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Mycobacterial ESX-1 may target mitochondria to modulate the immune response

Getachew, Konjit (2016) MOBT01 20161
Degree Projects in Molecular Biology
Popular Abstract
Tuberculosis (TB) is an infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb). Infection occurs through inhalation of bacteria-containing droplets. After entry into the respiratory tract the bacteria mainly reside within macrophages in the lung by using different strategies to escape killing by the immune system. The attenuated Mycobacterium bovis strain Bacille Calmette Guerin (BCG), is currently the only vaccine available for TB. Protection from BCG is very variable. Comparative functional genomics between the attenuated BCG vaccine strain and virulent Mtb have identified several regions that are missing in the BCG genome; theses regions are called regions of difference (RD). ESX-1 is encoded partly by the RD1... (More)
Tuberculosis (TB) is an infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb). Infection occurs through inhalation of bacteria-containing droplets. After entry into the respiratory tract the bacteria mainly reside within macrophages in the lung by using different strategies to escape killing by the immune system. The attenuated Mycobacterium bovis strain Bacille Calmette Guerin (BCG), is currently the only vaccine available for TB. Protection from BCG is very variable. Comparative functional genomics between the attenuated BCG vaccine strain and virulent Mtb have identified several regions that are missing in the BCG genome; theses regions are called regions of difference (RD). ESX-1 is encoded partly by the RD1 region and it is a secretion system that has been functionally associated with various virulence mechanisms of pathogenic mycobacteria. Virulent Mtb strains are known to modulate the immune response to promote their survival. A close relative of Mtb called Mycobacterium marinum (Mm) is commonly used as model to study mycobacterial pathogenesis in general and ESX-1 biology specifically.

ESX-1 from Mycobacterium tuberculosis and Mycobacterium marinum (Mm) has been shown to exploit type I IFN-signaling to promote a IL-12low/IL-10high regulatory macrophage phenotype characterized by secretion of IL-10, IL-27 and IL-6. Type I IFNs (IFN-α/β) are known to be potent antiviral cytokines. However, in the case of tuberculosis, it is now clear that type I IFNs are host detrimental and serve to favor bacterial survival and growth in vivo. Besides, activation of the inflammasome is one key function of innate immune responses that is known to regulate inflammation and mycobacterial survival in vivo. After recognition of pathogen or danger associated molecular patterns by their receptors, caspase-1 is activated and promotes secretion of IL-1β. Nevertheless, the molecular mechanism of Type I IFNs and inflammasome activation during tuberculosis is not fully understood.

Thus, the aim of this study was to gain insight into whether ESX-1 targets mitochondria to activate both the cytosolic surveillance pathway and the inflammasome. For this work, we used different knockout macrophages that lack genes of our interest, pharmacological approaches to inhibit pathways of interest, as well as an approach to specifically deplete mitochondrial DNA in macrophages. Our preliminary experiments were performed using the drug cyclosporin A (CsA), an inhibitor of cyclophilin D that regulates the opening of the mitochondrial permeability transition pore (mPTP), thus regulating mitochondrial integrity. Interestingly, our preliminary findings suggest that manipulation of mitochondrial integrity may be central to ESX-1-mediated modulation of the immune response during infection.

Advisor: Fredric Carlsson & Julia Lienard
Master´s Degree Project 60 credits in Molecular Biology (microbiology), 2016
Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Getachew, Konjit
supervisor
organization
course
MOBT01 20161
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
8891755
date added to LUP
2016-09-14 14:59:04
date last changed
2016-09-14 14:59:04
@misc{8891755,
  author       = {Getachew, Konjit},
  language     = {eng},
  note         = {Student Paper},
  title        = {Mycobacterial ESX-1 may target mitochondria to modulate the immune response},
  year         = {2016},
}