The role and mechanism of mycobacterial secreted virulence effectors in disease pathogenesis (360G-Wellcome-105388_Z_14_Z)

£160,792

Host immune evasion, modulation, and exploitation are key strategies pathogenic mycobacteria use to establish infection and transmit to new hosts. Yet the molecular mechanisms used remain surprisingly elusive. Mutational analysis has identified several bacterial virulence determinants and their mechanisms are under active study. I plan to dissect the mechanism of action of two secreted mycobacterial virulence factors, Erp and ESAT6, which act at distinct steps of the infection process. Erp promotes bacterial growth within macrophages. ESAT6 promotes bacterial expansion in granulomas by inducing the concerted processes of apoptosis of infected macrophages and recruitment of new macrophages, which phagocytose bacteria from the dying cells. I will pursue the understanding of the molecular bases of these processes as follows: 1. ESAT6: ESAT6 has membranolytic activity that is tightly linked to its virulence. ESAT6 is necessary, but insufficient for membranolysis, suggesting additional determinants are involved. I will investigate the ESAT6-dependent mechanism of host membrane disruption by determining what is required and how membranolysis is occurring. 2. Erp: Erp induces virulence by promoting intramacrophage bacterial growth. I will determine the mechanisms whereby mycobacteria maintain membrane integrity by studying the structural and secreted roles of Erp and investigating the host defences countered by Erp function.

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Grant Details

Amount Awarded 160792
Applicant Surname Shanahan
Approval Committee PhD Studentships
Award Date 2014-07-14T00:00:00+00:00
Financial Year 2013/14
Grant Programme: Title PhD Studentship (Basic)
Internal ID 105388/Z/14/Z
Lead Applicant Mr Jonathan Shanahan
Partnership Value 160792
Planned Dates: End Date 2018-09-30T00:00:00+00:00
Planned Dates: Start Date 2014-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region East of England
Sponsor(s) Prof Paul Lehner