Project description:TraDIS study on Salmonella Typhi subjected to serum bactericidal assays.These data are part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Project description:Sequencing of RNA of selected Salmonella Typhi strains from typhoid-endemic regions of Asia and Africahttp://www.sanger.ac.uk/resources/downloads/bacteria/salmonella.htmlThese data are part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
Project description:Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like Salmonella enterica serovar Typhi (S. Typhi), the cause of Typhoid fever. One key dynamic during infection is competition for nutrients: host cells attempt to restrict intracellular replication by depriving bacteria of key nutrients or delivering toxic metabolites in a process called nutritional immunity. Here, a cellular genome-wide association study of intracellular replication by S. Typhi in nearly a thousand cell lines from around the world—and extensive follow-up using intracellular S. Typhi transcriptomics and manipulation of magnesium concentrations—demonstrates that the divalent cation channel mucolipin-2 (MCOLN2) restricts S. Typhi intracellular replication through magnesium deprivation. Our results reveal natural diversity in Mg2+ limitation as a key component of nutritional immunity against S. Typhi.
Project description:Global expression profiles of Salmonella typhi grown in the supernatant of infection and within human macrophages at 0h, 2h, 8h and 24h were obtained. Stringent analytical methods were used to compare Salmonella typhi cDNAs and revealed that known virulence factors, such as the SPI-1 and SPI-2 encoded type III secretion systems, were found to be expressed as predicted during infection by Salmonella. Intracellular Typhi expressed many genes encoding antimicrobial peptides, used the glyoxylate bypass for fatty acid utilization, and, did not induce the SOS response or the oxidative stress response. Genes coding for the flagellar apparatus, chemotaxis and the iron transport system were down-regulated in vivo. The combined use of SCOTS and microarray is an effective way to determine global bacterial gene expression profiling in the context of host infection, without the need of increasing the multiplicity of infection beyond what is seen in nature. Keywords: Time course
Project description:Macrophages provide a crucial environment for Salmonella enterica serovar Typhi (S. Typhi) to multiply during typhoid fever, yet our understanding of how human macrophages and S. Typhi interact remains limited. In this study, we delve into the dynamics of S. Typhi replication within human macrophages and the resulting heterogeneous transcriptomic responses of macrophages during infection. Our study reveals key factors that influence macrophage diversity, uncovering distinct immune and metabolic pathways associated with different stages of S. Typhi intracellular replication in macrophages. Of note, we found that macrophages harboring replicating S. Typhi are skewed towards an M1 pro-inflammatory state, whereas macrophages containing non-replicating S. Typhi exhibit neither a distinct M1 pro-inflammatory nor M2 anti-inflammatory state. Additionally, macrophages with replicating S. Typhi were characterized by the increased expression of genes associated with STAT3 phosphorylation and the activation of the STAT3 transcription factor. Our results shed light on transcriptomic pathways involved in the susceptibility of human macrophages to intracellular S. Typhi replication, thereby providing crucial insight into host phenotypes that restrict and support S. Typhi infection.
Project description:Salmonella enterica subsp. enterica contains more than 2,600 serovars of which four are of major medical relevance for humans. While the typhoidal serovars (Typhi and Paratyphi A) are human-restricted and cause enteric fever, non-typhoidal Salmonella serovars (Typhimurium and Enteritidis) have a broad host range and predominantly cause gastroenteritis. In this study, we compared the core proteomes of Salmonella Typhi, Paratyphi A, Typhimurium and Enteritidis using contemporary proteomics. Five isolates, covering different geographical origins, and one reference strain per serovar were grown in vitro to the exponential phase. Protein levels of orthologous proteins between serovars were compared and subjected to gene ontology term enrichment and inferred regulatory interactions. Differential expression of the core proteomes of the typhoidal serovars appears mainly related to cell surface components and, for the non-typhoidal serovars, to pathogenicity. Our findings may guide future development of novel diagnostics and vaccines, and understanding of disease progression.
Project description:SdiA is a LuxR-type protein found in some Enterobacteriaceae. SdiA encoding bacteria do not encode a luxI homolog and rely on foreign bacteria for the production of N-acyl homoserine lactones (AHLs), SdiA's ligand. The regulon of Salmonella SdiA is largely unknown. In this study, we measured the sdiA dependent transcriptional changes of two serovars of Salmonella, Typhimurium and Typhi, exposed to synthetic AHLs. This was evaluated in two experiments. First, the wild-type and sdiA mutant were grown in the presence of AHLs. In the second, sdiA mutants harboring an arabinose inducible copy of SdiA on a plasmid and vector control were grown with AHLs and arabinose. From this a putative regulon was established and confirmed with subsequent characterization experiments.
Project description:This study describes how Salmonella Typhi, the pathogen responsible for typhoid fever, uses similar strategies to escape immune defense responses and survive within its human host. To elucidate the early mechanisms of typhoid fever, we performed studies using healthy human intestinal tissue samples to analyze gene expression changes in human intestinal specimens and bacterial cells both separately and after colonization. Our results showed mechanistic strategies that S. Typhi uses to rearrange the cellular machinery of the host cytoskeleton to successfully invade the intestinal epithelium, promote polarized cytokine release and evade immune system activation by downregulating genes involved in antigen sampling and presentation during infection.