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MBio May 2024serovar Typhi and Paratyphi A are the cause of typhoid and paratyphoid fever in humans, which are systemic life-threatening illnesses. Both serovars are exclusively...
UNLABELLED
serovar Typhi and Paratyphi A are the cause of typhoid and paratyphoid fever in humans, which are systemic life-threatening illnesses. Both serovars are exclusively adapted to the human host, where they can cause life-long persistent infection. A distinct feature of these serovars is the presence of a relatively high number of degraded coding sequences coding for metabolic pathways, most likely a consequence of their adaptation to a single host. As a result of convergent evolution, these serovars shared many of the degraded coding sequences although often affecting different genes in the same metabolic pathway. However, there are several coding sequences that appear intact in one serovar while clearly degraded in the other, suggesting differences in their metabolic capabilities. Here, we examined the functionality of metabolic pathways that appear intact in . Typhi but that show clear signs of degradation in . Paratyphi A. We found that, in all cases, the existence of single amino acid substitutions in . Typhi metabolic enzymes, transporters, or transcription regulators resulted in the inactivation of these metabolic pathways. Thus, the inability of . Typhi to metabolize Glucose-6-Phosphate or 3-phosphoglyceric acid is due to the silencing of the expression of the genes encoding the transporters for these compounds due to point mutations in the transcriptional regulatory proteins. In contrast, its inability to utilize glucarate or galactarate is due to the presence of point mutations in the transporter and enzymes necessary for the metabolism of these sugars. These studies provide additional support for the concept of adaptive convergent evolution of these two human-adapted serovars and highlight a limitation of bioinformatic approaches to predict metabolic capabilities.
IMPORTANCE
serovar Typhi and Paratyphi A are the cause of typhoid and paratyphoid fever in humans, which are systemic life-threatening illnesses. Both serovars can only infect the human host, where they can cause life-long persistent infection. Because of their adaptation to the human host, these bacterial pathogens have changed their metabolism, leading to the loss of their ability to utilize certain nutrients. In this study we examined the functionality of metabolic pathways that appear intact in . Typhi but that show clear signs of degradation in . Paratyphi A. We found that, in all cases, the existence of single amino acid substitutions in . Typhi metabolic enzymes, transporters, or transcription regulators resulted in the inactivation of these metabolic pathways. These studies provide additional support for the concept of adaptive convergent evolution of these two human-adapted serovars.
Topics: Metabolic Networks and Pathways; Salmonella typhi; Humans; Genome, Bacterial; Salmonella paratyphi A; Loss of Function Mutation; Bacterial Proteins; Typhoid Fever; Serogroup
PubMed: 38572992
DOI: 10.1128/mbio.00607-24 -
Frontiers in Immunology 2024None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV and Typhim Vi) is in part...
None of the typhoid Vi Polysaccharide (ViPS) subunit vaccines incorporate adjuvants, and the immunogenicity of ViPS vaccines (e.g. Typbar TCV and Typhim Vi) is in part due to associated TLR4 ligands such as endotoxin present in these vaccines. Since endotoxin content in vaccines is variable and kept very low due to inherent toxicity, it was hypothesized that incorporating a defined amount of a non-toxic TLR4-ligand such as monophosphoryl lipid A in ViPS vaccines would improve their immunogenicity. To test this hypothesis, a monophosphoryl lipid A-based adjuvant formulation named Turbo was developed. Admixing Turbo with Typbar TCV (ViPS-conjugated to tetanus toxoid) increased the levels of anti-ViPS IgM, IgG1, IgG2b, IgG2a/c, and IgG3 in inbred and outbred mice. In infant mice, a single immunization with Turbo adjuvanted Typbar TCV resulted in a significantly increased and durable IgG response and improved the control of bacterial burden compared to mice immunized without Turbo. Similarly, when adjuvanted with Turbo, the antibody response and control of bacteremia were also improved in mice immunized with Typhim Vi, an unconjugated vaccine. The immunogenicity of unconjugated ViPS is inefficient in young mice and is lost in adult mice when immunostimulatory ligands in ViPS are removed. Nevertheless, when adjuvanted with Turbo, poorly immunogenic ViPS induced a robust IgG response in young and adult mice, and this was observed even under antigen-limiting conditions. These data suggest that incorporation of Turbo as an adjuvant will make typhoid vaccines more immunogenic regardless of their intrinsic immunogenicity or conjugation status and maximize the efficacy across all ages.
Topics: Animals; Typhoid-Paratyphoid Vaccines; Mice; Toll-Like Receptor 4; Vaccines, Subunit; Antibodies, Bacterial; Adjuvants, Immunologic; Lipid A; Typhoid Fever; Immunoglobulin G; Female; Ligands; Polysaccharides, Bacterial; Immunogenicity, Vaccine; Adjuvants, Vaccine; Salmonella typhi; Mice, Inbred BALB C
PubMed: 38799439
DOI: 10.3389/fimmu.2024.1383476 -
Vaccine Aug 2023This study aimed to evaluate the parental acceptance of Typhoid Conjugate Vaccine (TCV) and to determine the predictors of TCV vaccination status among children in an...
BACKGROUND
This study aimed to evaluate the parental acceptance of Typhoid Conjugate Vaccine (TCV) and to determine the predictors of TCV vaccination status among children in an outbreak setting of extensively drug resistant (XDR) typhoid fever in Karachi, Pakistan.
METHODS
A cross-sectional survey using the WHO recommended rapid vaccine coverage assessment technique was conducted. Out of 11, four union councils (UCs) in Lyari Town were randomly selected. A parent or primary caretaker from the eligible household was interviewed. Data were collected using a locally validated vaccine attitudes scale (VAS). Sum of scores was calculated for VAS. A higher score denoted negative attitudes and perceptions regarding TCV and vice versa. Multivariable logistic regression was performed to determine the predictors of TCV vaccination status.
RESULTS
Based on the 14-item parental VAS, 78.0 % of the parents had a score between 0 to <40 and 22 % had a score ≥40. VAS score of <40 was significantly associated with higher odds of receiving TCV during the campaign setting (adjusted Odds Ratio (aOR): 1.30; 95 % Confidence Interval (CI): 1.02, 1.66). The odds of receiving TCV vaccination were higher among children whose parents were aware of the ongoing vaccination campaign in the area (aOR: 4.57; 95 % CI: 2.93, 7.12) and expressed willingness to get their child vaccinated against typhoid fever (aOR: 2.54; 95 % CI: 1.82, 3.55).
CONCLUSION
Parental awareness of the ongoing vaccination campaign, positive perception and attitudes towards vaccine were found to be significantly associated with TCV vaccination among children. Appropriately structured pre-vaccination awareness campaigns focused on childhood vaccination targeted towards parents are necessary to improve parental awareness, attitude and behavior towards vaccination.
Topics: Humans; Child; Typhoid Fever; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines; Pakistan; Cross-Sectional Studies; Vaccination; Parents; Disease Outbreaks
PubMed: 37463829
DOI: 10.1016/j.vaccine.2023.07.003 -
BioRxiv : the Preprint Server For... Feb 2024serovar Typhi and Paratyphi A are the cause of typhoid and paratyphoid fever in humans, which are systemic life-threatening illnesses. Both serovars are exclusively...
serovar Typhi and Paratyphi A are the cause of typhoid and paratyphoid fever in humans, which are systemic life-threatening illnesses. Both serovars are exclusively adapted to the human host, where they can cause life-long persistent infection. A distinct feature of these serovars is the presence of a relatively high number of degraded coding sequences coding for metabolic pathways, most likely a consequence of their adaptation to a single host. As a result of convergent evolution, these serovars shared many of the degraded coding sequences although often affecting different genes in the same metabolic pathway. However, there are several coding sequences that appear intact in one serovar while clearly degraded in the other, suggesting differences in their metabolic capabilities. Here, we examined the functionality of metabolic pathways that appear intact in . Typhi but that show clear signs of degradation in . Paratyphi A. We found that, in all cases, the existence of single amino acid substitutions in Typhi metabolic enzymes, transporters, or transcription regulators resulted in the inactivation of these metabolic pathways. Thus, the inability of . Typhi to metabolize Glucose-6-Phosphate or 3-phosphoglyceric acid is due to the silencing of the expression of the genes encoding the transporters for these compounds due to point mutations in the transcriptional regulatory proteins. In contrast, its inability to utilize glucarate or galactarate is due to the presence of point mutations in the transporter and enzymes necessary for the metabolism of these sugars. These studies provide additional support for the concept of adaptive convergent evolution of these two human-adapted serovars and highlight a limitation of bioinformatic approaches to predict metabolic capabilities.
PubMed: 38405738
DOI: 10.1101/2024.02.14.580360 -
PloS One 2023To estimate the coverage rate of typhoid conjugate vaccine (TCV) among children aged 6 months to 15 years in Lyari Town Karachi, Pakistan.
OBJECTIVE
To estimate the coverage rate of typhoid conjugate vaccine (TCV) among children aged 6 months to 15 years in Lyari Town Karachi, Pakistan.
METHODS
A cross-sectional survey was conducted to estimate the vaccine coverage of Typbar TCV in Lyari Town Karachi utilizing the World Health Organization (WHO) recommended rapid vaccine coverage assessment technique (30 clusters × 7 households). Sampling was powered at town level and multistage cluster sampling was used. Four union councils were randomly selected from a total of 11 and the survey was conducted in those union councils. After consent was obtained, parents of age-eligible children living in the selected union councils were invited to participate in the survey and information was collected on Typbar TCV vaccination status of children aged 6 months to 15 years.
RESULTS
Overall, 2325 children were included in the survey. The mean age of the participants was 7.60 ± 3.84 years. The ratio of males to females was equal in the survey sample; 1163 (50.02%) were male. In the total target population, 82% children were found to be vaccinated; however, the vaccination status could be verified for 80%. The vaccine coverage of TCV was comparable among the four union councils and the overall coverage of TCV vaccine in Lyari Town was found to be 80%. The coverage was significantly lower in younger children, 5% and 17% among children aged 6 months to < 2 years and 2 years to < 5 years respectively and 78% among children aged 5 years to 15 years.
CONCLUSION
The overall immunization coverage rate with TCV was found to be satisfactory. Immunization coverage was comparable among both sexes and the selected union councils but it was relatively low among children in younger age groups.
Topics: Female; Humans; Male; Child; Infant; Child, Preschool; Typhoid Fever; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines; Pakistan; Cross-Sectional Studies; Poverty Areas
PubMed: 37549155
DOI: 10.1371/journal.pone.0289582 -
The Lancet. Global Health Apr 2024
Topics: Humans; Typhoid Fever; Vaccines, Conjugate; Typhoid-Paratyphoid Vaccines
PubMed: 38485415
DOI: 10.1016/S2214-109X(24)00055-X -
ImmunoHorizons Jan 2024Activation of B cells and T cells requires the engagement of costimulatory signaling pathways in addition to Ag receptor signaling for efficient immune responses. None...
Activation of B cells and T cells requires the engagement of costimulatory signaling pathways in addition to Ag receptor signaling for efficient immune responses. None of the typhoid Vi polysaccharide (ViPS) subunit vaccines contains adjuvants that could activate costimulatory signaling pathways, yet these vaccines are very immunogenic. I hypothesized that residual TLR ligands present in the ViPS preparation used for making typhoid subunit vaccines account for the robust immune response generated by these vaccines. I show the presence of endotoxin, a potent agonist of TLR4, in ViPS preparations and ViPS vaccines. Furthermore, I found that ViPS obtained from various sources induces the production of proinflammatory cytokines such as IL-6 from mouse peritoneal exudate cells. Unconjugated and tetanus toxoid-conjugated ViPS vaccines activate human and mouse TLR4. Mice deficient in TLR4 or the signaling adaptors MyD88 and Trif (Toll/IL-1R domain-containing adapter inducing IFN-β) are severely impaired in generating anti-ViPS responses to these vaccines. Elimination of the TLR4 agonist in ViPS preparation resulted in the loss of immunogenicity, and addition of lipid A, a known TLR4 agonist, restored the immunogenicity. These data highlight the importance of associated TLR ligands in the immunogenicity of ViPS subunit vaccines.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Adjuvants, Immunologic; B-Lymphocytes; Ligands; Toll-Like Receptor 4; Typhoid Fever; Typhoid-Paratyphoid Vaccines; Vaccines, Subunit; Immunogenicity, Vaccine
PubMed: 38180344
DOI: 10.4049/immunohorizons.2300085 -
The Lancet. Global Health Sep 2023
Topics: Humans; Typhoid-Paratyphoid Vaccines; Vaccines, Conjugate; Typhoid Fever; Vaccination
PubMed: 37591573
DOI: 10.1016/S2214-109X(23)00365-0 -
Frontiers in Cellular and Infection... 2024Different serovars of Salmonella enterica cause systemic diseases in humans including enteric fever, caused by S. Typhi and S. Paratyphi A, and invasive nontyphoidal...
INTRODUCTION
Different serovars of Salmonella enterica cause systemic diseases in humans including enteric fever, caused by S. Typhi and S. Paratyphi A, and invasive nontyphoidal salmonellosis (iNTS), caused mainly by S. Typhimurium and S. Enteritidis. No vaccines are yet available against paratyphoid fever and iNTS but different strategies, based on the immunodominant O-Antigen component of the lipopolysaccharide, are currently being tested. The O-Antigens of S. enterica serovars share structural features including the backbone comprising mannose, rhamnose and galactose as well as further modifications such as O-acetylation and glucosylation. The importance of these O-Antigen decorations for the induced immunogenicity and cross-reactivity has been poorly characterized.
METHODS
These immunological aspects were investigated in this study using Generalized Modules for Membrane Antigens (GMMA) as delivery systems for the different O-Antigen variants. This platform allowed the rapid generation and in vivo testing of defined and controlled polysaccharide structures through genetic manipulation of the O-Antigen biosynthetic genes.
RESULTS
Results from mice and rabbit immunization experiments highlighted the important role played by secondary O-Antigen decorations in the induced immunogenicity. Moreover, molecular modeling of O-Antigen conformations corroborated the likelihood of cross-protection between S. enterica serovars.
DISCUSSION
Such results, if confirmed in humans, could have a great impact on the design of a simplified vaccine composition able to maximize functional immune responses against clinically relevant Salmonella enterica serovars.
Topics: Humans; Animals; Mice; Rabbits; O Antigens; Salmonella enterica; Salmonella typhimurium; Serogroup; Salmonella Infections; Immunity; Models, Animal; Salmonella Vaccines
PubMed: 38487353
DOI: 10.3389/fcimb.2024.1347813 -
Journal of Genetics 2024Typhoid is endemic in India and has high global incidence. There were large outbreaks of typhoid in India between 1990 and 2018. Available typhoid vaccines induce...
Typhoid is endemic in India and has high global incidence. There were large outbreaks of typhoid in India between 1990 and 2018. Available typhoid vaccines induce variable levels of protective antibodies among recipients; thus, there is variability in response to the vaccine. Interindividual genomic differences is hypothesized to be a determinant of the variability in response. We studied the antibody response of ~1000 recipients of the Vi-polysaccharide typhoid vaccine from Kolkata, India, who showed considerable variability of antibody response, i.e., anti-Vi-polysaccharide antibody level 28 days postvaccination relative to prevaccination. For each vaccinee, wholegenome genotyping was performed using the Infinium Global Screening Array (Illumina). We identified 39 SNPs that mapped to 13 chromosomal regions to be associated with antibody response to the vaccine; these included SNPs on genes (15q26.3), (1q43), (9p23), (2q31.3), (7p21.2), and (18q21.2). Many of these loci are known to be associated with various blood cell traits, autoimmune traits and responses to other vaccines; these genes are involved in immune related functions, including TLR response, JAK-STAT signalling, phagocytosis and immune homeostasis.
Topics: Humans; Typhoid-Paratyphoid Vaccines; Antibody Formation; Typhoid Fever; Genomics; Polysaccharides; RGS Proteins
PubMed: 38444027
DOI: No ID Found