The Mycobacterium tuberculosis protein pair PE9 (Rv1088)-PE10 (Rv1089) forms heterodimers and induces macrophage apoptosis through Toll-like receptor 4

Abstract

Toll-like receptor (TLR)-mediated interactions of Mycobacterium tuberculosis (M.tb) with macrophages are major determinant in the outcome of innate immune defence and subsequent adaptive immune responses. Here we report a novel interaction of the M.tb protein pair PE9 (Rv1088)-PE10 (Rv1089) with the macrophage TLR4 leading to apoptosis and modulation of cytokine levels. We demonstrate that the two proteins physically interact, and that PE9 is required for the cell wall localization of PE10 in Mycobacterium smegmatis. Interaction of the PE9-PE10 complex with TLR4 in THP-1 macrophages was associated with increased levels of phospho-IRF-3, which correlated with an increase in transcript levels of its target gene interferon-β. THP-1 macrophages treated with PE9-PE10 complex showed multiple hallmarks of apoptosis and modulation of interleukin (IL)-1b and IL-10 levels. All of these effects were abrogated when cells were treated either with an antibody to PE10 or an anti-TLR4 antibody, indicating that the complex specifically interacts with TLR4 through PE10, establishing this protein pair as a TLR4 ligand. This novel observation of two proline-glutamate (PE) proteins forming functional heterodimers represents a considerable expansion of the PE_PPE repertoire in the context of receptor engagement and the concomitant modulation of host responses by this unique class of proteins. © 2015 John Wiley