Dataset Information

Toll-Like Receptor Activation by Generalized Modules for Membrane Antigens from Lipid A Mutants of Salmonella enterica Serovars Typhimurium and Enteritidis.

ABSTRACT: Invasive nontyphoidal Salmonella (iNTS) disease is a neglected disease with high mortality in children and HIV-positive individuals in sub-Saharan Africa, caused primarily by Africa-specific strains of Salmonella enterica serovars Typhimurium and Enteritidis. A vaccine using GMMA (generalized modules for membrane antigens) fromS.Typhimurium andS.Enteritidis containing lipid A modifications to reduce potential in vivo reactogenicity is under development. GMMA with penta-acylated lipid A showed the greatest reduction in the level of cytokine release from human peripheral blood monocytes from that for GMMA with wild-type lipid A. Deletion of the lipid A modification genes msbB and pagP was required to achieve pure penta-acylation. Interestingly, ?msbB? pagP GMMA from S. Enteritidis had a slightly higher stimulatory potential than those from S. Typhimurium, a finding consistent with the higher lipopolysaccharide (LPS) content and Toll-like receptor 2 (TLR2) stimulatory potential of the former. Also, TLR5 ligand flagellin was found in Salmonella GMMA. No relevant contribution to the stimulatory potential of GMMA was detected even when the flagellin protein FliC from S. Typhimurium was added at a concentration as high as 10% of total protein, suggesting that flagellin impurities are not a major factor for GMMA-mediated immune stimulation. Overall, the stimulatory potential of S. Typhimurium and S. Enteritidis ?msbB ?pagP GMMA was close to that of Shigella sonnei GMMA, which are currently in phase I clinical trials.

SUBMITTER: Rossi O

PROVIDER: S-EPMC4820502 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Toll-Like Receptor Activation by Generalized Modules for Membrane Antigens from Lipid A Mutants of Salmonella enterica Serovars Typhimurium and Enteritidis.

Rossi Omar O Caboni Mariaelena M Negrea Aurel A Necchi Francesca F Alfini Renzo R Micoli Francesca F Saul Allan A MacLennan Calman A CA Rondini Simona S Gerke Christiane C

Clinical and vaccine immunology : CVI 20160404 4

Invasive nontyphoidal Salmonella (iNTS) disease is a neglected disease with high mortality in children and HIV-positive individuals in sub-Saharan Africa, caused primarily by Africa-specific strains of Salmonella enterica serovars Typhimurium and Enteritidis. A vaccine using GMMA (generalized modules for membrane antigens) fromS.Typhimurium andS.Enteritidis containing lipid A modifications to reduce potential in vivo reactogenicity is under development. GMMA with penta-acylated lipid A showed th ...[more]

PMID: 26865597

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Project description:Salmonella enterica serovars Enteritidis (S. Enteritidis) can survive extreme food processing environments including bactericidal sodium hypochlorite (NaClO) treatments generally recognized as safe. In order to reveal the molecular regulatory mechanisms underlying the phenotypes, the overall regulation of genes at the transcription level in S. Enteritidis after NaClO stimulation were investigated by RNA-sequencing. We identified 1399 differentially expressed genes (DEG) of S. Enteritidis strain CVCC 1806 following treatment in liquid culture with 100 mg/L NaClO for 20 min (915 upregulated and 484 downregulated). NaClO stress affects the transcription of genes related to a range of important biomolecular processes such as membrane damage, membrane transport function, energy metabolism, oxidative stress, DNA repair, and other important processes in Salmonella enterica. First, NaClO affects the structural stability of cell membranes, which induces the expression of a range of outer and inner membrane proteins. This may lead to changes in cell membrane permeability, accelerating the frequency of DNA conversion and contributing to the production of drug-resistant bacteria. In addition, the expression of exocytosis pump genes (emrB, yceE, ydhE, and ydhC) was able to expel NaClO from the cell, thereby increasing bacterial tolerance to NaClO. Secondly, downregulation of genes related to the Kdp-ATPase transporter system (kdpABC) and the amino acid transporter system (aroP, brnQ and livF) may to some extent reduce active transport by bacterial cells, thereby reducing their own metabolism and the entry of disinfectants. Downregulation of genes related to the tricarboxylic acid (TCA) cycle may drive bacterial cells into a viable but non-culturable (VBNC) state, resisting NaClO attack by reducing energy metabolism. In addition, significant upregulation of genes related to oxidative stress could mitigate damage caused by disinfectants by eliminating alkyl hydroperoxides, while upregulation of genes related to DNA repair could repair damage to bacterial cells caused by oxidative stress. Therefore, this study indicated that S. Enteritidis has genomic mechanisms to adapt to NaClO stress.

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Project description:Avian gastrointestinal (GI) tracts are highly populated with a diverse array of microorganisms that share a symbiotic relationship with their hosts and contribute to the overall health and disease state of the intestinal tract. The microbiome of the young chick is easily prone to alteration in its composition by both exogenous and endogenous factors, especially during the early posthatch period. The genetic background of the host and exposure to pathogens can impact the diversity of the microbial profile that consequently contributes to the disease progression in the host. The objective of this study was to profile the composition and structure of the gut microbiota in young chickens from two genetically distinct highly inbred lines. Furthermore, the effect of the Salmonella Enteritidis infection on altering the composition makeup of the chicken microbiome was evaluated through the 16S rRNA gene sequencing analysis. One-day-old layer chicks were challenged with S. Enteritidis and the host cecal microbiota profile as well as the degree of susceptibility to Salmonella infection was examined at 2 and 7?days post infection. Our result indicated that host genotype had a limited effect on resistance to S. Enteritidis infection. Alpha diversity, beta diversity, and overall microbiota composition were analyzed for four factors: host genotype, age, treatment, and postinfection time points. S. Enteritidis infection in young chicks was found to significantly reduce the overall diversity of the microbiota population with expansion of Enterobacteriaceae family. These changes indicated that Salmonella colonization in the GI tract of the chickens has a direct effect on altering the natural development of the GI microbiota. The impact of S. Enteritidis infection on microbial communities was also more substantial in the late stage of infection. Significant inverse correlation between Enterobacteriaceae and Lachnospiraceae family in both non-infected and infected groups, suggested possible antagonistic interaction between members of these two taxa, which could potentially influences the overall microbial population in the gut. Our results also revealed that genetic difference between two lines had minimal effect on the establishment of microbiota population. Overall, this study provided preliminary insights into the contributing role of S. Enteritidis in influencing the overall makeup of chicken's gut microbiota.

Dataset Information

Toll-Like Receptor Activation by Generalized Modules for Membrane Antigens from Lipid A Mutants of Salmonella enterica Serovars Typhimurium and Enteritidis.

Publications

Toll-Like Receptor Activation by Generalized Modules for Membrane Antigens from Lipid A Mutants of Salmonella enterica Serovars Typhimurium and Enteritidis.

Similar Datasets

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