Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is a very successful pathogen, strictly adapted to humans and the cause of tuberculosis. Its success is associated with its ability to inhibit host cell intrinsic immune responses by using an arsenal of virulence factors of different nature. It has evolved to synthesize a series of complex lipids which form an outer membrane and may also be released to enter host cell membranes. In addition, secreted protein effectors of Mtb are entering the host cell cytosol to interact with host cell proteins. We briefly discuss the current model, involving the ESX-1 type seven secretion system and the Mtb lipid phthiocerol dimycoserosate (PDIM), of how Mtb creates pores in the phagosomal membrane to allow Mtb proteins to access to the host cell cytosol. We provide an exhaustive list of Mtb secreted proteins that have effector functions. They modify (mostly inhibit but sometimes activate) host cell pathways such as: phagosome maturation, cell death, cytokine response, xenophagy, reactive oxygen species (ROS) response via NADPH oxidase 2 (NOX2), nitric oxide (NO) response via NO Synthase 2 (NOS2) and antigen presentation via MHC class I and class II molecules. We discuss the host cell targets for each lipid and protein effector and the importance of the Mtb effector for virulence of the bacterium.

Keywords: ESX-1; Mycobacterium tuberculosis; NOX2; cell death; cytokines; effector; lipids; phagosome maturation.

Figure 1

Model of the mechanism of membrane lysis by the cooperation of ESX-1 and PDIM. ESX-1 secretes EsxA and EsxB in a 1:1 heterodimer. This dimer is separated upon pH decrease and / or post-translational modifications, and free EsxA can induce pore formation. PDIM can potentiate EsxA membranolytic activity by either synergizing the pore forming activity of EsxA or by acting on the EsxA/B heterodimer complex separation.

Figure 2

Host cell targets of EsxA and/or the EsxA/B complex. EsxA can antagonistically bind MHCI and TLR2, while it can bind to SR-B1 to enhance invading the lung epithelium. EsxA targets the phagosomal membrane for pore formation.

Figure 3

Models of mycobacterial envelope and lipid transfer. (Left) Simplified model of the organization of the mycobacterial envelope with the main virulence lipids highlighted. (Right) Representation of the different potential mechanisms of lipid release and transfer to the host cell membrane. Lipids can be release by emission of membrane vesicles, or by shedding of the capsular layer into the phagosome lumen or due to close physical contact directly into the phagosome membrane. SL, Sulfolipids; PDIM, Phthiocerol Dimycerosates; TDM, Trehalose Dimycolates; MA, Mycolic Acid; LAM, Lipoarabinomannan.