Manipulation of rab GTPase function by intracellular bacterial pathogens

Abstract

Intracellular bacterial pathogens have evolved highly specialized mechanisms to enter and survive within their eukaryotic hosts. In order to do this, bacterial pathogens need to avoid host cell degradation and obtain nutrients and biosynthetic precursors, as well as evade detection by the host immune system. To create an intracellular niche that is favorable for replication, some intracellular pathogens inhibit the maturation of the phagosome or exit the endocytic pathway by modifying the identity of their phagosome through the exploitation of host cell trafficking pathways. In eukaryotic cells, organelle identity is determined, in part, by the composition of active Rab GTPases on the membranes of each organelle. This review describes our current understanding of how selected bacterial pathogens regulate host trafficking pathways by the selective inclusion or retention of Rab GTPases on membranes of the vacuoles that they occupy in host cells during infection.

FIG. 1.

M. tuberculosis. M. tuberculosis cells replicate in a phagosome where the normal maturation process has been blocked at an early stage. The phagosome retains Rab5, Rab14, and Rab22 but does not acquire Rab7 and does not fuse with lysosomes. The phagosome receives iron by continued fusion with early/recycling endosomes and also receives cargo from the trans-Golgi network (such as immature cathepsins). Despite the presence of Rab5 on M. tuberculosis phagosomes, its downstream effector EEA1 was not recruited. Bacterial products target the formation/retention of PI3P on M. tuberculosis phagosomes to block phagosome maturation. EE, early endosome; RE, recycling endosome; LE, late endosome; Lys, lysosome.

FIG. 2.

C. burnetii. C. burnetii cells replicate in a bacterium-modified vacuole that shares many characteristics with lysosomes as well as with autophagosomes. Although C. burnetii cells passively traffic through the default endocytic pathway, as evidenced by the sequential recruitment of Rab5 and Rab7, their delivery to lysosomes is delayed as a result of interactions with the host autophagy pathway. Interactions with the autophagy pathway, such as the recruitment of LC3 and Rab24, as well as the formation of the spacious replicative vacuole require bacterial protein synthesis. EE, early endosome; LE, late endosome; Lys, lysosome, AP, autophagosome.

FIG. 3.

H. pylori. H. pylori-containing vacuoles originate from the fusion of late endocytic vesicles in a process mediated by the VacA-dependent retention of active Rab7 and the interaction of Rab7 with RILP. Rab7 retention on the bacterium-containing vacuoles inhibits further maturation of the vacuole, thus limiting the degradative capabilities of the vacuole and enhancing the intracellular survival of the organism. In the absence of VacA, spacious vacuoles fail to form, and vacA-containing vacuoles acquire cathepsin D, resulting in a decrease in the intracellular survival of the bacteria. EE, early endosome; LE, late endosome; Lys, lysosome.

FIG. 4.

S. enterica serovar Typhimurium. S. enterica serovar Typhimurium cells replicate in SCVs in host cells. The SCV undergoes a multistep interaction with the host endosomal system but blocks fusion with lysosomes. Up to 18 Rabs are present on the SCV during its maturation sequence. Those Rabs enriched on SCVs containing wild-type bacteria are indicated. Some Rabs are enriched on model phagosomes containing noninvasive bacteria that traffic to and are killed in lysosomes (ΔinvA/Inv). Importantly, these Rabs are excluded from wild-type SCVs, suggesting that the bacteria actively modulate Rab localization to prevent SCV fusion with lysosomes. Several hours after infection, the SCV undergoes extensive fusion with late endosomes. This gives rise to the formation of membrane tubules that extend away from SCVs, known as Sifs. Rab7 and Rab9 are both required for Sif formation. The late SCV may also receive cargo from the trans-Golgi network, possibly providing nutrients for bacteria in vacuoles. EE, early endosome; RE, recycling endosome; LE, late endosome; Lys, lysosome.

FIG. 5.

Chlamydia species. Chlamydiae replicate within a nonacidified inclusion that is actively remodeled by chlamydiae during the first 2 h p.i. by processes that require chlamydial protein synthesis. As a result of this chlamydia-mediated remodeling, fusion with lysosomes is inhibited, and the inclusion is trafficked to the peri-Golgi region, where it intercepts Golgi apparatus- and MVB-derived vesicles as well as lipid bodies. Multiple Rabs, including both endocytic (Rab4 and Rab11) and secretory (Rab1, Rab6, and Rab10) Rabs, are recruited to the inclusion in a guanine nucleotide-dependent fashion. For at least one Rab, Rab4, recruitment to the inclusion is mediated by a chlamydia-encoded inclusion membrane protein, Inc CT229. Neither the functional role nor the host source of inclusion-localized Rabs has been identified. EE, early endosome; RE, recycling endosome; LE, late endosome; Lys, lysosome.

FIG. 6.

L. pneumophila. L. pneumophila cells replicate within an ER-derived vacuole that avoids fusion with the default endocytic pathway. Legionella first recruits and fuses with early secretory vesicles and then subsequently interacts with the ER in an Icm/DotA-dependent manner, resulting in a ribosome-studded RV. In primary macrophages derived from bone marrow of the permissive A/J mouse, after a “pregnant pause,” the RV is delivered to lysosomes. Legionella exploits the early secretory pathway by targeting key regulators of ER-to-Golgi apparatus trafficking, including the small GTPases Rab1, Arf1, and Sar1. Rab1 is recruited to the LCV via a direct interaction with the type IV secreted effector DrrA/SidM, which functions as a Rab1-specific GEF, while LidA plays a cooperative role in recruiting and activating Rab1. Arf1 is recruited to the LCV via a direct interaction with the type IV secreted effector RalF, which functions as an Arf1 GEF. EE, early endosome; LE, late endosome; Lys, lysosome.