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Dissecting the immunogenicity of RD1-recombinant live tuberculosis vaccine candidates studying host-pathogen interaction in human primary dendritic cells

ABSTRACT: New tuberculosis vaccines are highly desirable and urgently needed since the attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) provides only variable efficacy against the pulmonary form of the disease. The region of difference 1 (RD1), which is deleted in BCG and strongly impacts on Mycobacterium tuberculosis (Mtb) virulence and immunogenicity, represents a crucial locus to be engineered for either the improvement of the current BCG vaccine, or the attenuation of Mtb. Therefore, mutants secreting or not wild-type or mutated variants of the RD1-encoded 6 kDa early secreted antigenic target (ESAT-6) were generated. Comparative analysis of the transcriptome, phenotype, cytokine production profiles and the capacity to promote T cell responses were conducted in human primary dendritic cells (DCs), as they represent critical regulators of vaccine-induced immunity, unveiling a distinct immunogenic potential for BCG or Mtb mutants. In contrast to Mtb, BCG induced a poor DC maturation, and to our surprise, a BCG strain complemented with the RD1 region only partially restored DC maturation and expansion of interferon (IFN)-γ producing T cells. In contrast, infection with a recombinant attenuated Mtb strain, secreting a truncated version of ESAT-6 lacking 11 amino acids at the C-terminus portion, drove full maturation in infected DC and maintained their capacity to promote polarization of T helper (Th) 1 cells, as observed upon infection with the virulent Mtb.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62423 | GEO | 2016/01/01

SECONDARY ACCESSION(S): PRJNA264064

REPOSITORIES: GEO

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Project description:The innate immune system provides the first response to pathogen infection and orchestrates the activation of the adaptive immune system. Though a large component of the innate immune response is common to all infections, pathogen-specific innate immune responses have been documented as well. The innate immune response is thought to be especially critical for fighting infection with Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB). While TB can be a deadly disease, only 5-10% of individuals infected with MTB develop active disease, and this inter-individual variation is, at least partly, heritable. Studies of inter-individual variation in the innate immune response to MTB infection may therefore shed light on the genetic basis for variation in susceptibility to TB. Yet, to date, we still do not know which properties of the innate immune response are specific to MTB infection and which represent a general response to pathogen infection. To begin addressing this gap, we infected macrophages with eight different bacterial pathogens, including different MTB strains and related mycobacteria, and studied the transcriptional response to infection. We found that although the gene expression changes were largely consistent across the bacterial infection treatments, we were able to identify a novel subset of genes whose regulation was affected specifically by infection with mycobacteria. Genetic variants that are associated with regulatory differences in these genes should be considered candidate loci for explaining inter-individual susceptibility TB. RNA-seq of monocyte-derived macrophages isolated from 6 healthy European males at 4, 18, and 48 hours post-infection with the following 8 bacteria: Mycobacterium tuberculosis (MTB) H37Rv, Mycobacterium tuberculosis GC1237, MTB GC1237, bacillus Calmette-Guérin (BCG), Mycobacterium smegmatis, Yersinia pseudotuberculosis, Salmonella typhimurium, and Staphylococcus epidermidis. table-s1.txt is a tab-delimited text file that contains the batch-corrected log2 counts per million for each of the 156 samples, as well as the Ensembl gene ID and gene name. BCG = bacillus Calmette-Guérin GC = Mycobacterium tuberculosis GC1237 Rv = Mycobacterium tuberculosis (MTB) H37Rv Rv+ = heat-inactivated MTB H37Rv Salm = Salmonella typhimurium Smeg = Mycobacterium smegmatis Staph = Staphylococcus epidermidis Yers = Yersinia pseudotuberculosis

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Dissecting the immunogenicity of RD1-recombinant live tuberculosis vaccine candidates studying host-pathogen interaction in human primary dendritic cells

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