Mycolic acid nanoparticle vaccination leads to lipid antigen persistence and unique differentiation of mycobacterial-specific T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA938471 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23616938.fastq.gz | Fastqsanger.gz | |||
| SRR23616939.fastq.gz | Fastqsanger.gz | |||
| SRR23616940.fastq.gz | Fastqsanger.gz | |||
| SRR23616941.fastq.gz | Fastqsanger.gz | |||
| SRR23616942.fastq.gz | Fastqsanger.gz |
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Project description:Mycobacterium tuberculosis (Mtb) infection elicits both protein and lipid antigen-specific T cell responses. However, the incorporation of lipid antigens into subunit vaccine strategies and formulations has been underexplored, and the properties of vaccine-induced Mtb lipid-specific memory T cells remained elusive. Mycolic acid (MA), a major lipid component of the Mtb cell wall, is presented by human CD1b molecules to T cells. MA-specific CD1b-restricted T cells have been detected in the blood and disease sites of Mtb-infected individuals, suggesting MA is a promising lipid antigen for incorporation into multicomponent subunit vaccines. In this study, we utilized bicontinuous nanospheres (BCN) to efficiently encapsulate MA and deliver it to MA-specific T cells both alone and in combination with an immunodominant Mtb protein antigen (Ag85B). Pulmonary delivery of MA-loaded BCN (MA-BCN) elicited MA-specific T cell responses in humanized CD1 transgenic mice. Simultaneous delivery of MA and Ag85B within BCN activated both MA- and Ag85B-specific T cells. Interestingly, pulmonary vaccination with MA-Ag85B-BCN led to the persistence of MA, but not Ag85B, within alveolar macrophages in the lung. Vaccination of MA-BCN through intravenous or subcutaneous route, or with attenuated Mtb likewise reproduced MA persistence. Moreover, MA-specific T cells in MA-BCN-vaccinated mice differentiated to have a T follicular helper-like phenotype. Overall, BCN platform allows for the dual encapsulation of lipid and protein antigen and leads to persistent lipid depots that could offer long-lasting immune response and protection.
2023-04-25 | GSE226075 | GEO
Project description:The mycobacterial cell wall is a distinctive thick layer that protects the tubercle bacillus from general antibiotics and the host’s immune system. Mycolic acids, which are long-chain α-alkyl-β-hydroxy fatty acids, are the major constituents of this protective layer, and their synthesis has been shown to be critical for the survival of M. tuberculosis. This model captures the mycolic acid pathway in M. tuberculosis with 197 metabolites participating in 219 reactions catalysed by 28 proteins. The model helps in the rational identification of potential anti-tubercular drug targets.
2024-09-02 | BIOMD0000001046 | BioModels
Project description:Bacille Calmette Guerin (BCG) is the most widely administered vaccine in the world yet its mechanism of action remains unclear. In this study, we have used samples from a human mycobacterial challenge study in which previously BCG-vaccinated or BCG-naïve UK adults were challenged intradermally with a standard dose of BCG vaccine. BCG remaining at the site of vaccination was quantified by polymerase chain reaction from a skin biopsy sample taken two weeks post-challenge and was used as a measure of BCG growth and functional anti-mycobacterial immunity. Using gene expression microarrays and flow cytometric analysis of intracellular cytokine production, we show that the magnitude of the immune response is greater in previously vaccinated volunteers and that this correlates with reduced mycobacterial growth but increased scarring at the vaccination site. In particular the IFNγ and IL-17 pathways are strongly induced in previously vaccinated volunteers and correlate with reduced mycobacterial growth in this population. This study supports the use of BCG challenge as a tool for evaluating vaccine efficacy and identifying mechanisms of anti-mycobacterial immunity
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Project description:Intravenous Nanoparticle Vaccination Generates Stem-Like TCF1+ Neoantigen-Specific CD8 T Cells
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Project description:Purpose: Single cell RNA sequencing technologies have dramatically increased the resolution at which cells can be characterized. The goal of this study was to characterize the expression differences between neoantigen (neoAg) specific CD8 T cells elicited by a TLR7/8 agonist nanoparticle vaccine delivered intravenously (IV) or subcutaneously (SC). Previous flow cytometry experiments had suggested that IV vaccination resulted in more TCF1+ cells as compared to the SC route. Methods: Mice (n=5) were vaccinated twice, with a 2 week interval between vaccinations. Two weeks after the boost, mice were sacrificed and spleens collected, dissociated and stained with hashtag antibodies/flow cytometry antibodies. NeoAg-specific cells were labelled with a tetramer and sorted on a FACS Aria. Cells were processed through the 10X pipeline. Results: We identified 12 clusters within our antigen specific CD8 T cells. The IV route elicited neoAg+ CD8 T cells with a predominantly stem-like gene signature whereas the SC route elicited more effector genes.
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Project description:Mycobacterium tuberculosis has a complex cell envelope that is remodelled throughout infection to respond and survive the hostile and variable intracellular conditions within the host. Despite the importance of cell wall homeostasis in pathogenicity, little is known about the environmental signals and regulatory networks controlling cell wall biogenesis in mycobacteria. The mycolic acid desaturase regulator (MadR) is a transcriptional repressor responsible for regulation of the essential aerobic desaturases desA1 and desA2 that are differentially regulated throughout infection along with mycolate modification genes and thus, likely involved in mycolic acid remodelling. Here we generated a madR null mutant in M. smegmatis that exhibited traits of an impaired cell wall with increased permeability, susceptibility to rifampicin and cell surface disruption as a consequence of desA1/desA2 dysregulation. Analysis of mycolic acids revealed the presence of a highly desaturated mycolate in the null mutant that exists in relative trace amounts in the wildtype, but increases in abundance upon cell surface disruption as a result of relieved repression on the desA1/desA2 promoters. Transcriptomic profiling confirmed MadR as a cell surface disruption responsive regulator of desA1/desA2 and further implicating it in the control of bespoke β-oxidation pathways and transport evolutionarily diversified subnetworks associated with virulence. In vitro characterisation of MadR using electromobility shift assays and analysis of binding affinities is suggestive of a unique acyl-CoA pool sensing mechanism, whereby MadR is able to bind a range of acyl-CoA but MadR repression of desA1/desA2 promoters is only relieved upon binding of saturated acyl-CoA of chain length C16-C24. We propose this acyl effector ligand mechanism as distinct to other regulators of mycolic acid biosynthesis or fatty acid desaturases and places MadR as the key regulatory checkpoint that coordinates mycolic acid remodelling in response to host derived cell surface perturbation
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Project description:We constructed mycolic acid synthesis key gene pks13 mutant strain and analyzed its impacts on whole cell at gene expression level compared to the wild-type ATCC13869.
2018-01-01 | GSE104833 | GEO
Project description:The spread of antibiotic resistance is a major challenge for treatment of Mycobacterium tuberculosis infection. In addition, efficacy of drugs is often limited by the restricted permeability of the mycomembrane. Frontline antibiotics inhibit mycomembrane biosynthesis leading to rapid cell death. Inspired by this mechanism we exploit β-lactones as putative mycolic acid mimics to block serine hydrolases involved in their biosynthesis. Among a collection of β-lactones we found one hit with potent anti-mycobacterial and bactericidal activity. Chemical proteomics using an alkynylated probe identified Pks13 and Ag85 serine hydrolases as major targets. Validation via enzyme assays and customized 13C metabolite profiling showed that both targets are functionally impaired by the β-lactone. Co-administration with front-line antibiotics enhanced the potency against M. tuberculosis by more than 100-fold demonstrating a therapeutic potential of targeting mycomembrane biosynthesis serine hydrolases.
2022-01-19 | PXD007699 | Pride
Project description:Mycobacterium tuberculosis (Mtb) infection elicits both protein and lipid antigen-specific T cell responses. However, the incorporation of lipid antigens into subunit vaccine strategies and formulations has been underexplored, and the characteristics of vaccine-induced Mtb lipid-specific memory T cells have remained elusive. Mycolic acid (MA), a major lipid component of the Mtb cell wall, is presented by human CD1b molecules to unconventional T cell subsets. These MA-specific CD1b-restricted T cells have been detected in the blood and disease sites of Mtb-infected individuals, suggesting that MA is a promising lipid antigen for incorporation into multicomponent subunit vaccines. In this study, we utilized the enhanced stability of bicontinuous nanospheres (BCN) to efficiently encapsulate MA for in vivo delivery to MA-specific T cells, both alone and in combination with an immunodominant Mtb protein antigen (Ag85B). Pulmonary administration of MA-loaded BCN (MA-BCN) elicited MA-specific T cell responses in humanized CD1 transgenic mice. Simultaneous delivery of MA and Ag85B within BCN activated both MA- and Ag85B-specific T cells. Notably, pulmonary vaccination with MA-Ag85B-BCN resulted in the persistence of MA, but not Ag85B, within alveolar macrophages in the lung. Vaccination of MA-BCN through intravenous or subcutaneous route, or with attenuated Mtb likewise reproduced MA persistence. Moreover, MA-specific T cells in MA-BCN-vaccinated mice differentiated into a T follicular helper-like phenotype. Overall, the BCN platform allows for the dual encapsulation and in vivo activation of lipid and protein antigen-specific T cells and leads to persistent lipid depots that could offer long-lasting immune responses.
| S-EPMC10028924 | biostudies-literature
Project description:Mycobacterium tuberculosis (Mtb) infection elicits both protein and lipid antigen-specific T cell responses. However, the incorporation of lipid antigens into subunit vaccine strategies and formulations has been underexplored, and the characteristics of vaccine-induced Mtb lipid-specific memory T cells have remained elusive. Mycolic acid (MA), a major lipid component of the Mtb cell wall, is presented by human CD1b molecules to unconventional T cell subsets. These MA-specific CD1b-restricted T cells have been detected in the blood and disease sites of Mtb-infected individuals, suggesting that MA is a promising lipid antigen for incorporation into multicomponent subunit vaccines. In this study, we utilized the enhanced stability of bicontinuous nanospheres (BCN) to efficiently encapsulate MA for in vivo delivery to MA-specific T cells, both alone and in combination with an immunodominant Mtb protein antigen (Ag85B). Pulmonary administration of MA-loaded BCN (MA-BCN) elicited MA-specific T cell responses in humanized CD1 transgenic mice. Simultaneous delivery of MA and Ag85B within BCN activated both MA- and Ag85B-specific T cells. Notably, pulmonary vaccination with MA-Ag85B-BCN resulted in the persistence of MA, but not Ag85B, within alveolar macrophages in the lung. Vaccination of MA-BCN through intravenous or subcutaneous route, or with attenuated Mtb likewise reproduced MA persistence. Moreover, MA-specific T cells in MA-BCN-vaccinated mice differentiated into a T follicular helper-like phenotype. Overall, the BCN platform allows for the dual encapsulation and in vivo activation of lipid and protein antigen-specific T cells and leads to persistent lipid depots that could offer long-lasting immune responses.
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