Virulence strategies for mycobacterial persistence: investigating the role of the mammalian cell entry proteins

The global burden of mycobacterial infections, especially tuberculosis, is inconceivable with at least one new case of infection arising every second and about two million people dying annually. Persistence of mycobacteria arises from long durations of dormancy in host macrophages evading host defense mechanisms and using unusual nutrients. Mycobacterial mammalian cell entry (Mce) transport systems play an important role in facilitating cell entry and they also import nutrients such as cholesterol or lipid.

We will characterise the Mce4 proteins and their assembly in the Mce4 transport system. One of the key goals is to isolate a minimal hetero-complex of the Mce proteins forming the transport channel for structural and functional studies. Two possible models for organisation are proposed: a heterohexamer of six Mce proteins or a stack of six homo-hexamers of individual Mce proteins. Biochemical characterisation of individual Mce proteins and interaction studies between different Mce proteins will help establish the organisation model of Mce4 proteins. Structural studies using X-ray crystallography or other techniques and functional characterisation for cholesterol binding and cell invasion will shed light on the structure and function of Mce4 proteins within the transport assembly.

This study will improve our understanding of mycobacterial persistence.