Dataset Information

Salmonella promotes virulence by repressing cellulose production.

ABSTRACT: Cellulose is the most abundant organic polymer on Earth. In bacteria, cellulose confers protection against environmental insults and is a constituent of biofilms typically formed on abiotic surfaces. We report that, surprisingly, Salmonella enterica serovar Typhimurium makes cellulose when inside macrophages. We determine that preventing cellulose synthesis increases virulence, whereas stimulation of cellulose synthesis inside macrophages decreases virulence. An attenuated mutant lacking the mgtC gene exhibited increased cellulose levels due to increased expression of the cellulose synthase gene bcsA and of cyclic diguanylate, the allosteric activator of the BcsA protein. Inactivation of bcsA restored wild-type virulence to the Salmonella mgtC mutant, but not to other attenuated mutants displaying a wild-type phenotype regarding cellulose. Our findings indicate that a virulence determinant can promote pathogenicity by repressing a pathogen's antivirulence trait. Moreover, they suggest that controlling antivirulence traits increases long-term pathogen fitness by mediating a trade-off between acute virulence and transmission.

SUBMITTER: Pontes MH

PROVIDER: S-EPMC4413311 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Salmonella promotes virulence by repressing cellulose production.

Pontes Mauricio H MH Lee Eun-Jin EJ Choi Jeongjoon J Groisman Eduardo A EA

Proceedings of the National Academy of Sciences of the United States of America 20150406 16

Cellulose is the most abundant organic polymer on Earth. In bacteria, cellulose confers protection against environmental insults and is a constituent of biofilms typically formed on abiotic surfaces. We report that, surprisingly, Salmonella enterica serovar Typhimurium makes cellulose when inside macrophages. We determine that preventing cellulose synthesis increases virulence, whereas stimulation of cellulose synthesis inside macrophages decreases virulence. An attenuated mutant lacking the mgt ...[more]

PMID: 25848006

Similar Datasets

Project description:LeuO, initially identified as a leucine regulator in Escherichia coli, has since been identified as a global regulator required for bacterial pathogenicity in a broad range of bacteria, including gram-negative pathogens, such as Salmonella, Shigella, and Vibrio; and gram-positive bacteria, such as Streptococcus pneumoniae. However, the regulatory roles and targets of LeuO vary among species. In the Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium), LeuO represses the transcription of Salmonella pathogenicity island (SPI)-1, thus diminishing the ability of the bacteria to invade host cells. However, its regulatory effect on SPI-2, essential for survival within macrophages, remains poorly understood. This study aimed to determine the regulatory role of LeuO in the intracellular persistence of S. Typhimurium. Overexpression of LeuO repressed the transcription of SPI-2 genes and accordingly decreased its protein levels. Chromatin immunoprecipitation sequencing revealed the genome-wide binding sites of LeuO in S. Typhimurium 14028 and identified a distinctive 23-nucleotide motif with high similarity to that previously discovered in E. coli. Notably, multiple LeuO-binding sites were predicted within SPI-2, primarily adjacent to the ssrA and ssrB loci. In vitro binding assays verified the high binding affinity between LeuO and three specific motifs located at positions -35 to -12 (ssrA1),+231 to +254 (ssrA2) near ssrA, and at positions -622 to -599 (ssrB3) near ssrB, relative to their transcription start sites. Furthermore, LeuO overexpression abolished the transcription of lacZ fused to the ssrA promoter containing ssrA1 and ssrA2, suggesting the direct repression of ssrA via LeuO-binding. The absence of LeuO increased the intracellular survival of S. Typhimurium within macrophages, whereas its overexpression attenuated bacterial persistence, which was presumably associated with the downregulation of SPI-2 by LeuO. This study reveals the versatile regulatory mechanisms of LeuO and underscores its pivotal role in modulating SPI-2 expression, thereby providing key insights into the fine tuning of virulence by Salmonella during systemic infection.

Project description:The intracellular pathogen Salmonella enterica serovar Typhimurium has emerged as a major cause of foodborne illness, representing a severe clinical and economic concern worldwide. The capacity of this pathogen to efficiently infect and survive inside the host depends on its ability to synchronize a complex network of virulence mechanisms. Therefore, the identification of new virulence determinants has become of paramount importance in the search of new targets for drug development. BolA-like proteins are widely conserved in all kingdoms of life. In Escherichia coli, this transcription factor has a critical regulatory role in several mechanisms that are tightly related to bacterial virulence. Therefore, in the present work we used the well-established infection model Galleria mellonella to evaluate the role of BolA protein in S Typhimurium virulence. We have shown that BolA is an important player in S Typhimurium pathogenesis. Specifically, the absence of BolA leads to a defective virulence capacity that is most likely related to the remarkable effect of this protein on S Typhimurium evasion of the cellular response. Furthermore, it was demonstrated that BolA has a critical role in bacterial survival under harsh conditions since BolA conferred protection against acidic and oxidative stress. Hence, we provide evidence that BolA is a determining factor in the ability of Salmonella to survive and overcome host defense mechanisms, and this is an important step in progress to an understanding of the pathways underlying bacterial virulence.IMPORTANCE BolA has been described as an important protein for survival in the late stages of bacterial growth and under harsh environmental conditions. High levels of BolA in stationary phase and under stresses have been connected with a plethora of phenotypes, strongly suggesting its important role as a master regulator. Here, we show that BolA is a determining factor in the ability of Salmonella to survive and overcome host defense mechanisms, and this is an important step in progress to an understanding of the pathways underlying bacterial virulence. This work constitutes a relevant step toward an understanding of the role of BolA protein and may have an important impact on future studies in other organisms. Therefore, this study is of utmost importance for understanding the genetic and molecular bases involved in the regulation of Salmonella virulence and may contribute to future industrial and public health care applications.

Project description:OBJECTIVE:Enteroendocrine cells (EECs) of the gastro-intestinal tract sense gut luminal factors and release peptide hormones or serotonin (5-HT) to coordinate energy uptake and storage. Our goal is to decipher the gene regulatory networks controlling EECs specification from enteroendocrine progenitors. In this context, we studied the role of the transcription factor Rfx6 which had been identified as the cause of Mitchell-Riley syndrome, characterized by neonatal diabetes and congenital malabsorptive diarrhea. We previously reported that Rfx6 was essential for pancreatic beta cell development and function; however, the role of Rfx6 in EECs differentiation remained to be elucidated. METHODS:We examined the molecular, cellular, and metabolic consequences of constitutive and conditional deletion of Rfx6 in the embryonic and adult mouse intestine. We performed single cell and bulk RNA-Seq to characterize EECs diversity and identify Rfx6-regulated genes. RESULTS:Rfx6 is expressed in the gut endoderm; later, it is turned on in, and restricted to, enteroendocrine progenitors and persists in hormone-positive EECs. In the embryonic intestine, the constitutive lack of Rfx6 leads to gastric heterotopia, suggesting a role in the maintenance of intestinal identity. In the absence of intestinal Rfx6, EECs differentiation is severely impaired both in the embryo and adult. However, the number of serotonin-producing enterochromaffin cells and mucosal 5-HT content are increased. Concomitantly, Neurog3-positive enteroendocrine progenitors accumulate. Combined analysis of single-cell and bulk RNA-Seq data revealed that enteroendocrine progenitors differentiate in two main cell trajectories, the enterochromaffin (EC) cells and the Peptidergic Enteroendocrine (PE) cells, the differentiation programs of which are differentially regulated by Rfx6. Rfx6 operates upstream of Arx, Pax6 and Isl1 to trigger the differentiation of peptidergic EECs such as GIP-, GLP-1-, or CCK-secreting cells. On the contrary, Rfx6 represses Lmx1a and Tph1, two genes essential for serotonin biosynthesis. Finally, we identified transcriptional changes uncovering adaptive responses to the prolonged lack of enteroendocrine hormones and leading to malabsorption and lower food efficiency ratio in Rfx6-deficient mouse intestine. CONCLUSION:These studies identify Rfx6 as an essential transcriptional regulator of EECs specification and shed light on the molecular mechanisms of intestinal failures in human RFX6-deficiencies such as Mitchell-Riley syndrome.

Dataset Information

Salmonella promotes virulence by repressing cellulose production.

Publications

Salmonella promotes virulence by repressing cellulose production.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets