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04/20/2017

AIMMS scientists add crucial knowledge to understanding of the biology of tuberculosis causing bacterium

In a paper published recently in Nature Microbiology, Edith Houben’s group (Molecular Microbiology) together with scientists from across Europe reveal the first structure of an assembly of membrane proteins known as the Type VII secretion system found in a group of bacteria which cause diseases such as tuberculosis.

These results represent a big step forward in our understanding of how some of the deadliest pathogenic bacteria such as Mycobacterium tuberculosis function. These findings can be used as a basis to investigate secretion as a mechanism by which mycobacteria infect and interact with the human host.

New drugs are urgently needed in the fight against tuberculosis as the bacteria responsible for causing the disease becomes increasingly resistant to current antibiotics. According to the World Health Organisation, tuberculosis resulted in 1.8 million deaths and 10.4 million new infections in 2015, making it one of the top 10 causes of death in humans worldwide.

Secretion systems

The bacterium responsible, Mycobacterium tuberculosis (Mtb), has a complex biology and a comprehensive understanding of this is crucial to inform the development of new drugs. Mtb relies heavily on Type VII secretion systems, or T7SSs (see figure), to transport molecules across its cell envelope upon infection, disarming and damaging the host cell. Due to their crucial role, these secretion systems are important targets for much needed new drugs. Drugs designed to block these systems could stop the pathogen in its tracks. However, just how these secretion systems work is poorly understood.

In total, five T7SS systems are found in mycobacteria. Known as ESX-1 to ESX-5, these systems are all very similar but each transport specific molecules. A major research focus of the Houben group is the biochemical and functional analysis of the T7SSs. In this new study, they collaborated together with Matthias Wilmanns’ group at EMBL Hamburg to isolate these membrane complexes to high homogeneity and electron microscopy (EM) data were subsequently collected by Thomas Marlovits’ group at the IMP-IMBA Vienna, allowing the first reconstruction of a T7SS structure. The membrane complex consists of a large assembly of 4 types of proteins that form a ring around a central pore. The particular challenge during the structural analysis was that the sample contains a rigid core from which flexible domains project away. The group at EMBL Hamburg collected Small Angle X-ray Scattering (SAXS) data to help understand what the flexible protein domains look like and how these parts of the secretion system might move. Possibly, these arm-like proteins help to move the molecules of different shapes and sizes from the inside of the bacterial cell through the pore of the secretion system. Further biochemical and genetic experiments carried out at VU Amsterdam provide in vivo insights into the components required for assembly of the secretion system.

Tuberculosis_figure
(credits: Luciano Ciccarelli)

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