Abstract
Mycobacterium tuberculosis (Mtb) genes encoding proteins targeted by vaccines and drugs should be expressed in the lung, the main organ affected by Mtb, for these to be effective. However, the pulmonary expression of most Mtb genes and their proteins remains poorly characterized. The aim of this study is to fill this knowledge gap. We analyzed large scale transcriptomic datasets from specimens of Mtb-infected humans, TB-hypersusceptible (C3H/FeJ) and TB-resistant (C57BL/6J) mice and compared data to in vitro cultured Mtb gene-expression profiles. Results revealed high concordance in the most abundantly in vivo expressed genes between pulmonary Mtb transcriptomes from different datasets and different species. As expected, this contrasted with a lower correlation found with the highest expressed Mtb genes from in vitro datasets. Among the most consistently and highly in vivo expressed genes, 35 have not yet been explored as targets for vaccination or treatment. More than half of these genes are involved in protein synthesis or metabolic pathways. This first lung-oriented multi-study analysis of the in vivo expressed Mtb-transcriptome provides essential data that considerably increase our understanding of pulmonary TB infection biology, and identifies novel molecules for target-based TB-vaccine and drug development.
Highlights
Tuberculosis (TB) is an ancient disease caused by the airborne pathogen Mycobacterium tuberculosis (Mtb), which has infected billions of people and has killed more people than any other bacterial infectious agent (1)
We have hypothesized that in order for vaccine antigens to be protective, a minimal requirement is that they are expressed in the lung of Mtb infected individuals, preferably over prolonged periods of time such that immune cells can recognize and eliminate infected targets cells presenting these antigens; or that TB drugs are able to act effectively on such Mtb target molecules. To address this important issue, which cannot be studied in humans, we recently reported a novel in vivo pulmonary Mtb gene expression analysis based on the Mtb RNA expression patterns in the lung of highly susceptible (C3HeB/FeJ) as well as resistant (C57BL/6J) mice after aerosol Mtb (Erdman) infection, from early to late time points (8)
By analysing the expression of 2068 Mtb genes [selected to represent the first genes of most predicted Mtb operons, in order to enhance representative “genome wide” coverage (9)] in their lungs during early and late phase Mtb infection, we identified upregulated Mtb genes that were designated in vivo expressed Mtb (IVE-TB) genes
Summary
Tuberculosis (TB) is an ancient disease caused by the airborne pathogen Mycobacterium tuberculosis (Mtb), which has infected billions of people and has killed more people than any other bacterial infectious agent (1). Recent human phase II studies showed that sustained Mtb infection can be prevented by BCG revaccination of Mtb uninfected individuals (as measured by interferon gamma release assay conversion), and that incidence of new TB cases can be reduced amongst persons with LTBI by the M72 TB subunit vaccine (4, 5). While these results are highly encouraging, the immune mechanisms underlying these protective effects remain poorly understood. Many of the most advanced TB subunit candidates are based on Mtb proteins historically identified from in vitro cultured Mtb which were thereafter tested for antigenicity using peripheral blood cells from Mtb exposed individuals (7)
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