Unveiling the role of Stem Cells in Mycobacterium evasion of the immune system in chronic bacterial infection

Mesenchymal Stem cells (MSCs) have immunomodulatory roles and respond to bacteria [1]. Recent reports in rodents and humans revealed a key role of MSCs in Mycobacterium tuberculosis (M. tuberculosis) infection. As a result, MSCs are now being actively studied as a target to tackle human tuberculosis (TB). However, the relevance of MSCs in other Mycobacterium infections, including those caused by M. bovis (TB in both cattle and humans) and M. avium subsp. Paratuberculosis (MAP; Johne’s Disease in cattle) which constitute a major worldwide health problem and cost for the livestock industry, has yet to be assessed. A hallmark of Mycobacterium spp. infections is the formation of granulomas by infected macrophages surrounded by other immune cells (e.g. T lymphocytes) as a way to constrain infection. Importantly, M. tuberculosis evades host immunity by recruiting MSCs which locate around these granulomas [2]. Therefore, this project will study the role of MSCs in infection and granuloma formation by M. bovis and MAP. Experiments will include the use of multicellular granuloma models [3] and archived material from previous experiments to reduce and replace the use of experimental animals.

Objectives of the project:
1) To characterize MSC populations in bovine granulomas caused by M. bovis and MAP.

2) To study infection of MSC by M. bovis and MAP, and establish the impact of infected MSCs on macrophage and T lymphocyte activity and phenotype. Changes of MSC gene expression will be assessed by RNAseq.

3) To test the function of MSC genes (identified in objective 2) and establish their relevance in Mycobacterium spp infection and granuloma formation, by using multicellular granuloma models.

The student will become proficient in molecular biology techniques, bacterial and mammalian cell culture, immunohistochemistry, ELISA, flow-cytometry, gene expression analyses by next-generation sequencing, qPCR, siRNA. He/she will build expertise in stem cell biology, immunology and microbiology.