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Current Opinion in Microbiology Feb 2017Typhoid toxin is a unique AB exotoxin and an important virulence factor for Salmonella Typhi, the cause of typhoid fever. In the decade since its initial discovery,... (Review)
Review
Typhoid toxin is a unique AB exotoxin and an important virulence factor for Salmonella Typhi, the cause of typhoid fever. In the decade since its initial discovery, great strides have been made in deciphering the unusual biological program of this toxin, which is fundamentally different from related toxins in many ways. Purified typhoid toxin administered to laboratory animals causes many of the symptoms of typhoid fever, suggesting that typhoid toxin is a central factor in this disease. Further advances in understanding the biology of this toxin will help guide the development of badly needed diagnostics and therapeutic interventions that target this toxin to detect, prevent or treat typhoid fever.
Topics: Animals; Bacterial Toxins; Exotoxins; Humans; Mice; Salmonella typhi; Typhoid Fever; Virulence Factors
PubMed: 28213043
DOI: 10.1016/j.mib.2017.01.012 -
PLoS Neglected Tropical Diseases Mar 2020Salmonella Typhi (S. Typhi) is the causative agent of typhoid fever; a systemic disease affecting ~20 million people per year globally. There are little data regarding...
Salmonella Typhi (S. Typhi) is the causative agent of typhoid fever; a systemic disease affecting ~20 million people per year globally. There are little data regarding the contemporary epidemiology of typhoid in Latin America. Consequently, we aimed to describe some recent epidemiological aspects of typhoid in Colombia using cases reported to the National Public Health Surveillance System (Sivigila) between 2012 and 2015. Over the four-year reporting period there were 836 culture confirmed cases of typhoid in Colombia, with the majority (676/836; 80.1%) of reported cases originated from only seven departments. We further characterized 402 S. Typhi isolates with available corresponding data recovered from various departments of Colombia through antimicrobial susceptibility testing and molecular subtyping. The majority (235/402; 58.5%) of these typhoid cases occurred in males and were most commonly reported in those aged between 10 and 29 years (218/402; 54.2%); there were three (0.74%) reported fatalities. The overwhelming preponderance (339/402; 84.3%) of S. Typhi were susceptible to all tested antimicrobials. The most common antimicrobial to which the organisms exhibited non-susceptibility was ampicillin (30/402;7.5%), followed by nalidixic acid (23/402, 5.7%). Molecular subtyping identified substantial genetic diversity, which was well distributed across the country. Despite the diffuse pattern of S. Typhi genotypes, we identified various geographical hotspots of disease associated with local dominant genotypes. Notably, we found limited overlap of Colombian genotypes with organisms reported in other Latin American countries. Our work highlights a substantial burden of typhoid in Colombia, characterized by sustained transmission in some regions and limited epidemics in other departments. The disease is widely distributed across the country and associated with multiple antimicrobial susceptible genotypes that appear to be restricted to Colombia. This study provides a current perspective for typhoid in Latin America and highlights the importance of pathogen-specific surveillance to add insight into the limited epidemiology of typhoid in this region.
Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Child; Child, Preschool; Colombia; Drug Resistance, Bacterial; Epidemiological Monitoring; Female; Genetic Variation; Genotype; Humans; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Typing; Retrospective Studies; Salmonella typhi; Sex Distribution; Typhoid Fever; Young Adult
PubMed: 32155148
DOI: 10.1371/journal.pntd.0008040 -
Gut Microbes 2012The host restricts dissemination of invasive enteric pathogens, such as non-typhoidal Salmonella serovars, by mounting acute inflammatory responses characterized by the... (Review)
Review
The host restricts dissemination of invasive enteric pathogens, such as non-typhoidal Salmonella serovars, by mounting acute inflammatory responses characterized by the recruitment of neutrophils. However, some enteric pathogens, such as Salmonella enterica serovar Typhi (S. typhi), can bypass these defenses and cause an invasive bloodstream infection known as typhoid fever. Recent studies on virulence mechanisms of S. typhi suggest that tight regulation of virulence gene expression during the transition from the intestinal lumen into the intestinal mucosa enables this pathogen to evade detection by the innate immune system, thereby penetrating defenses that prevent bacterial dissemination. This example illustrates how the outcome of host pathogen interaction at the intestinal mucosal interface can alter the clinical presentation and dictate the disease outcome.
Topics: Bacterial Proteins; Gene Expression Regulation, Bacterial; Humans; Immune Evasion; Salmonella typhi; Typhoid Fever; Virulence; Virulence Factors
PubMed: 22156762
DOI: 10.4161/gmic.18602 -
Nature Genetics Aug 2008Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated...
Isolates of Salmonella enterica serovar Typhi (Typhi), a human-restricted bacterial pathogen that causes typhoid, show limited genetic variation. We generated whole-genome sequences for 19 Typhi isolates using 454 (Roche) and Solexa (Illumina) technologies. Isolates, including the previously sequenced CT18 and Ty2 isolates, were selected to represent major nodes in the phylogenetic tree. Comparative analysis showed little evidence of purifying selection, antigenic variation or recombination between isolates. Rather, evolution in the Typhi population seems to be characterized by ongoing loss of gene function, consistent with a small effective population size. The lack of evidence for antigenic variation driven by immune selection is in contrast to strong adaptive selection for mutations conferring antibiotic resistance in Typhi. The observed patterns of genetic isolation and drift are consistent with the proposed key role of asymptomatic carriers of Typhi as the main reservoir of this pathogen, highlighting the need for identification and treatment of carriers.
Topics: Bacteriophages; Evolution, Molecular; Genome, Bacterial; Genomic Islands; Humans; Molecular Sequence Data; Phylogeny; Plasmids; Polymorphism, Single Nucleotide; Recombination, Genetic; Salmonella typhi; Sequence Analysis, DNA; Typhoid Fever
PubMed: 18660809
DOI: 10.1038/ng.195 -
PloS One 2021Sepsis is a syndromic response to infections and is becoming an emerging threat to the public health sector, particularly in developing countries. Salmonella Typhi (S....
Sepsis is a syndromic response to infections and is becoming an emerging threat to the public health sector, particularly in developing countries. Salmonella Typhi (S. Typhi), the cause of typhoid fever, is one primary cause of pediatric sepsis in typhoid endemic areas. Extensively drug-resistant (XDR) S. Typhi is more common among pediatric patients, which is responsible for over 90% of the reported XDR typhoid cases, but the majority of antibiotic resistance studies available have been carried out using S. Typhi isolates from adult patients. Here, we characterized antibiotic-resistance profiles of XDR S. Typhi isolates from a medium size cohort of pediatric typhoid patients (n = 45, 68.89% male and 31.11% female) and determined antibiotic-resistance-related gene signatures associated with common treatment options to typhoid fever patients of 18 XDR S. Typhi representing all 45 isolates. Their ages were 1-13 years old: toddlers aging 1-2 years old (n = 9, 20%), pre-schoolers aging 3-5 years old (n = 17, 37.78%), school-age children aging 6-12 years old (n = 17, 37.78%), and adolescents aging 13-18 years old (n = 2, 4.44%). Through analyzing blaTEM1, dhfR7, sul1, and catA1genes for multidrug-resistance, qnrS, gyrA, gyrB, parC, and parE for fluoroquinolone-resistance, blaCTX-M-15 for XDR, and macAB and acrAB efflux pump system-associated genes, we showed the phenotype of the XDR S. Typhi isolates matches with their genotypes featured by the acquisitions of the genes blaTEM1, dhfR7, sul1, catA1, qnrS, and blaCTX-M-15 and a point mutation on gyrA. This study informs the molecular basis of antibiotic-resistance among recent S. Typhi isolates from pediatric septicemia patients, therefore providing insights into the development of molecular detection methods and treatment strategies for XDR S. Typhi.
Topics: Adolescent; Anti-Bacterial Agents; Bacterial Proteins; Child; Child, Preschool; Cohort Studies; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant; Male; Point Mutation; Salmonella typhi; Sepsis; Typhoid Fever
PubMed: 34582469
DOI: 10.1371/journal.pone.0257744 -
Journal of Infection in Developing... Feb 2020The multidrug-resistant (MDR) Salmonella enterica serovar Typhi isolates have been increasingly reported from the Asian and African countries. The emergence of isolates...
INTRODUCTION
The multidrug-resistant (MDR) Salmonella enterica serovar Typhi isolates have been increasingly reported from the Asian and African countries. The emergence of isolates with decreased susceptibility to fluoroquinolones and cephalosporins has worsened the situation. Recently, an outbreak from Sindh, Pakistan was reported caused by extensively drug-resistant (XDR) S. Typhi strains.
METHODOLOGY
In the present study, a total of 82 cases of typhoid have been investigated during 2018 from the febrile children referred to a tertiary care hospital in the population-wise largest province (Punjab) of Pakistan. S. Typhi was identified by standard microbiological techniques and isolates were characterized for antimicrobial resistance profiling and minimum inhibitory concentrations were determined. The presence of various ESBL genes in S. Typhi was confirmed by the PCR.
RESULTS
Out of the 82 isolates tested, 35 (43%) were found to be XDR; resistant to the first-line drugs. The resistance to third-generation cephalosporins was mainly mediated by extended-spectrum beta-lactamases i.e. blaTEM and blaCTX-M genes.
CONCLUSIONS
The higher prevalence of ESBL producing Salmonella typhi clinical strains raises the concern about transmission prevention and infection management in the community as well as clinical settings. Moreover, the study highlights the problem concerning the declining antibiotic arsenal for the therapeutic management of typhoid fever and the emergence and spread of XDR strains in Pakistan.
Topics: Adolescent; Anti-Bacterial Agents; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Pakistan; Polymerase Chain Reaction; Salmonella typhi; Tertiary Care Centers; Typhoid Fever; beta-Lactam Resistance; beta-Lactamases
PubMed: 32146451
DOI: 10.3855/jidc.12049 -
Journal of Bacteriology Jun 2020LtrR is a LysR-type regulator involved in the positive expression of to promote and expression. This regulatory network is fundamental for the control of bacterial...
The Salmonella enterica Serovar Typhi Gene Encodes Two Proteins Whose Transcriptional Expression Is Upregulated by Alkaline pH and Repressed at Their Promoters and Coding Regions by H-NS and Lrp.
LtrR is a LysR-type regulator involved in the positive expression of to promote and expression. This regulatory network is fundamental for the control of bacterial transformation and resistance to the bile salt sodium deoxycholate in serovar Typhi. In this work, the transcriptional regulation of was characterized, revealing that the use of alternative promoters results in two transcripts. The larger one, the mRNA, was repressed at promoter and coding regions by H-NS, whereas Lrp repressed its expression at the coding region. In the case of the second and shorter transcript, it was repressed only at the coding region by H-NS and Lrp. Remarkably, pH 7.5 is a positive signal involved in the transcriptional expression of both units. Translational fusions and Western blot experiments demonstrated that and mRNAs encode the LtrR2 and LtrR1 proteins. This study adds new data on the complex genetic and regulatory characteristics of one of the most predominant types of transcriptional factors in bacteria, the LysR-type transcriptional regulators. The LysR-type transcriptional regulators are present in viruses, archaea, bacteria, and eukaryotic cells. Furthermore, these proteins are the most abundant transcriptional factors in bacteria. Here, we demonstrate that two LysR-type proteins are generated from the gene. These proteins are genetically induced by pH and repressed at the promoter and coding regions by the global regulators H-NS and Lrp. Thus, novel basic aspects of the complex genetic regulation of the LysR-type transcriptional regulators are described.
Topics: Alkalies; Bacterial Proteins; DNA-Binding Proteins; Gene Expression Regulation, Bacterial; Hydrogen-Ion Concentration; Operon; Promoter Regions, Genetic; Salmonella typhi; Transcription Factors
PubMed: 32284321
DOI: 10.1128/JB.00783-19 -
BMC Microbiology Jan 2023Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor...
Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses.
Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor hygienic environments. To find novel therapeutic targets and inhibitors, We employed a subtractive genomics strategy towards Salmonella Typhi and the complete genomes of eight strains were primarily subjected to the EDGAR tool to predict the core genome (n = 3207). Human non-homology (n = 2450) was followed by essential genes identification (n = 37). The STRING database predicted maximum protein-protein interactions, followed by cellular localization. The virulent/immunogenic ability of predicted genes were checked to differentiate drug and vaccine targets. Furthermore, the 3D models of the identified putative proteins encoded by the respective genes were constructed and subjected to druggability analyses where only "highly druggable" proteins were selected for molecular docking and simulation analyses. The putative targets ATP-dependent CLP protease proteolytic subunit, Imidazole glycerol phosphate synthase hisH, 7,8-dihydropteroate synthase folP and 2,3-bisphosphoglycerate-independent phosphoglycerate mutase gpmI were screened against a drug-like library (n = 12,000) and top hits were selected based on H-bonds, RMSD and energy scores. Finally, the ADMET properties for novel inhibitors ZINC19340748, ZINC09319798, ZINC00494142, ZINC32918650 were optimized followed by binding free energy (MM/PBSA) calculation for ligand-receptor complexes. The findings of this work are expected to aid in expediting the identification of novel protein targets and inhibitors in combating typhoid Salmonellosis, in addition to the already existing therapies.
Topics: Humans; Anti-Bacterial Agents; Endopeptidase Clp; Genomics; Molecular Docking Simulation; Salmonella typhi; Typhoid Fever
PubMed: 36681806
DOI: 10.1186/s12866-023-02756-6 -
Frontiers in Immunology 2019infections remain a challenging health issue, causing significant morbidity and mortality worldwide. Current vaccines against typhoid fever display moderate efficacy...
infections remain a challenging health issue, causing significant morbidity and mortality worldwide. Current vaccines against typhoid fever display moderate efficacy whilst no licensed vaccines are available for paratyphoid fever or invasive non-typhoidal salmonellosis. Therefore, there is an urgent need to develop high efficacy broad-spectrum vaccines that can protect against typhoidal and non-typhoidal . The outer membrane porins OmpC and OmpF, have been shown to be highly immunogenic antigens, efficiently eliciting protective antibody, and cellular immunity. Furthermore, enterobacterial porins, particularly the OmpC, have a high degree of homology in terms of sequence and structure, thus making them a suitable vaccine candidate. However, the degree of the amino acid conservation of OmpC among typhoidal and non-typhoidal serovars is currently unknown. Here we used a bioinformatical analysis to classify the typhoidal and non-typhoidal OmpC amino acid sequences into different clades independently of their serological classification. Further, our analysis determined that the porin OmpC contains various amino acid sequences that are highly conserved among both typhoidal and non-typhoidal serovars. Critically, some of these highly conserved sequences were located in the transmembrane β-sheet within the porin β-barrel and have immunogenic potential for binding to MHC-II molecules, making them suitable candidates for a broad-spectrum vaccine. Collectively, these findings suggest that these highly conserved sequences may be used for the rational design of an effective broad-spectrum vaccine against .
Topics: Amino Acid Sequence; Bacterial Proteins; Conserved Sequence; Humans; Phylogeny; Porins; Protein Conformation, alpha-Helical; Salmonella; Salmonella Infections; Salmonella typhi; Sequence Alignment; Typhoid Fever
PubMed: 31998292
DOI: 10.3389/fimmu.2019.02966 -
Genes Nov 2020Typhoid fever, caused by serovar Typhi ( Typhi), is a global health concern and its treatment is problematic due to the rise in antimicrobial resistance (AMR). Rapid...
Typhoid fever, caused by serovar Typhi ( Typhi), is a global health concern and its treatment is problematic due to the rise in antimicrobial resistance (AMR). Rapid detection of patients infected with AMR positive Typhi is, therefore, crucial to prevent further spreading. lustered egularly nterspaced hort alindromic epeats and CRISPR-associated genes (CRISPR-Cas), is an adaptive immune system that initially was used for typing purposes. Later, it was discovered to play a role in defense against phages and plasmids, including ones that carry AMR genes, and, at present, it is being explored for its usage in diagnostics. Despite the availability of whole-genome sequences (WGS), very few studied the CRISPR-Cas system of Typhi, let alone in typing purposes or relation to AMR. In the present study, we analyzed the CRISPR-Cas system of Typhi using WGS data of 1059 isolates obtained from Bangladesh, India, Nepal, and Pakistan in combination with demographic data and AMR status. Our results reveal that the Typhi CRISPR loci can be classified into two groups: A (evidence level >2) and B (evidence level ≤2), in which we identified a total of 47 unique spacers and 15 unique direct repeats. Further analysis of the identified spacers and repeats demonstrated specific patterns that harbored significant associations with genotype, demographic characteristics, and AMR status, thus raising the possibility of their usage as biomarkers. Potential spacer targets were identified and, interestingly, the phage-targeting spacers belonged to the group-A and plasmid-targeting spacers to the group-B CRISPR loci. Further analyses of the spacer targets led to the identification of an Typhi protospacer adjacent motif (PAM) sequence, TTTCA/T. New -genes known as , , and were also discovered in the Typhi genome. However, a specific variant of the gene was only identified in the extensively drug-resistant (XDR) lineage from Pakistan and ciprofloxacin-resistant lineage from Bangladesh. From this work, we conclude that there are strong correlations between variations identified in the Typhi CRISPR-Cas system and endemic AMR positive Typhi isolates.
Topics: Bangladesh; CRISPR-Cas Systems; Drug Resistance, Bacterial; Genetic Variation; Genome, Bacterial; Humans; India; Nepal; Pakistan; Salmonella typhi; Typhoid Fever
PubMed: 33218076
DOI: 10.3390/genes11111365