Mycobacterium tuberculosis has a unique repertoire of virulence mechanisms and generates a diverse spectrum of clinical disease. M. tuberculosis has two large families of proteins, the PE and the PPE proteins, which are likely to be critical to virulence. The PE and PPE proteins are rare in nonpathogenic mycobacteria but account for four percent of the M. tuberculosis genome. Many are secreted or surface localized and thus perfectly positioned to play critical roles in host-pathogen interactions. It has been difficult to use genetics to define the function of these proteins because of the sheer number of potentially redundant gene products. However, the fact that PE and PPE proteins are secreted in the absence of a signal sequence for the general secretory pathway suggests that there is an alternative secretion system for these proteins.
In Aim 1, we will identify and target this secretion pathway in M. tuberculosis. We expect that by disrupting the appropriate processing of some or all PE and PPE proteins, we will define the contribution of these proteins to the growth and virulence of M. tuberculosis. In the Aim 2, we will study the relationship between PE and PPE protein secretion, post-translational modification and the immunogenicity of these proteins. This work will refine our model of how PE and PPE proteins generate antigenic diversity in M. tuberculosis. Together, these data will dramatically increase our understanding of PE and PPE proteins and provide a foundation for future studies of their function and role in pathogenesis ? ? Despite the fact that tuberculosis kills millions of people annually, little is known about how it causes disease. Here we will develop tools to define the function of a unique family of mycobacterial proteins, the PE and PPE proteins that are likely to be critical to virulence. This work will provide a foundation for understanding the role of these proteins in the interaction between M. tuberculosis and the infected host. ? ? ? ?
| Millington, Kerry A; Fortune, Sarah M; Low, Jeffrey et al. (2011) Rv3615c is a highly immunodominant RD1 (Region of Difference 1)-dependent secreted antigen specific for Mycobacterium tuberculosis infection. Proc Natl Acad Sci U S A 108:5730-5 |
| Garces, Alejandra; Atmakuri, Krishnamohan; Chase, Michael R et al. (2010) EspA acts as a critical mediator of ESX1-dependent virulence in Mycobacterium tuberculosis by affecting bacterial cell wall integrity. PLoS Pathog 6:e1000957 |
