Mitochondrial dysfunction in cholesterol accumulated infected macrophages: Mycobacterium tuberculosis factors mediate persistence Suman Asalla, Krishnaveni Mohareer and Sharmistha Banerjee Molecular Pathogenesis Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India-500046 Email: email@example.com
Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression? The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses. In the present study, we evaluated the role of sub-pathological level of cholesterol representing dyslipidemic condition (borderline risk cholesterol profile) on persistence of Mycobacterium tuberculosis in THP-1 macrophages using cell culture based model system. Impact of sub-pathological concentration of cholesterol caused impaired clearance of mycobacteria. It was distinctly observed that cholesterol exposure caused changes in both structure and function of mitochondria in mycobacteria infected macrophages as compared to uninfected but cholesterol exposed cells. However, this situation is reversed upon pharmacological supplementation of a small molecule M1 that restores mitochondrial structure and therefore function and helps in macrophage clearance of mycobacteria. Our observations from the cell culture model were strengthened when similar assays were performed with PBMC derived macrophages. PBMC derived macrophages from borderline high cholesterol profile responded similar to sub-pathological cholesterol treated THP-1 macrophages that impaired clearance of mycobacteria. Small molecule M1 could again restore macrophage ability to clear mycobacteria in cholesterol exposed PBMC derived macrophages. To investigate further into mycobacterial infection induced mitochondrial dysfunction, we performed in silico analyses to identify mycobacterial factors targeted to host mitochondria. We further validated the candidates based on score for mitochondrial localisation, persistence and perturbation of mitochondrial function. Based on our studies, we propose that restoration of mitochondrial signalling through molecules like M1 can be explored further for host-directed therapy.
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