Cause Of Typhoid Fever Research Articles

Salmonella enterica Serovar Typhi Induces Host Metabolic Reprogramming to Increase Glucose Availability for Intracellular Replication.

Salmonella enterica serovar Typhi (S. Typhi) is a human-limited intracellular pathogen and the cause of typhoid fever, a severe systemic disease. Pathogen–host interaction at the metabolic level affects the pathogenicity of intracellular pathogens, but it remains unclear how S. Typhi infection influences host metabolism for its own benefit. Herein, using metabolomics and transcriptomics analyses, combined with in vitro and in vivo infection assays, we investigated metabolic responses in human macrophages during S. Typhi infection, and the impact of these responses on S. Typhi intracellular replication and systemic pathogenicity. We observed increased glucose content, higher rates of glucose uptake and glycolysis, and decreased oxidative phosphorylation in S. Typhi-infected human primary macrophages. Replication in human macrophages and the bacterial burden in systemic organs of humanized mice were reduced by either the inhibition of host glucose uptake or a mutation of the bacterial glucose uptake system, indicating that S. Typhi utilizes host-derived glucose to enhance intracellular replication and virulence. Thus, S. Typhi promotes its pathogenicity by inducing metabolic changes in host macrophages and utilizing the glucose that subsequently accumulates as a nutrient for intracellular replication. Our findings provide the first metabolic signature of S. Typhi-infected host cells and identifies a new strategy utilized by S. Typhi for intracellular replication.

Comparison of different tests for the diagnosis of Salmonella typhi in Nineveh Governorate

Salmonella typhi is one of the most common causes of typhoid fever in Iraq. The aim of this study was to test the synergistic between different tests for the diagnosis of S. typhi . It was found, there are ability for preparing local Media which can be used instead of Blood agar for diagnosing typhoid fever by using dates, alfalfa and fish extractors. Both fish and dates extractors were used to prepare a local medium as well as alfalfa and fish. The results showed that dates - fish medium are more efficient than blood agar and alfalfa - fish medium to isolate S. typhi. When contrasting culture results with Widal test data of laboratories , it had shown differences in these results because only (57)% from Widal test was confirmed by culture. When Widal test results were evaluated which is done in different health analysing laboratories in Nineveh Governorate by using Widal test (dilution method) the results showed great differences of results whether result type (positive or negative) or kind of antigens which showed positive results. Leukocyte count was done as a test to enhance the diagnosis of this microbe, it was clear that there is a relation between typhoid fever and decreasing white blood cell count.

Study of Typhoid Fever: A Review

Salmonella typhi and Salmonella paratyphi, all members of the Enterobacteriaceae family, are the primary causes of typhoid fever. Salmonella enterica serovar and enteritidis are isolated by multiplex quantitative polymerase chain reaction PCR after detailed study. Salmonella nontyphoidal (NTS) is most frequent in infants, although the majority of cases are limited to gastroenteritis. Salmonella is spread by polluted water, raw food, and large groups of sick people, and is most prevalent in heavily populated cities, civil disorder, and inadequate sanitation. It can only be passed from one sick individual to another and humans are the only ones that can spread it. Chickens, milk, and uncommon tortoises are the most common causes of salmonella. The Patients went directly to the Observed Treatment in the Dept. of Medicine, at DMMC, SMHRC Nagpur. Enteric fever is still a major public health concern around the world, particularly in developing countries. Typhoid cases in cities are estimated to be about 800-900 per year, according to studies. While inexpensive and widely available, the Widal exam should be used with caution. Massive public awareness campaigns should be undertaken to inform citizens about the importance of taking preventative measures, vaccines, and seeing a doctor, among other items. Doctors should be aware of the emergence of newer antibacterial agents that are both safe and reliable, as well as the gradual development of antibiotic resistance. Aside from that, the discipline should anticipate newer curative and preventative interventions.

Mechanisms of typhoid toxin neutralization by antibodies targeting glycan receptor binding and nuclease subunits

SummaryNearly all clinical isolates of Salmonella Typhi, the cause of typhoid fever, are antibiotic resistant. All S. Typhi isolates secrete an A2B5 exotoxin called typhoid toxin to benefit the pathogen during infection. Here, we demonstrate that antibiotic-resistant S. Typhi secretes typhoid toxin continuously during infection regardless of antibiotic treatment. We characterize typhoid toxin antibodies targeting glycan-receptor-binding PltB or nuclease CdtB, which neutralize typhoid toxin in vitro and in vivo, as demonstrated by using typhoid toxin secreted by antibiotic-resistant S. Typhi during human cell infection and lethal dose typhoid toxin challenge to mice. TyTx11 generated in this study neutralizes typhoid toxin effectively, comparable to TyTx4 that binds to all PltB subunits available per holotoxin. Cryoelectron microscopy explains that the binding of TyTx11 to CdtB makes this subunit inactive through CdtB catalytic-site conformational change. The identified toxin-neutralizing epitopes are conserved across all S. Typhi clinical isolates, offering critical insights into typhoid toxin-neutralizing strategies.

Mechanisms of Typhoid Toxin Neutralization by Antibodies Targeting Receptor-Binding and Nuclease Subunits

Nearly all clinical isolates of Salmonella Typhi, the cause of typhoid fever, are antibiotic-resistant. All S. Typhi isolates secrete an A2B5 exotoxin called typhoid toxin to benefit the pathogen during infection. Here, we demonstrate that antibiotic-resistant S. Typhi secretes typhoid toxin continuously during infection regardless of antibiotic treatment. Typhoid toxin neutralizing antibodies (nAbs) generated in this study target receptor-binding PltB or nuclease CdtB. All nAbs neutralize typhoid toxin in vitro and in vivo, as demonstrated by using typhoid toxin secreted by antibiotic-resistant S. Typhi during human cell infection and lethal-dose typhoid toxin challenge to mice. Cryo-EM analyses explain the mechanisms of how two nAbs, TyTx4 and TyTx11, are more productive; TyTx4 binds to all PltB subunits available per holotoxin, while TyTx11 makes CdtB inactive through CdtB catalytic-site conformational change. The identified toxin neutralizing epitopes are conserved across all S. Typhi clinical isolates, offering critical insights into typhoid toxin neutralizing strategies.

Transcutaneous Vaccination with Conjugate Typhoid Vaccine Vi-DT Induces Systemic, Mucosal, and Memory Anti-Polysaccharide Responses.

.Transcutaneous vaccination can induce both mucosal and systemic immune responses. However, there are few data on anti-polysaccharide responses following transcutaneous vaccination of polysaccharides, despite the role that anti-polysaccharide responses play in protecting against intestinal mucosal and respiratory pathogens. Whether transcutaneous vaccination with a conjugate polysaccharide vaccine would be able to induce memory responses is also unknown. To address this, we transcutaneously vaccinated mice with virulence antigen (Vi) polysaccharide of Salmonella enterica serovar Typhi (the cause of typhoid fever), either in unconjugated or conjugated form (the latter as a Vi-DT conjugate). We also assessed the ability of the immunoadjuvant cholera toxin to impact responses following vaccination. We found that presenting Vi in a conjugate versus nonconjugate form transcutaneously resulted in comparable serum IgG responses but higher serum and lamina propria lymphocyte IgA anti-Vi responses, as well as increased IgG memory responses. The addition of immunoadjuvant did not further increase these responses; however, it boosted fecal IgA and serum IgG anti-Vi responses. Our results suggest that transcutaneous vaccination of a conjugate vaccine can induce systemic as well as enhanced mucosal and memory B-cell anti-polysaccharide responses.

Molecular and Bacteriological Method for Identification of Lactose Fermenting Salmonella in Mosul Province

The genus Salmonella consists of more than 2570 antigenic types. Salmonella Paratyphi A, B, C and Salmonella typhi are known to be non-lactose fermenters and the cause of typhoid fever.

Hubungan Kualitas Air Minum dan Kebiasaan Makan/Minum di Luar Rumah dengan Terjadinya Demam Tifoid pada Pasien Rawat Inap di RSUD Kota Kendari

ABSTRACT Background: Typhoid fever is a disease which arouse from the infection from Salmonella Typhi superbug through either the contaminated food or drink.It is recorded in 2016, Typhoid fever belongs to the highest ten contagious diseases in Southeast Sulawesi and comes in fifth with the cases of 4.641 sufferers. Purpose: This research study is aimed to know the bearing of quality of water, source of hygienic water and outdoor eating/drinking habit and the cause of typhoid fever to inpatients at Regional General Hospital in Kendari. Method: This research is an observational- descriptive study with a cross sectional design. 38 people of all the inpatients who had more than three days fever were used to be the total of sampling of this research. The instrument of this study is in the form of questioner. The Chi-square trial formula at significant rates (α = 0.05) was used in this research to analyze the data. Result: It is found that out of the 38 respondents, those who measure up for the quality of water are 16 respondents while who do not are 22 respondents with the value of (p=0,544). Meanwhile, there are 20 respondents of good outdoor eating or drinking habit and 18 respondents of the bad one with the value of (p=0,049).Keyword: typhoid fever, outdoor eating/drinking habit, quality of water

Alternate subunit assembly diversifies the function of a bacterial toxin

Bacterial toxins with an AB5 architecture consist of an active (A) subunit inserted into a ring-like platform comprised of five delivery (B) subunits. Salmonella Typhi, the cause of typhoid fever, produces an unusual A2B5 toxin known as typhoid toxin. Here, we report that upon infection of human cells, S. Typhi produces two forms of typhoid toxin that have distinct delivery components but share common active subunits. The two typhoid toxins exhibit different trafficking properties, elicit different effects when administered to laboratory animals, and are expressed using different regulatory mechanisms and in response to distinct metabolic cues. Collectively, these results indicate that the evolution of two typhoid toxin variants has conferred functional versatility to this virulence factor. More broadly, this study reveals a new paradigm in toxin biology and suggests that the evolutionary expansion of AB5 toxins was likely fueled by the plasticity inherent to their structural design coupled to the functional versatility afforded by the combination of homologous toxin components.

Unique features in the intracellular transport of typhoid toxin revealed by a genome-wide screen.

Typhoid toxin is a virulence factor for Salmonella Typhi and Paratyphi, the cause of typhoid fever in humans. This toxin has a unique architecture in that its pentameric B subunit, made of PltB, is linked to two enzymatic A subunits, the ADP ribosyl transferase PltA and the deoxyribonuclease CdtB. Typhoid toxin is uniquely adapted to humans, recognizing surface glycoprotein sialoglycans terminated in acetyl neuraminic acid, which are preferentially expressed by human cells. The transport pathway to its cellular targets followed by typhoid toxin after receptor binding is currently unknown. Through a genome-wide CRISPR/Cas9-mediated screen we have characterized the mechanisms by which typhoid toxin is transported within human cells. We found that typhoid toxin hijacks specific elements of the retrograde transport and endoplasmic reticulum-associated degradation machineries to reach its subcellular destination within target cells. Our study reveals unique and common features in the transport mechanisms of bacterial toxins that could serve as the bases for the development of novel anti-toxin therapeutic strategies.

Bacterial aetiology and antimicrobial resistance pattern in culture positive enteric fever in a private hospital in Sri Lanka

There is a paucity of information on enteric fever in Sri Lanka. This laboratory-based study aimed to identify the causative agent and demographic profile of patients with blood culture confirmed enteric fever at a private hospital in Colombo between February 2011 and November 2012. There were 100 isolates, S. Paratyphi A (n=92) and S. Typhi (n=8). Eighty-three patients were below 40 years. Antimicrobial resistance was seen to ciprofloxacin and azithromycin. If the emergence of S. Paratyphi A as an important cause of enteric fever is confirmed by further studies, the development of a bivalent vaccine effective against both typhoid and paratyphoid fever will be required for prevention of enteric fever.

Progress in Typhoid Fever Epidemiology.

Salmonella enterica subspecies enterica serovar Typhi (Salmonella Typhi) is the cause of typhoid fever and a human host–restricted organism. Our understanding of the global burden of typhoid fever has improved in recent decades, with both an increase in the number and geographic representation of high-quality typhoid fever incidence studies, and greater sophistication of modeling approaches. The 2017 World Health Organization Strategic Advisory Group of Experts on Immunization recommendation for the introduction of typhoid conjugate vaccines for infants and children aged >6 months in typhoid-endemic countries is likely to require further improvements in our understanding of typhoid burden at the global and national levels. Furthermore, the recognition of the critical and synergistic role of water and sanitation improvements in concert with vaccine introduction emphasize the importance of improving our understanding of the sources, patterns, and modes of transmission of Salmonella Typhi in diverse settings.

Pengaruh Kombinasi Ekstrak Pahit Pare (Momordica charantia) dan Sapodilla (Manilkara zapota) terhadap Pertumbuhan Bakteri Salmonella typhi dengan Menggunakan InVivo pada Tikus Kecil Usus

Salmonella typhi bacteria is a main cause of typhoid fever. The fever can be healed by using medical and traditional way. Bitter melon plantand Sapodilla have a lot of active compound, having potential as antimicroba as like salmonella typhi. The problem of this research is to find out whether the extract combination of bitter melon and sapodillais effective in inhibitingthe growing of Salmonella typhi in mice small intestine. Thisresearch aims to determine inhibitory concentration in the growing of Salmonella typhi in mice small intestine. 
 This researchused experimental design with post test group. This research used experimental animals that is mice which is given Salmonella typhi and is given the extract of bitter melon and sapodilla in different kinds of concentration with sonde. The measurement of bacteria is first by taking small intestine mucosa and put it SSA media. Then, it is being identified and accounted. After that, the data result is being tested by ANOVA with the data requirement that is normally distributed and homogeneous by using SPSS with α=0.05
 The research result shows that there is 300 groups in positive control, while on the other way there is no groups found, except in 100% bitter melon group of seven bacteria groups. After being tested, the data shows that the score is not normal (sig. 0.000 < α =0.005). As the result, the data is being tested by using non parametric test and Kruskal-wallis test. Lastly, the test result shows there is a significant difference among treatment groups (sig. 0.013 < α =0.05)
 This research concludes that the combination extract of bitter melon and sapodilla effectively can inhibit the growing of Salmonella typhi by using in vivo in the mice small intestine.

Virulotyping of Salmonella enterica serovar Typhi isolates from Pakistan: Absence of complete SPI-10 in Vi negative isolates.

The pathogenesis of Salmonella enterica serovar Typhi (S. Typhi), the cause of typhoid fever in humans, is mainly attributed to the acquisition of horizontally acquired DNA elements. Salmonella pathogenicity islands (SPIs) are indubitably the most important form of horizontally acquired DNA with respect to pathogenesis of this bacterium. The insertion or deletion of any of these transferrable SPIs may have impact on the virulence potential of S. Typhi. In this study, the virulence potential and genetic relatedness of 35 S. Typhi isolates, collected from 2004 to 2013 was determined by identification of SPI and non-SPI virulence factors through a combination of techniques including virulotyping, Whole Genome Sequencing (WGS), and Variable Number of Tandem Repeats (VNTR) profiling. In order to determine the virulence potential of local S. Typhi isolates, 56 virulence related genes were studied by PCR. These genes are located in the core as well as accessory genome (SPIs and plasmid). Major variations among studied virulence determinants were found in case of SPI-7 and SPI-10 associated genes. On the basis of presence of virulence related genes, the studied S. Typhi isolates from Pakistan were clustered into two virulotypes Vi-positive and Vi-negative. Interestingly, SPI-7 and SPI-10 were collectively absent or present in Vi-negative and Vi-positive strains, respectively. Two Vi-negative and 11 Vi-positive S. Typhi strains were also analyzed by whole genome sequencing (WGS) and their results supported the PCR results. Genetic diversity was tested by VNTR-based molecular typing. All 35 isolates were clustered into five groups. Overall, all Vi-negative isolates were placed in a single group (T5) whereas Vi-positive isolates were grouped into four types. Vi-negative and Vi-positive isolates were mutually exclusive. This is the first report on the comparative distribution of SPI and non-SPI related virulence genes in Vi-negative and Vi-positive S. Typhi isolates with an important finding that SPI-10 is absent in all Vi-negative isolates.

Improving Our Understanding of Salmonella enterica Serovar Paratyphi B through the Engineering and Testing of a Live Attenuated Vaccine Strain.

Enteric fever is caused by three Salmonella enterica serovars: Typhi, Paratyphi A, and Paratyphi B sensu stricto Although vaccines against two of these serovars are licensed (Typhi) or in clinical development (Paratyphi A), as yet there are no candidates for S. Paratyphi B. To gain genomic insight into these serovars, we sequenced 38 enteric fever-associated strains from Chile and compared these with reference genomes. Each of the serovars was separated genomically based on the core genome. Genomic comparisons identified loci that were aberrant between serovars Paratyphi B sensu stricto and Paratyphi B Java, which is typically associated with gastroenteritis; however, the majority of these were annotated as hypothetical or phage related and thus were not ideal vaccine candidates. With the genomic information in hand, we engineered a live attenuated S. Paratyphi B sensu stricto vaccine strain, CVD 2005, which was capable of protecting mice from both homologous challenge and heterologous challenge with S. Paratyphi B Java. These findings extend our understanding of S. Paratyphi B and provide a viable vaccine option for inclusion in a trivalent live attenuated enteric fever vaccine formulation.IMPORTANCE We developed a live attenuated Salmonella enterica serovar Paratyphi B vaccine that conferred protection in mice against challenge with S Paratyphi B sensu stricto and S Paratyphi B Java, which are the causes of enteric fever and gastroenteritis, respectively. Currently, the incidence of invasive S. Paratyphi B sensu stricto infections is low; however, the development of new conjugate vaccines against other enteric fever serovars could lead to the emergence of S. Paratyphi B to fill the niche left by these other pathogens. As such, an effective S. Paratyphi B vaccine would be a useful tool in the armamentarium against Salmonella infections. Comparative genomics confirmed the serovar-specific groupings of these isolates and revealed that there are a limited number of genetic differences between the sensu stricto and Java strains, which are mostly hypothetical and phage-encoded proteins. The observed level of genomic similarity likely explains why we observe some cross-protection.

Salmonella enterica genomes from victims of a major sixteenth-century epidemic in Mexico.

Indigenous populations of the Americas experienced high mortality rates during the early contact period as a result of infectious diseases, many of which were introduced by Europeans. Most of the pathogenic agents that caused these outbreaks remain unknown. Through the introduction of a new metagenomic analysis tool called MALT, applied here to search for traces of ancient pathogen DNA, we were able to identify Salmonella enterica in individuals buried in an early contact era epidemic cemetery at Teposcolula-Yucundaa, Oaxaca in southern Mexico. This cemetery is linked, based on historical and archaeological evidence, to the 1545-1550 CE epidemic that affected large parts of Mexico. Locally, this epidemic was known as 'cocoliztli', the pathogenic cause of which has been debated for more than a century. Here, we present genome-wide data from ten individuals for Salmonella enterica subsp. enterica serovar Paratyphi C, a bacterial cause of enteric fever. We propose that S. Paratyphi C be considered a strong candidate for the epidemic population decline during the 1545 cocoliztli outbreak at Teposcolula-Yucundaa.

Decoding a Salmonella Typhi Regulatory Network that Controls Typhoid Toxin Expression within Human Cells

Salmonella Typhi is the cause of typhoid fever, a major global health concern. An essential virulence factor of this pathogen is typhoid toxin. In contrast to most AB-type toxins, typhoid toxin is exclusively expressed by intracellular bacteria. The regulatory networks that ensure this unique gene expression pattern are unknown. Here, we developed FAST-INSeq,a genome-wide screening approach to identify S. Typhi genes required for typhoid toxin expression within infected cells. We find that typhoid toxin expression is controlled by a silencing and counter-silencing mechanism through the opposing actions of the PhoP/PhoQ two-component regulatory system and the histone-like protein H-NS. The screen also identified bacterial mutants that alter the proportion of intracellular S. Typhi that reside withinan intravacuolar environment, which was essentialfor toxin expression. Collectively, these data describe a regulatory mechanism that allows a bacterial pathogen to exclusively express a virulence factor when located within a specific intracellular compartment.

In vivo tropism of Salmonella Typhi toxin to cells expressing a multiantennal glycan receptor.

Typhoid fever is a life-threatening disease, but little is known about the molecular bases for its unique clinical presentation. Typhoid toxin, a unique virulence factor of Salmonella Typhi (the cause of typhoid fever), recapitulates in an animal model many symptoms of typhoid fever. Typhoid toxin binding to its glycan receptor Neu5Ac is central, but, due to the ubiquity of Neu5Ac, how typhoid toxin causes specific symptoms remains elusive. Here we show that typhoid toxin displays in vivo tropism to cells expressing multiantennal glycoprotein receptors, particularly on endothelial cells of arterioles in the brain and immune cells, which is in line with typhoid symptoms. Neu5Ac displayed by multiantennal N-glycans, rather than a single Neu5Ac, appears to serve as the high-affinity receptor, as typhoid toxin possesses five identical binding pockets per toxin. Human counterparts also express the multiantennal Neu5Ac receptor. Here we also show that mice immunized with inactive typhoid toxins and challenged with wild-type typhoid toxin presented neither the characteristic in vivo tropism nor symptoms. These mice were protected against a lethal-dose toxin challenge, but Ty21a-vaccinated mice were not. Cumulatively, these results reveal remarkable features describing how a bacterial exotoxin induces virulence exclusively in specific cells at the organismal level.

Evolution of host adaptation in the Salmonella typhoid toxin.

The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host1–5. Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogen Salmonella Typhi6,7, the cause of typhoid fever in humans8–12. Typhoid toxin has a unique A2B5 architecture with two covalently linked enzymatic “A” subunits, PltA and CdtB, associated to a homopentameric “B” subunit made up of PltB, which has binding specificity for N-acetylneuraminic acid (Neu5Ac) sialoglycans6,13 predominantly present in humans14. Here we examined the functional and structural relationship between typhoid toxin and ArtAB, an evolutionarily related AB5 toxin encoded by the broad-host Salmonella Typhimurium15. We found that ArtA and ArtB, homologs of PltA and PltB, can form a functional complex with the typhoid toxin CdtB subunit after substitution of a single amino acid in ArtA, while ArtB can form a functional complex with wild type PltA and CdtB. We also found that after addition of a single terminal Cys residue, a CdtB homolog from cytolethal distending toxin can form a functional complex with ArtA and ArtB. In line with the broad host specificity of S. Typhimurium, we found that ArtB binds human glycans, terminated in N-acetylneuraminic acid, as well as glycans terminated in N-glycolylneuraminic acid (Neu5Gc), which are expressed in most other mammals14. The atomic structure of ArtB bound to its receptor shows the presence of an additional glycan-binding site, which broadens its binding specificity. Despite equivalent toxicity in vitro, we found that the ArtB/PltA/CdtB chimeric toxin exhibits reduced lethality in an animal model, indicating that the host specialization of typhoid toxin has optimized its targeting mechanisms to the human host. This is a remarkable example of toxin evolution to broaden its enzymatic activities and adapt to a specific host.

English

Enteric fever is an invasive life-threatening systemic disease caused by the Salmonella enterica human-adapted serovars typhi and paratyphi. Increased incidence of infection with S. enterica serovar paratyphi A poses a significant health concern in some areas of the world. In this study, the incidence of enteric fever confirmed by isolation of Salmonella paratypi A or S. typhi from blood cultures of patients presenting with clinical symptoms was 5.1%. Of the total isolates, 64.13% were S. paratyphi A, and 35.87% were Salmonella typhi. All isolates were susceptible to amoxicillin, ceftriaxone and cefixime. Conventional antibiotics (ampicillin, cloramphenicol and co-trimoxazole) showed 100% sensitivity rate towards S. paratyphi A and 96.9% towards S. typhi. Overall nalidixic acid-resistance (NAR) rate was extremely high (92.39%). Nalidixic acid resistant (MIC ≥ 32 µg/ml) S. paratyphi A showed increased MICs of the fluoroquinolone than nalidixic acid resistant S. typhi ranges from 0.125-8 µg/ml with ciprofloxacin and 0.25-4 µg/ml with levofloxacin and was statistically significant (p≤0.001). Immunization with currently available vaccines against typhoid fever does not provide cross protection against paratyphoid fever. This may contribute to the emergence of paratyphoid fever as the major cause of enteric fever in Nepal and possibly other geographical locations. Key words: Enteric fever, Salmonella paratyphi A, Salmonella typhi, fluoroquinolones (FQs), Nepal.