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PLoS Computational Biology Jun 2024Carbohydrates and glycoproteins modulate key biological functions. However, experimental structure determination of sugar polymers is notoriously difficult....
Carbohydrates and glycoproteins modulate key biological functions. However, experimental structure determination of sugar polymers is notoriously difficult. Computational approaches can aid in carbohydrate structure prediction, structure determination, and design. In this work, we developed a glycan-modeling algorithm, GlycanTreeModeler, that computationally builds glycans layer-by-layer, using adaptive kernel density estimates (KDE) of common glycan conformations derived from data in the Protein Data Bank (PDB) and from quantum mechanics (QM) calculations. GlycanTreeModeler was benchmarked on a test set of glycan structures of varying lengths, or "trees". Structures predicted by GlycanTreeModeler agreed with native structures at high accuracy for both de novo modeling and experimental density-guided building. We employed these tools to design de novo glycan trees into a protein nanoparticle vaccine to shield regions of the scaffold from antibody recognition, and experimentally verified shielding. This work will inform glycoprotein model prediction, glycan masking, and further aid computational methods in experimental structure determination and refinement.
PubMed: 38913746
DOI: 10.1371/journal.pcbi.1011895 -
JCI Insight May 2024Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection...
Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; SAIDS Vaccines; Macaca mulatta; Immunity, Innate; CD8-Positive T-Lymphocytes; Antibodies, Viral; Male; Vaccines, Attenuated
PubMed: 38912579
DOI: 10.1172/jci.insight.175800 -
Heliyon Jun 2024The development of tumor vaccines has become a hot topic in immunotherapy for osteosarcoma (OS); however, more tumor antigens with stronger immunogenicity need to be...
PURPOSE
The development of tumor vaccines has become a hot topic in immunotherapy for osteosarcoma (OS); however, more tumor antigens with stronger immunogenicity need to be identified.
METHODS
We downloaded six sets of gene expression profile data from online databases. The overexpressed genes were analyzed, intersected, and used to calculate the immune infiltration abundance in the TARGET OS dataset based on their expression matrix. Potential tumor antigen genes were identified based on whether they exhibited a high correlation with the antigen-presenting cells (APCs). A total of 1330 immune-related genes (IRGs) from the ImmPort website were retrieved based on their expression, and the Consensus Cluster method was used to obtain immune subtypes of the OS samples. Prognosis, immune microenvironment, and sensitivity to drugs were compared among the immune subtypes.
RESULTS
In total, 680 genes were overexpressed in at least two datasets, of which and were positively correlated with different APCs. Based on the expression matrix of 1330 IRGs in TARGET-OS, two immune subtypes, IS1 and IS2, were identified. The prognosis of the IS1 subtype was better than that of IS2, the expression of immune checkpoint (ICP)-related genes was higher in patients with the IS1 subtype, and immune cell infiltration and sensitivity to 16 drugs were generally higher in IS1 subtype patients.
CONCLUSION
We identified three APC-correlated genes that can be considered to code for potential novel tumor antigens for OS vaccines. Two immune subtypes in patients with OS were identified to implement personalized treatments using mRNA vaccines.
PubMed: 38912457
DOI: 10.1016/j.heliyon.2024.e32231 -
Frontiers in Microbiology 2024() is a strict microaerophilic bacterial species that exists in the stomach, and infection is one of the most common chronic bacterial infections affecting humans.... (Review)
Review
() is a strict microaerophilic bacterial species that exists in the stomach, and infection is one of the most common chronic bacterial infections affecting humans. Eradicating is the preferred method for the long-term prevention of complications such as chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer. However, first-line treatment with triple therapy and quadruple therapy has been unable to cope with increasing antibacterial resistance. To provide an updated review of infections and antibacterial resistance, as well as related treatment options, we searched PubMed for articles published until March 2024. The key search terms were "", " infection", " diseases", " eradication", and " antibacterial resistance." Despite the use of antimicrobial agents, the annual decline in the eradication rate of continues. Emerging eradication therapies, such as the development of the new strong acid blocker vonoprazan, probiotic adjuvant therapy, and vaccine therapy, are exciting. However, the effectiveness of these treatments needs to be further evaluated. It is worth mentioning that the idea of altering the oxygen environment in gastric juice for to not be able to survive is a hot topic that should be considered in new eradication plans. Various strategies for eradicating , including antibacterials, vaccines, probiotics, and biomaterials, are continuously evolving. A novel approach involving the alteration of the oxygen concentration within the growth environment of has emerged as a promising eradication strategy.
PubMed: 38912349
DOI: 10.3389/fmicb.2024.1418129 -
PeerJ 2024The development of serodiagnostic tests and vaccines for COVID-19 depends on the identification of epitopes from the SARS-CoV-2 genome. An epitope is the specific part...
BACKGROUND
The development of serodiagnostic tests and vaccines for COVID-19 depends on the identification of epitopes from the SARS-CoV-2 genome. An epitope is the specific part of an antigen that is recognized by the immune system and can elicit an immune response. However, when the genetic variants contained in epitopes are used to develop rapid antigen tests (Ag-RDTs) and DNA or RNA vaccines, test sensitivity and vaccine efficacy can be low.
METHODS
Here, we developed a "variant on epitope (VOE)" software, a new Python script for identifying variants located on an epitope. Variant analysis and sensitivity calculation for seven recommended epitopes were processed by VOE. Variants in 1,011 Omicron SRA reads from two variant databases (BCFtools and SARS-CoV-2-Freebayes) were processed by VOE.
RESULTS
A variant with HIGH or MODERATE impact was found on all epitopes from both variant databases except the epitopes KLNDLCFTNV, RVQPTES, LKPFERD, and ITLCFTLKRK on the S gene and ORF7a gene. All epitope variants from the BCFtools and SARS-CoV-2 Freebayes variant databases showed about 100% sensitivity except epitopes APGQTGK and DSKVGGNYN on the S gene, which showed respective sensitivities of 28.4866% and 6.8249%, and 87.7349% and 71.1177%.
CONCLUSIONS
Therefore, the epitopes KLNDLCFTNV, RVQPTES, LKPFERD, and ITLCFTLKRK may be useful for the development of an epitope-based peptide vaccine and GGDGKMKD on the N gene may be useful for the development of serodiagnostic tests. Moreover, VOE can also be used to analyze other epitopes, and a new variant database for VOE may be further established when a new variant of SARS-CoV-2 emerges.
Topics: Humans; SARS-CoV-2; COVID-19; COVID-19 Vaccines; Epitopes; Software; Sensitivity and Specificity
PubMed: 38912043
DOI: 10.7717/peerj.17504 -
Frontiers in Immunology 2024Non-typhoidal (NTS) generally causes self-limiting gastroenteritis. However, older adults (≥65 years) can experience more severe outcomes from NTS infection. We have...
INTRODUCTION
Non-typhoidal (NTS) generally causes self-limiting gastroenteritis. However, older adults (≥65 years) can experience more severe outcomes from NTS infection. We have previously shown that a live attenuated . Typhimurium vaccine, CVD 1926 (I77 Δ Δ Δ Δ), was immunogenic in adult but not aged mice. Here we describe modification of CVD 1926 through deletion of , a effector responsible for host immune escape, which we hypothesized would increase immunogenicity in aged mice.
METHODS
Mel Juso and/or mutuDC cells were infected with . Typhimurium I77, CVD 1926, and their respective mutants, and the MHC-II levels were evaluated. Aged (18-month-old) C57BL/6 mice received two doses of PBS, CVD 1926, or CVD 1926 Δ perorally (10 CFU) and the number of FliC-specific CD4 T cells were determined. Lastly, aged C57BL/6 mice received three doses of PBS, CVD 1926, or CVD 1926 Δ perorally (10 CFU) and then were challenged perorally with wild-type . Typhimurium SL1344 (10 CFU). These animals were also evaluated for antibody responses.
RESULTS
MHC-II induction was higher in cells treated with mutants, compared to their respective parental strains. Compared to PBS-vaccinated mice, CVD 1926 Δ elicited significantly more FliC-specific CD4 T cells in the Peyer's Patches. There were no significant differences in FliC-specific CD4 T cells in the Peyer's patches or spleen of CVD 1926- versus PBS-immunized mice. CVD 1926 and CVD 1926 Δ induced similar serum and fecal anti-core and O polysaccharide antibody titers after three doses. After two immunizations, the proportion of seroconverters for CVD 1926 Δ was 83% (10/12) compared to 42% (5/12) for CVD 1926. Compared to PBS-immunized mice, mice immunized with CVD 1926 Δ had significantly lower . Typhimurium counts in the spleen, cecum, and small intestine upon challenge. In contrast, there were no differences in bacterial loads in the tissues of PBS-vaccinated and CVD 1926-immunized animals.
CONCLUSION
These data suggest that the deletion enhanced the immunogenicity of our live attenuated . Typhimurium vaccine. Deletion of immune evasion genes could be a potential strategy to improve the immunogenicity of live attenuated vaccines in older adults.
Topics: Animals; Salmonella Vaccines; Salmonella typhimurium; Mice; Vaccines, Attenuated; Mice, Inbred C57BL; Antibodies, Bacterial; Immune Evasion; Bacterial Proteins; Female; Gene Deletion; Salmonella Infections; Aging; CD4-Positive T-Lymphocytes; Immunogenicity, Vaccine
PubMed: 38911854
DOI: 10.3389/fimmu.2024.1376734 -
EClinicalMedicine Jul 2024
PubMed: 38911838
DOI: 10.1016/j.eclinm.2024.102670 -
Vaccine Jun 2024In New Zealand, approximately half reported pertussis cases are adult. Studies indicate underestimated pertussis burden in this population and probable reservoir for...
Pertussis epidemiology in adults: Retrospective analysis of pertussis incidence and association with comorbidities among adult populations in Aotearoa New Zealand, using national administrative datasets.
BACKGROUND
In New Zealand, approximately half reported pertussis cases are adult. Studies indicate underestimated pertussis burden in this population and probable reservoir for childhood pertussis. Pertussis is linked to chronic obstructive pulmonary disease (COPD) development and increased risk with pre-existing COPD. While acellular pertussis vaccines are available for adults, data on pertussis disease burden in adults and association with COPD remain limited.
AIM
To estimate pertussis incidence in New Zealand adult health service user (HSU) population aged ≥ 18 between 2008-2019 and inform adult pertussis vaccination strategies by assessing disease burden and risk factors in different adult populations.
METHODS
Retrospective observational cohort study using an HSU cohort, formed by linking administrative health data using unique National Health Index identifier. For primary analysis, annual incidence rates were calculated using pertussis hospitalisations and notifications. In secondary analysis, Cox proportional hazards survival analyses explored association between pertussis in adults and chronic comorbidities.
RESULTS
The cohort had 2,907,258 participants in 2008 and grew to 3,513,327 by 2019, with 11,139 pertussis cases reported. Highest annual incidence rate of 84.77 per 100,000 PYRS in 2012, notably affecting females, those aged 30-49 years, and European or Māori ethnicity. Adjusting for sociodemographic variables found no significant risk of prior pertussis notification leading to comorbidity diagnosis (Adjusted-HR: 0.972). However, individuals with prior comorbidity diagnosis had 16 % greater risk of receiving pertussis notification or diagnosis (Adjusted-HR: 1.162).
CONCLUSIONS
Study found significant pertussis burden among the HSU adult cohort and highlighted higher risk of pertussis for those with recent comorbidity diagnoses. Vaccination for pertussis should be recommended for individuals with comorbidities to reduce infection risk and disease severity. GPs must have capability to test for pertussis, given it is notifiable disease with implications for individuals, their families, and broader population. High-quality disease surveillance is crucial for informing policy decisions.
PubMed: 38910093
DOI: 10.1016/j.vaccine.2024.06.016 -
Poultry Science Jun 2024As a highly infectious and contagious pathogen in chickens, infectious bronchitis virus (IBV) is currently grouped into nine genotypes (GI to GIX). However, the...
As a highly infectious and contagious pathogen in chickens, infectious bronchitis virus (IBV) is currently grouped into nine genotypes (GI to GIX). However, the classification of serotypes of IBV is still not clear. In this study, 270 field strains of IBV were isolated from dead or diseased chicken flocks in eastern and southern China during January 2021 to April 2023. These isolated IBV strains could be classified into 2 genotypes, GI (including 5 lineages GI-1, GI-13, GI-19, GI-22, and GI-28) and GVI based on the complete S1 sequence. Further analysis showed that the GI-19, GI-13, GI-22, GI-28, and GVI were the dominant genotypes with the proportions of 61.48, 8.89, 8.89, 7.78, and 8.89% respectively, and the homology of S1 protein of these isolates ranged from 86.85 to 100% in GI-19, 92.22 to 100% in GI-13, 83.1 to 100% in GI-22, 94.81 to 100% in GI-28 and 90.0 to 99.8% in GVI, respectively. Moreover, cross-neutralization test with sera revealed that these isolates in GI-19 lineage could be classified into at least 3 serotypes according to the antigenic relationship. In addition, structure assay using PyMOL indicated that one mutation such as S120 in receptor binding site (RBD) of GI-19 might alter the antigenicity and conformation of S protein of IBV. Overall, our data demonstrate that not only multiple genotypes, but also multiple serotypes in a single genotype or lineage have been co-circulated in eastern and southern China, providing novel insights into the molecular evolution of the antigenicity of IBV and highlighting the significance of the selection of the dominant isolate for vaccine development in IBV endemic region.
PubMed: 38909507
DOI: 10.1016/j.psj.2024.103939 -
Nature Communications Jun 2024Porcine deltacoronavirus (PDCoV) is an emerging enteric pathogen that has recently been detected in humans. Despite this zoonotic concern, the antigenic structure of...
Porcine deltacoronavirus (PDCoV) is an emerging enteric pathogen that has recently been detected in humans. Despite this zoonotic concern, the antigenic structure of PDCoV remains unknown. The virus relies on its spike (S) protein for cell entry, making it a prime target for neutralizing antibodies. Here, we generate and characterize a set of neutralizing antibodies targeting the S protein, shedding light on PDCoV S interdomain crosstalk and its vulnerable sites. Among the four identified antibodies, one targets the S1A domain, causing local and long-range conformational changes, resulting in partial exposure of the S1B domain. The other antibodies bind the S1B domain, disrupting binding to aminopeptidase N (APN), the entry receptor for PDCoV. Notably, the epitopes of these S1B-targeting antibodies are concealed in the prefusion S trimer conformation, highlighting the necessity for conformational changes for effective antibody binding. The binding footprint of one S1B binder entirely overlaps with APN-interacting residues and thus targets a highly conserved epitope. These findings provide structural insights into the humoral immune response against the PDCoV S protein, potentially guiding vaccine and therapeutic development for this zoonotic pathogen.
Topics: Spike Glycoprotein, Coronavirus; Animals; Antibodies, Neutralizing; Swine; Antibodies, Viral; Epitopes; Humans; Deltacoronavirus; CD13 Antigens; Coronavirus Infections; Protein Domains; Protein Binding; Swine Diseases; HEK293 Cells
PubMed: 38909062
DOI: 10.1038/s41467-024-49693-0