Leading a sheltered life: intracellular pathogens and maintenance of vacuolar compartments

Abstract

Many intracellular pathogens survive in vacuolar niches composed of host-derived membranes modified extensively by pathogen proteins and lipids. Although intracellular lifestyles offer protection from humoral immune responses, vacuole-bound pathogens nevertheless face powerful intracellular innate immune surveillance pathways that can trigger fusion with lysosomes, autophagy, and host cell death. Strategies used by vacuole-bound pathogens to invade and establish a replicative vacuole are well described, but how the integrity and stability of these parasitic vacuoles are maintained is poorly understood. Here, we identify potential mechanisms of pathogenic vacuole maintenance and the consequences of vacuole disruption by highlighting select bacterial and protozoan parasites.

Figure 1. Interaction of vacuolar niches of intracellular pathogens with host endomembrane system

Bacterial pathogens invade their hosts via the endophagocytic pathway and establish vacuolar niches that share features with one or more host organelles. These include Mycobacteria pathogen vacuole (MPV), Salmonella containing vacuole (SCV), Brucella (BCV) and Legionella (LCV) containing vacuole. Others such as C. trachomatis inclusion (INC), and Toxoplasma (PV) appear devoid of any markers of the endocytic traffic. While avoiding fusion with degradative compartments these organelles retain the ability to selectively intercept host vesicular traffic for nutrient acquisition. EE- early endosomes, RE-recycling endosomes, LE-late endosomes, Ly-Lysosomes, Autophag- Autophagosomes,

Figure 2. Integrity of pathogenic vacuoles is essential for avoidance of host immune surveillance

A. Pathogens such as Chlamydiae and Salmonella modulate interactions with host cytoskeleton and cytoskeletal motors (I), which may directly influence structural stability as well as membrane dynamics of their vacuoles. In T. gondii, interactions with host MTs mediate acquisition of host membranes via organelle scavenging. Interception of host membrane traffic is also mediated by differential interactions with host fusion machinery (II). Modulation of vacuolar membrane lipids especially cholesterol (III) may further influence vacuolar stability. Pathogens likely regulate the unique properties and interactions of their vacuoles via secretion of effector proteins (IV). B. Maintenance of vacuolar integrity is essential to avoid cytoplasmic immune defense pathways that include detection of microbial ligands by pathogen recognition receptors (PRRs). Such recognition is followed by activation of diverse pathways that can trigger not only host cell death and adaptive immune responses but also direct disruption of pathogenic vacuoles by IRG proteins.