Mycobacterium tuberculosis infection suppresses the expression of host genes involved in lysosomal targeting in the macrophage
Flynn, R. (2022). Mycobacterium tuberculosis infection suppresses the expression of host genes involved in lysosomal targeting in the macrophage. (Unpublished Doctoral thesis, St. Georges, University of London)
Abstract
Mycobacterial modulation of phagosome maturation in infected cells is a widely studied area in host-pathogen interactions, yet there is still no definitive understanding of all the mechanisms involved. Infection with M. tuberculosis (M.tb) is well known for a resultant modulation of gene expression of the host cell. This study identified and investigated three macrophage genes suppressed during M.tb infection, involved in lysosomal trafficking pathways: RILP, OSBPL1a and RIN2, with the hypothesis that M.tb infection actively suppresses the expression in order to disrupt phagolysosome fusion resulting in pathogen survival.
Two approaches were taken, the first, co-localisation studies using constructed cell lines over-expressing RILP, OSBPL1a and RIN2. The second approach was to analyse host cell gene expression in response to M.tb mutants known to be trafficked to the lysosome. Fluorescence microscopy co-location studies in RIN2 over-expressing transfected macrophage cell lines exhibited differential trafficking of M.tb. Gene expression of M.tb in response to RILP, RIN2 and OSBPL1a over-expression revealed changes to notable genes associated with exposure to the phagosomal environment. Finally, macrophage infections with M.tb mutants known to be trafficked to the lysosome, revealed that a moaC1 mutant was unable to suppress the expression of RILP and OSBPL1a, indicating an active role in M.tb survival by blocking phago-lysosomal maturation.
The intention of this study was to gain a better understanding of the mechanisms by which M.tb evades lysosomal destruction to aid in devising potential new host-directed and pathogen-directed strategies for treatment and prevention of the disease, tuberculosis.
| Publication Type: | Thesis (Doctoral) |
|---|---|
| Subjects: | R Medicine > R Medicine (General) R Medicine > RB Pathology R Medicine > RC Internal medicine |
| Departments: | School of Health & Medical Sciences > Infection and Immunity Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses |
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