LprE Suppresses TLR2-Dependent Cathelicidin and Autophagy Expression to Enhance Bacterial Survival in Macrophages

Despite representing a very important class of virulence proteins, the role of lipoproteins in the pathogenesis of remains elusive. In this study, we investigated the role of putative lipoprotein LprE in the subversion of host immune responses using the CDC1551 LprE (LprE ) mutant (∆LprE). We show that deletion of LprE results in reduction of virulence in human and mouse macrophages due to upregulation of vitamin D3-responsive cathelicidin expression through the TLR2-dependent p38-MAPK-CYP27B1-VDR signaling pathway. Conversely, episomal expression of LprE in improved bacterial survival. Infection in siTLR2-treated or macrophages reduced the survival of LprE expressing and because of a surge in the expression of cathelicidin. Infection with the LprE mutant also led to accumulation of autophagy-related proteins (LC3, Atg-5, and Beclin-1) and augmented recruitment of phagosomal (EEA1 and Rab7) and lysosomal (LAMP1) proteins, thereby resulting in the reduction of the bacterial count in macrophages. The inhibition of phago-lysosome fusion by LprE was found to be due to downregulation of IL-12 and IL-22 cytokines. Altogether, our data indicate that LprE is an important virulence factor that plays a crucial role in mycobacterial pathogenesis in the context of innate immunity.