Project

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Structural studies of type VII secretion system

Applicant Pojer Florence
Number 129026
Funding scheme Marie Heim-Voegtlin grants
Research institution Global Health Institute EPFL SV-DO
Institution of higher education EPF Lausanne - EPFL
Main discipline Biochemistry
Start/End 01.02.2010 - 31.01.2012
Approved amount 271'400.00
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All Disciplines (3)

Discipline
Biochemistry
Molecular Biology
Biophysics

Keywords (3)

X-ray crystallography; Type VII secretion system; Mycobacterium tuberculosis

Lay Summary (English)

Lead
Lay summary
The recently identified type VII secretion systems (T7SS) are found in various Gram-positive bacteria, pathogenic or not, and probably play a general role in bacterial homeostasis and cell-to-cell communication. However, T7SS do play important roles in pathogenesis, e.g. in the human pathogens Mycobacterium tuberculosis (M. tb) and Staphylococcus aureus, by secreting virulence factors into the host cells. T7SS are encoded by conserved gene clusters comprising approximately 20 open reading frames, which contain genes coding for the core components of T7SS, for accessory proteins and secreted proteins (model of T7SS in SciencePart page 6). Five T7SSs clusters are present in M. tb, one of them, ESX-1 being the major virulence determinant, which has been lost in the vaccine strain M. bovis BCG.

My objective is to establish the functional architecture of T7SS using X-ray crystallography coupled to in vitro biochemical studies. I will focus my work on T7SS of Mycobacterium species for several reasons. My host laboratory is specialized in TB and Leprosy research, and all the necessary biological input and background can be found in the lab. TB is a leading infectious killer, causing more deaths per day than AIDS. We hope that understanding the molecular basis of T7SS will change our way of thinking about the virulence of M. tb and give new opportunities to combat TB, in the form of drug targets.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
EspD Is Critical for the Virulence-Mediating ESX-1 Secretion System in Mycobacterium tuberculosis
Chen JM, Boy-Rottger S, Dhar N, Sweeney N, Buxton RS, Pojer F, Rosenkrands I, Cole ST (2012), EspD Is Critical for the Virulence-Mediating ESX-1 Secretion System in Mycobacterium tuberculosis, in JOURNAL OF BACTERIOLOGY, 194(4), 884-893.
Atypical DNA recognition mechanism used by the EspR virulence regulator of Mycobacterium tuberculosis
Blasco B, Stenta M, Alonso-Sarduy L, Dietler G, Dal Peraro M, Cole ST, Pojer F (2011), Atypical DNA recognition mechanism used by the EspR virulence regulator of Mycobacterium tuberculosis, in MOLECULAR MICROBIOLOGY, 82(1), 251-264.
Towards anti-virulence drugs targeting ESX-1 mediated pathogenesis of Mycobacterium tuberculosis
Chen J.M. Pojer F.* Blasco B.and Cole S.T. (2010), Towards anti-virulence drugs targeting ESX-1 mediated pathogenesis of Mycobacterium tuberculosis, in Drug Discovery Today – Disease Mechanisms, 7(1), e25-e31.

Collaboration

Group / person Country
Types of collaboration
NKI Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Synchrotron Soleil France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
SLS/PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Abstract

The recently identified type VII secretion systems (T7SS) are found in various Gram-positive bacteria, pathogenic or not, and probably play a general role in bacterial homeostasis and cell-to-cell communication. However, T7SS do play important roles in pathogenesis, e.g. in the human pathogens Mycobacterium tuberculosis (M. tb) by secreting virulence factors into the host cells. T7SS are encoded by conserved gene clusters comprising approximately 20 open reading frames, which contain genes coding for the core components of T7SS, for accessory proteins and secreted proteins. Five T7SSs clusters are present in M. tb, one of them, ESX-1 being the major virulence determinant, which has been lost in the vaccine strain M. bovis BCG. My host laboratory is a world leader in tuberculosis (TB) research aiming to discover and develop new drugs for the treatment of TB through an integrated approach. We propose to use protein X-ray crystallography coupled to biochemical analysis to establish the organization, architecture and function of this newly discovered T7 secretory apparatus, which represents a potential target for new classes of TB drugs.
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