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Immunopeptidomics informs discovery and delivery of Mycobacterium tuberculosis MHC-II antigens for vaccine design

ABSTRACT: No currently licensed vaccine reliably prevents pulmonary tuberculosis, a leading cause of infectious disease mortality with a growing rate of extensive drug resistance. Developing effective new vaccines will likely require identifying Mycobacterium tuberculosis (Mtb)-derived antigens presented on MHC class II (MHC-II) by infected phagocytes that CD4+ T cells can recognize to mediate protective immunity. To prime T cells capable of recognizing infected cells, vaccines will also need to deliver antigens to appropriate processing pathways. Here, we use mass spectrometry (MS) to identify 27 Mtb-derived MHC-II peptides presented by infected human dendritic cells, derived from 13 source proteins. Using targeted quantitative MS, we assess and optimize the ability of vaccines to drive presentation of MHC-II epitopes that match those presented by Mtb-infected cells, including the existing Bacillus Calmette Guerin (BCG) vaccine and new mRNA-encoded immunogens. Our results identify potential antigenic targets and immunogen design principles for tuberculosis vaccine development.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Dendritic Cell, Macrophage

DISEASE(S): Tuberculosis

SUBMITTER: Owen Leddy

LAB HEAD: Forest White

PROVIDER: PXD055952 | Pride | 2025-09-18

REPOSITORIES: Pride

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			Action	DRS
	020123_donor_M_MoDC_MHC_II_Mock.mzML	Mzml
	020123_donor_M_MoDC_MHC_II_Mock.mzid.gz	Mzid
	020123_donor_M_MoDC_MHC_II_Mock.raw	Raw
	020123_donor_M_MoDC_MHC_II_Mtb.mzML	Mzml
	020123_donor_M_MoDC_MHC_II_Mtb.mzid.gz	Mzid

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Project description:Background: Conflicting results have been reported about the role of the two-component sensor and transcriptional regulator DosS/DosR, controlling the expression of the dormancy DosR regulon, for in vivo virulence of M. tuberculosis. Here, we have used a new approach to further analyze the relevance of the dosRS system, by driving DosR (Rv3133c) expression under the control of a constitutive promoter (phsp60). Methodology/Principal Findings: M. tuberculosis H37Rv constitutively expressing the transcriptional regulator DosR (Mtb::DosR) was compared to wild type M. tuberculosis (Mtb+/+) for in vitro growth kinetics and expression of the target genes of the DosR dormancy regulon, for in vivo virulence and for immunogenicity in mice. Under aerobic conditions, hsp60-driven DosR induced the expression of 28 out of 39 tested DosR regulon genes. In vitro growth characteristics were comparable for both strains, but Mtb::DosR showed an attenuated in vivo phenotype in immunocompetent mice, as indicated by reduced bacterial replication, reduced pulmonary immunopathology, reduced cachexia and significantly prolonged survival time as compared Mtb+/+. In immunodeficient SCID mice, Mtb::DosR was fully virulent. RT-qPCR analysis revealed a strong and comparable pulmonary TNF-?? and IL-23 expression following intratracheal infection, whereas IL-12 and IL-17 expression was slightly higher with wild type Mtb+/+. Finally, mice persistently infected with Mtb::DosR for 8 months showed five to tenfold higher lung IFN-?? responses against ten of the 48 DosR regulon encoded antigens (Rv1733c, Rv1734, Rv1738, Rv1996, Rv1997, Rv2029c, Rv2623, Rv2627c, Rv2628 and Rv3127) than mice actively infected with Mtb+/+. In spleen however, DosR regulon encoded antigen specific IFN-?? responses were similar in both groups. Conclusions/Significance. Collectively, these results suggest that increased DosR regulon encoded antigen specific pulmonary T cell responses are responsible for the attenuated phenotype of Mtb::DosR and that infection with Mtb::DosR could be used as a new animal model for studying key aspects of latent tuberculosis. Set of arrays that are part of repeated experiments

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Immunopeptidomics informs discovery and delivery of Mycobacterium tuberculosis MHC-II antigens for vaccine design

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