Establishing the intracellular niche of obligate intracellular vacuolar pathogens

Abstract

Obligate intracellular pathogens occupy one of two niches - free in the host cell cytoplasm or confined in a membrane-bound vacuole. Pathogens occupying membrane-bound vacuoles are sequestered from the innate immune system and have an extra layer of protection from antimicrobial drugs. However, this lifestyle presents several challenges. First, the bacteria must obtain membrane or membrane components to support vacuole expansion and provide space for the increasing bacteria numbers during the log phase of replication. Second, the vacuole microenvironment must be suitable for the unique metabolic needs of the pathogen. Third, as most obligate intracellular bacterial pathogens have undergone genomic reduction and are not capable of full metabolic independence, the bacteria must have mechanisms to obtain essential nutrients and resources from the host cell. Finally, because they are separated from the host cell by the vacuole membrane, the bacteria must possess mechanisms to manipulate the host cell, typically through a specialized secretion system which crosses the vacuole membrane. While there are common themes, each bacterial pathogen utilizes unique approach to establishing and maintaining their intracellular niches. In this review, we focus on the vacuole-bound intracellular niches of Anaplasma phagocytophilum, Ehrlichia chaffeensis, Chlamydia trachomatis, and Coxiella burnetii.

Keywords: Anaplasma; Chlamydia; Coxiella; Ehrlichia; egress; membrane; pathogen vacuole; vesicular trafficking.

Figure 1

Pathogen interactions with the host vesicular trafficking pathways. Vesicular trafficking pathways in the host cell are rich in amino acids, lipids, and other resources essential for pathogen replication. The Ehrlichia chaffeensis vacuole (EcV) interacts with early endosomes and autophagosomes while the Anaplasma phagocytophilum vacuole (ApV) primarily interacts with autophagosomes and recycling endosomes. The Chlamydia trachomatis inclusion intercepts secretory and other Golgi-derived vesicles. Finally, Coxiella burnetii survives in a vacuole known as the CCV, a modified phagolysosome which readily interacts with host endosomes and autophagosomes. CCV, Coxiella containing vacuole; ApV, Anaplasma phagocytophilum containing vacuole; EcV, Ehrlichia chaffeensis containing vacuole. Created with Biorender.

Figure 2

Pathogen escape from the host cell. In order to perpetuate an infection, most bacterial pathogens actively escape from the host cell to infect neighboring cells. The vacuoles harboring Chlamydia trachomatis, Anaplasma phagocytophilum, and Ehrlichia chaffeensis fuse with the host cell plasma membrane, releasing bacteria into the extracellular space. The C. trachomatis inclusion can also be directly released from the cell, similar to exosomes. E. chaffeensis utilizes a third mechanism of cell-to-cell spread, where the vacuole is transported directly to neighboring cells by filopodia. Finally, the mechanism of egress for Coxiella burnetii has not been identified and is thought to occur by spontaneous lysis of the host cell after the bacteria’s developmental cycle has been completed. CCV, Coxiella containing vacuole; LCV, Coxiella Large Cell Variant; SCV, Coxiella Small Cell Variant; ApV, Anaplasma phagocytophilum containing vacuole; RC, reticulate cell; DC, dense cell EcV, Ehrlichia chaffeensis containing vacuole. Created with Biorender.