The cell wall lipid PDIM mediates phagosomal escape and host cell exit of Mycobacterium tuberculosis

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Mycobacterium tuberculosis (Mtb) has a complex interaction with host cell death signaling pathways. Mtb inhibits apoptosis at early stages of infection but transitions to promote necrosis at later stages of infection to allow for host cell exit. Mtb phagosomal escape has proven to be a crucial step in the transition to the pro-necrotic phase of infection. However, Mtb phagosomal escape is poorly understood. Previously, we described a transcriptional repressor, Rv3167c that regulates Mtb phagosomal escape and necrosis induction. MtbΔRv3167c demonstrates increased phagosomal escape accompanied by increased necrosis induction in infected macrophages. Here, we show that MtbΔRv3167c over expresses the Mtb virulence lipid phthiocerol dimycocerosates (PDIM) and the over expression of PDIM is responsible for the increased necrosis seen in MtbΔRv3167c. Further, we demonstrate that PDIM contributes to the phagosomal escape of Mtb. This work ascribes a novel, and crucial, role of PDIM in Mtb pathogenesis.