The Experts below are selected from a list of 45270 Experts worldwide ranked by ideXlab platform
Jorge E Galan - One of the best experts on this subject based on the ideXlab platform.
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Alternate subunit assembly diversifies the function of a bacterial toxin
Nature Communications, 2019Co-Authors: Casey C. Fowler, Gabrielle Stack, Xuyao Jiao, Maria Lara-tejero, Jorge E GalanAbstract:Bacterial toxins with an AB_5 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 A_2B_5 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 AB_5 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. Salmonella Typhi produces the Typhoid toxin. Here, Fowler et al. show that S . Typhi produces two forms of Typhoid toxin that are differentially regulated and display different trafficking properties and different effects when administered to laboratory animals.
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Unique features in the intracellular transport of Typhoid toxin revealed by a genome-wide screen
2019Co-Authors: Shu-jung Chang, Xuyao Jiao, Sheng Chih Jin, Jorge E GalanAbstract: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.
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Emerging insights into the biology of Typhoid toxin.
Current opinion in microbiology, 2017Co-Authors: Casey C. Fowler, Xiang Gao, Shu-jung Chang, Tobias Geiger, Gabrielle Stack, Jorge E GalanAbstract:Typhoid toxin is a unique A2B5 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.
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9 – Typhoid toxin
The Comprehensive Sourcebook of Bacterial Protein Toxins, 2015Co-Authors: Jorge E GalanAbstract:Typhoid toxin is a unique virulence factor of the Salmonella enterica serovars Typhi and Paratyphi, which are the cause of Typhoid fever, a life-threatening systemic disease in humans. Composed of two A subunits linked to a pentameric B subunit, Typhoid toxin is the only known toxin of its family with an A2B5 architecture. When administered to experimental animals, Typhoid toxin can replicate most of the symptoms of Typhoid fever, thus placing this toxin at the center of the pathogenesis of this very important disease. In addition, its unique receptor binding specificity with exquisite selectivity for human glycans provides an explanation for the mechanisms of host specificity of the Salmonella enterica serovars that cause Typhoid fever.
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host adaptation of a bacterial toxin from the human pathogen salmonella typhi
Cell, 2014Co-Authors: Lingquan Deng, Jeongmin Song, Jorge E Galan, Xiang Gao, Jiawei Wang, Xi Chen, Nissi Varki, Yuko Naitomatsui, Ajit VarkiAbstract:Salmonella Typhi is an exclusive human pathogen that causes Typhoid fever. Typhoid toxin is a S. Typhi virulence factor that can reproduce most of the Typhoid fever symptoms in experimental animals. Toxicity depends on toxin binding to terminally sialylated glycans on surface glycoproteins. Human glycans are unusual because of the lack of CMAH, which in other mammals converts N-acetylneuraminic acid (Neu5Ac) to N-glycolylneuraminic acid (Neu5Gc). Here, we report that Typhoid toxin binds to and is toxic toward cells expressing glycans terminated in Neu5Ac (expressed by humans) over glycans terminated in Neu5Gc (expressed by other mammals). Mice constitutively expressing CMAH thus displaying Neu5Gc in all tissues are resistant to Typhoid toxin. The atomic structure of Typhoid toxin bound to Neu5Ac reveals the structural bases for its binding specificity. These findings provide insight into the molecular bases for Salmonella Typhi’s host specificity and may help the development of therapies for Typhoid fever.
Ismail Aziah - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Salmonella Typhi antigen YncE alongside HlyE for the detection of Typhoid fever and its carriers
Medical Microbiology and Immunology, 2020Co-Authors: Freddy Franklin, Chun Wie Chong, Leong Huat Chua, Amy Amilda Anthony, Mervyn W. O. Liew, Ismail Aziah, Eugene Boon Beng OngAbstract:Typhoid fever is a disease caused by Salmonella Typhi that was implicated in millions of illnesses worldwide annually. Individuals that do not recover fully from Typhoid fever can become asymptomatic carriers of the disease. Host antibodies against the S . Typhi antigens, HlyE (for acute Typhoid) and YncE (for carriers) were previously reported to be useful biomarkers for the disease. Here, we expressed and purified recombinant HlyE and YncE antigens and tested the IgG, IgA and IgM responses in 422 sera samples retrieved from acute Typhoid patients, other febrile, food handlers, and healthy individuals. The results showed that HlyE-IgG, -IgA and -IgM ELISAs have a collective sensitivity of 83% while YncE-IgG and -IgA ELISAs identified 16 possible carriers based on their antibody profiles. The identification of sensitive biomarkers for Typhoid carrier detection is crucial for disease eradication.
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Evaluation of Salmonella Typhi antigen YncE alongside HlyE for the detection of Typhoid fever and its carriers
Medical Microbiology and Immunology, 2020Co-Authors: Freddy Franklin, Chun Wie Chong, Leong Huat Chua, Amy Amilda Anthony, Mervyn W. O. Liew, Ismail AziahAbstract:Typhoid fever is a disease caused by Salmonella Typhi that was implicated in millions of illnesses worldwide annually. Individuals that do not recover fully from Typhoid fever can become asymptomatic carriers of the disease. Host antibodies against the S . Typhi antigens, HlyE (for acute Typhoid) and YncE (for carriers) were previously reported to be useful biomarkers for the disease. Here, we expressed and purified recombinant HlyE and YncE antigens and tested the IgG, IgA and IgM responses in 422 sera samples retrieved from acute Typhoid patients, other febrile, food handlers, and healthy individuals. The results showed that HlyE-IgG, -IgA and -IgM ELISAs have a collective sensitivity of 83% while YncE-IgG and -IgA ELISAs identified 16 possible carriers based on their antibody profiles. The identification of sensitive biomarkers for Typhoid carrier detection is crucial for disease eradication.
Freddy Franklin - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Salmonella Typhi antigen YncE alongside HlyE for the detection of Typhoid fever and its carriers
Medical Microbiology and Immunology, 2020Co-Authors: Freddy Franklin, Chun Wie Chong, Leong Huat Chua, Amy Amilda Anthony, Mervyn W. O. Liew, Ismail Aziah, Eugene Boon Beng OngAbstract:Typhoid fever is a disease caused by Salmonella Typhi that was implicated in millions of illnesses worldwide annually. Individuals that do not recover fully from Typhoid fever can become asymptomatic carriers of the disease. Host antibodies against the S . Typhi antigens, HlyE (for acute Typhoid) and YncE (for carriers) were previously reported to be useful biomarkers for the disease. Here, we expressed and purified recombinant HlyE and YncE antigens and tested the IgG, IgA and IgM responses in 422 sera samples retrieved from acute Typhoid patients, other febrile, food handlers, and healthy individuals. The results showed that HlyE-IgG, -IgA and -IgM ELISAs have a collective sensitivity of 83% while YncE-IgG and -IgA ELISAs identified 16 possible carriers based on their antibody profiles. The identification of sensitive biomarkers for Typhoid carrier detection is crucial for disease eradication.
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Evaluation of Salmonella Typhi antigen YncE alongside HlyE for the detection of Typhoid fever and its carriers
Medical Microbiology and Immunology, 2020Co-Authors: Freddy Franklin, Chun Wie Chong, Leong Huat Chua, Amy Amilda Anthony, Mervyn W. O. Liew, Ismail AziahAbstract:Typhoid fever is a disease caused by Salmonella Typhi that was implicated in millions of illnesses worldwide annually. Individuals that do not recover fully from Typhoid fever can become asymptomatic carriers of the disease. Host antibodies against the S . Typhi antigens, HlyE (for acute Typhoid) and YncE (for carriers) were previously reported to be useful biomarkers for the disease. Here, we expressed and purified recombinant HlyE and YncE antigens and tested the IgG, IgA and IgM responses in 422 sera samples retrieved from acute Typhoid patients, other febrile, food handlers, and healthy individuals. The results showed that HlyE-IgG, -IgA and -IgM ELISAs have a collective sensitivity of 83% while YncE-IgG and -IgA ELISAs identified 16 possible carriers based on their antibody profiles. The identification of sensitive biomarkers for Typhoid carrier detection is crucial for disease eradication.
Jeongmin Song - One of the best experts on this subject based on the ideXlab platform.
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In vivo tropism of Salmonella Typhi toxin to cells expressing a multiantennal glycan receptor
Nature Microbiology, 2018Co-Authors: Yi-an Yang, Lingquan Deng, Jun Zhao, Andrew J. Thompson, Ryan Mcbride, Buyankhishig Tsogtbaatar, James C. Paulson, Ruth Nussinov, Jeongmin SongAbstract: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. Multiantennal glycan receptors associated with in vivo tropism of Salmonella Typhi Typhoid toxin.
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host adaptation of a bacterial toxin from the human pathogen salmonella typhi
Cell, 2014Co-Authors: Lingquan Deng, Jeongmin Song, Jorge E Galan, Xiang Gao, Jiawei Wang, Xi Chen, Nissi Varki, Yuko Naitomatsui, Ajit VarkiAbstract:Salmonella Typhi is an exclusive human pathogen that causes Typhoid fever. Typhoid toxin is a S. Typhi virulence factor that can reproduce most of the Typhoid fever symptoms in experimental animals. Toxicity depends on toxin binding to terminally sialylated glycans on surface glycoproteins. Human glycans are unusual because of the lack of CMAH, which in other mammals converts N-acetylneuraminic acid (Neu5Ac) to N-glycolylneuraminic acid (Neu5Gc). Here, we report that Typhoid toxin binds to and is toxic toward cells expressing glycans terminated in Neu5Ac (expressed by humans) over glycans terminated in Neu5Gc (expressed by other mammals). Mice constitutively expressing CMAH thus displaying Neu5Gc in all tissues are resistant to Typhoid toxin. The atomic structure of Typhoid toxin bound to Neu5Ac reveals the structural bases for its binding specificity. These findings provide insight into the molecular bases for Salmonella Typhi’s host specificity and may help the development of therapies for Typhoid fever.
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Structure and function of the Salmonella Typhi chimaeric A_2B_5 Typhoid toxin
Nature, 2013Co-Authors: Jeongmin Song, Jorge E GalanAbstract:The biological basis for the pathogenic properties of Salmonella enterica serovar Typhi ( S . Typhi) is largely unknown. S . Typhi causes life-threatening systemic infections known as Typhoid fever, whereas most other Salmonella enterica serotypes are either harmless or associated with less-serious gastric infections or food poisoning. This study shows that administration of Typhoid toxin, a novel AB toxin composed of two A subunits unique to S . Typhi, reproduces many of the acute symptoms of Typhoid fever. The authors go on to identify carbohydrates on cell-surface glycoproteins as receptors for Typhoid toxin and determine the toxin's crystal structure, providing insights into these interactions. Theses advances suggest that antitoxin-based therapeutics may be effective in treating Typhoid. Unlike most salmonellae, Salmonella enterica serovar Typhi causes life-threatening systemic infections known as Typhoid fever, for which the molecular basis is unknown; here administration of Typhoid toxin produced by S. Typhi reproduces many of the acute symptoms of Typhoid fever, carbohydrates on cell surface glycoproteins are identified as receptors for Typhoid toxin and the toxin’s crystal structure is determined, providing insights into these interactions. Salmonella enterica serovar Typhi ( S. Typhi) differs from most other salmonellae in that it causes a life-threatening systemic infection known as Typhoid fever^ 1 . The molecular bases for its unique clinical presentation are unknown^ 2 . Here we find that the systemic administration of Typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of Typhoid fever in an animal model. We identify specific carbohydrate moieties on specific surface glycoproteins that serve as receptors for Typhoid toxin, which explains its broad cell target specificity. We present the atomic structure of Typhoid toxin, which shows an unprecedented A_2B_5 organization with two covalently linked A subunits non-covalently associated to a pentameric B subunit. The structure provides insight into the toxin’s receptor-binding specificity and delivery mechanisms and reveals how the activities of two powerful toxins have been co-opted into a single, unique toxin that can induce many of the symptoms characteristic of Typhoid fever. These findings may lead to the development of potentially life-saving therapeutics against Typhoid fever.
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structure and function of the salmonella typhi chimaeric a 2 b 5 Typhoid toxin
Nature, 2013Co-Authors: Jeongmin Song, Xiang Gao, Jorge E GalanAbstract:Salmonella enterica serovar Typhi (S. Typhi) differs from most other salmonellae in that it causes a life-threatening systemic infection known as Typhoid fever. The molecular bases for its unique clinical presentation are unknown. Here we find that the systemic administration of Typhoid toxin, a unique virulence factor of S. Typhi, reproduces many of the acute symptoms of Typhoid fever in an animal model. We identify specific carbohydrate moieties on specific surface glycoproteins that serve as receptors for Typhoid toxin, which explains its broad cell target specificity. We present the atomic structure of Typhoid toxin, which shows an unprecedented A2B5 organization with two covalently linked A subunits non-covalently associated to a pentameric B subunit. The structure provides insight into the toxin's receptor-binding specificity and delivery mechanisms and reveals how the activities of two powerful toxins have been co-opted into a single, unique toxin that can induce many of the symptoms characteristic of Typhoid fever. These findings may lead to the development of potentially life-saving therapeutics against Typhoid fever.
Jason R Andrews - One of the best experts on this subject based on the ideXlab platform.
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Typhoid conjugate vaccines a new tool in the fight against antimicrobial resistance
Lancet Infectious Diseases, 2019Co-Authors: Jason R Andrews, S Baker, Florian Marks, Marcella Alsan, Denise O Garrett, Bruce G Gellin, Samir K Saha, Farah Naz Qamar, Mohammad Tahir YousafzaiAbstract:Summary Typhoid fever is an acute systemic infectious disease responsible for an estimated 12–20 million illnesses and over 150 000 deaths annually. In March, 2018, a new recommendation was issued by WHO for the programmatic use of Typhoid conjugate vaccines in endemic countries. Health economic analyses of Typhoid vaccines have informed funding decisions and national policies regarding vaccine rollout. However, by focusing only on averted Typhoid cases and their associated costs, traditional cost-effectiveness analyses might underestimate crucial benefits of Typhoid vaccination programmes, because the potential effect of Typhoid vaccines on the treatment of patients with non-specific acute febrile illnesses is not considered. For every true case of Typhoid fever, three to 25 patients without Typhoid disease are treated with antimicrobials unnecessarily, conservatively amounting to more than 50 million prescriptions per year. Antimicrobials for suspected Typhoid might therefore be an important selective pressure for the emergence and spread of antimicrobial resistance globally. We propose that large-scale, more aggressive Typhoid vaccination programmes—including catch-up campaigns in children up to 15 years of age, and vaccination in lower incidence settings—have the potential to reduce the overuse of antimicrobials and thereby reduce antimicrobial resistance in many bacterial pathogens. Funding bodies and national governments must therefore consider the potential for broad reductions in antimicrobial use and resistance in decisions related to the rollout of Typhoid conjugate vaccines.
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comparison of strategies and incidence thresholds for vi conjugate vaccines against Typhoid fever a cost effectiveness modeling study
The Journal of Infectious Diseases, 2018Co-Authors: Ribhav Gupta, Denise O Garrett, Jeffrey D. Stanaway, Stephen P. Luby, Isaac I Bogoch, Jason R AndrewsAbstract:Background Typhoid fever remains a major public health problem globally. While new Vi conjugate vaccines hold promise for averting disease, the optimal programmatic delivery remains unclear. We aimed to identify the strategies and associated epidemiologic conditions under which Vi conjugate vaccines would be cost-effective. Methods We developed a dynamic, age-structured transmission and cost-effectiveness model that simulated multiple vaccination strategies with a Typhoid Vi conjugate vaccine from a societal perspective. We simulated 10-year vaccination programs with (1) routine immunization of infants (aged Results Vi conjugate Typhoid vaccines were highly cost-effective when administered by routine immunization activities through the EPI in settings with an annual incidence of >50 cases/100000 (95% uncertainty interval, 40-75 cases) and when administered through the EPI plus a catch-up campaign in settings with an annual incidence of >130 cases/100000 (95% uncertainty interval, 50-395 cases). The incidence threshold was sensitive to the Typhoid-related case-fatality rate, carrier contribution to transmission, vaccine characteristics, and country-specific economic threshold for cost-effectiveness. Conclusions Typhoid Vi conjugate vaccines would be highly cost-effective in low-income countries in settings of moderate Typhoid incidence (50 cases/100000 annually). These results were sensitive to case-fatality rates, underscoring the need to consider factors contributing to Typhoid mortality (eg, healthcare access and antimicrobial resistance) in the global vaccination strategy.
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extensively drug resistant Typhoid are conjugate vaccines arriving just in time
The New England Journal of Medicine, 2018Co-Authors: Jason R Andrews, Farah Naz Qamar, Richelle C Charles, Edward T RyanAbstract:Extensively Drug-Resistant Typhoid More than 1000 cases of XDR Salmonella Typhi have been confirmed in Pakistan. Until recently, vaccines against Typhoid have had limited efficacy and durability of immunogenicity, but an effective conjugate vaccine is now available to be used in Typhoid-control efforts.
