promotes the Systemic Infection of Salmonella Typhimurium in Mice

Response mechanisms to acid stress promote LF82 replication in macrophages

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