Project description:Salmonella strains encounter significant acid stress during gastrointestinal infection and within the intra-phagosome environment. Comparative studies on acid adaptation of typhoidal and non-typhoidal Salmonella (NTS) are limited. In this study, we compared the growth of S. Typhimurium 14028s and S. Typhi (Ty2) across pH range of 3-8 and observed that Salmonella enterica serovar Typhimurium exhibit enhanced growth at pH 4.5 compared to S. Typhi. Comparative transcriptomic profiling of S. Typhimurium and S. Typhi at acidic and neutral pH identified numerous differentially expressed genes (DEGs) in both the serovars. These DEGs include genes encoding membrane proteins, transcriptional regulators, and stress response proteins. Targeted deletion of these genes in S. Typhimurium significantly suppressed growth at acidic pH, confirming their role in acid response. Notably, we found that these resistance mechanisms are compromised in S. Typhi due to pseudogenization of several key genes. Heterologous expression of these pseudogenized genes in S. Typhi augmented its acid tolerance. Collectively, our findings suggest that multiple genes essential for acid survival in S. Typhimurium have become dispensable or lost in S. Typhi reflecting divergent evolutionary strategies between these two serovars.
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: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: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: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.