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Investigating the role of type I interferon driven Spi2A induction during Mycobacterium marinum infection

Laschanzky, Katie (2020) MOBN03 20192
Degree Projects in Molecular Biology
Popular Abstract
Unravelling type I interferon signalling during Mycobacterial infection

In 2018 alone, 1.2 million deaths worldwide were due to tuberculosis (TB), an infection, usually of the lung, which is caused by the bacterium Mycobacterium tuberculosis. While antibiotic treatments have been available for decades, antibiotic resistance, as well as the lack of an effective vaccine has prevented the eradication of TB. M. tuberculosis has evolved alongside humans since the start of civilization; the bacillus has adapted to life as pathogens by developing many methods of evading human the immune system. One such survival strategy employed by M. tuberculosis is using a type of immune cell- the macrophage- as a host to survive within the body.... (More)
Unravelling type I interferon signalling during Mycobacterial infection

In 2018 alone, 1.2 million deaths worldwide were due to tuberculosis (TB), an infection, usually of the lung, which is caused by the bacterium Mycobacterium tuberculosis. While antibiotic treatments have been available for decades, antibiotic resistance, as well as the lack of an effective vaccine has prevented the eradication of TB. M. tuberculosis has evolved alongside humans since the start of civilization; the bacillus has adapted to life as pathogens by developing many methods of evading human the immune system. One such survival strategy employed by M. tuberculosis is using a type of immune cell- the macrophage- as a host to survive within the body. Macrophages are present in lung tissue and normally act as first responders to infection. They recognize microbial threats (as well as damaged and dead cells) and attempt to remove them through the process of phagocytosis. Once M. tuberculosis is recognized, it is taken up by the cell into a compartment called the phagosome. Normally the macrophage can eliminate bacteria though the harsh, acidic environment of the phagosome, however M. tuberculosis is unusual in that it can exit this compartment and live freely within the cell and avoid being digested.

Phagosomal escape has been found to be essential for causing disease in humans and mice. This process is made possible by a group of genes in the region of difference 1 (RD1) area of the M. tuberculosis genome. These genes make up the ESX-1 type VII secretion system which, while still not fully understood, has been found to cause type I interferon (IFN) production. Type I IFN production is normally involved in a protective signaling pathway found during viral infection. However, when it is triggered during bacterial infections such as TB, it has found to be largely harmful. During this signaling response as set of over 300 genes is regulated in attempt to combat infection.

In our lab M. marinum, a close relative of M. tuberculosis, is used as a model organism to attempt to understand the role of various genes involved in the host response to intracellular infection. The gene serpina3g, which encodes the protein Spi2A, is very highly expressed during M. marinum infection and is regulated by type I IFN signalling. Spi2A is a serpin (serine protease inhibitor) which inactivates cathepsin B, an enzyme which degrades host cell proteins. Under normal conditions, cathepsin B is isolated a cellular compartment called the lysosome, but when cells become stressed, this compartment may burst and cause damage to the cell. When a lysosome bursts (ie. due to damage from infection), the cell starts being rapidly broken down and a cell death pathway called necrosis may rapidly occur. Necrosis during M. tuberculosis infection has been found to result in the release of bacteria from the dying cell, intensifying disease.

Our hypothesis is that an increase of cellular Spi2A production may play a role in limiting cathepsin B-driven cell death. If an increase in Spi2A limits the amount of damage caused by cathepsin B released during infection, it is possible that necrotic cell death could be limited. If this is the case, damaged cells would be able to trigger a controlled form of cell death, called apoptosis instead. Understanding the cell death pathways involved during mycobacterial infection is an essential step in investigating the mycobacterial disease progression on a molecular level.

Master’s Degree Project in Molecular Biology 60 credits 2020
Department of Biology, Lund University
Advisor: Fredric Carlsson
Molecular Cell Biology; Microbiology group (Less)
Please use this url to cite or link to this publication:
author
Laschanzky, Katie
supervisor
organization
course
MOBN03 20192
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9015135
date added to LUP
2020-06-09 14:21:49
date last changed
2020-06-09 14:21:49
@misc{9015135,
  author       = {{Laschanzky, Katie}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Investigating the role of type I interferon driven Spi2A induction during Mycobacterium marinum infection}},
  year         = {{2020}},
}