Life on the inside

focus on Microbial Host cell subversion

REVIEWS
Life on the inside: the intracellular lifestyle of cytosolic bacteria
Katrina Ray*, Benoit Marteyn*‡, Philippe J. Sansonetti‡ and Christoph M. Tang*

Abstract | Bacterial pathogens exploit a huge range of niches within their hosts. Many pathogens can invade non-phagocytic cells and survive within a membrane-bound compartment. However, only asmall number of bacteria, including Listeria monocytogenes, Shigella flexneri, Burkholderia pseudomallei, Francisella tularensis and Rickettsia spp., can gain access to and proliferate within the host cell cytosol. Here, we discuss the mechanisms by which these cytosolic pathogens escape into the cytosol, obtain nutrients to replicate and subvert host immune responses.
Trigger mechanism
Amechanism used by bacteria, such as the genera Shigella and Salmonella, to enter cells. Bacteria interact directly with the eukaryotic cell cytoskeleton by injecting bacterial effectors through a dedicated secretion system. These effectors cause massive cytoskeletal rearrangements to engulf the bacterium in an entry vacuole.

*Centre for Molecular Microbiology and Infection, Department ofMicrobiology, Flowers Building, Armstrong Road, Imperial College London, London SW7 2AZ, UK. ‡ Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 28 rue du Dr Roux, F ‑75724 Paris Cédex 15, France. Correspondence to C.M.T. e‑mail: c.tang@imperial.ac.uk doi:10.1038/nrmicro2112 Corrected online 16 April 2009

The ability to survive intracellularly is crucial for several pathogenic bacteriaafter they invade their eukaryotic target cells. Following entry using a trigger mechanism or zipper mechanism1, bacteria are internalized within a membrane-bound vacuole. Under normal circumstances, the vacuole progressively acidifies as it develops into a mature degradative phagolysosome2. Some pathogens survive in this niche either by preventing vacuole–lysosome fusion or by modifying theenvironment within the phagolysosome. Many of the mechanisms by which pathogens remain within a membrane-bound compartment and manipulate this subcellular site to their advantage have been defined. By contrast, other bacteria have evolved to escape from the vacuole and continue their life cycle within the cytosol1,3,4. In this Review, we refer to this category of pathogens as cytosolic bacteria. Farless is known about the cytosol as a site of bacterial replication. It is easy to assume that the cytosol provides a rich source of nutrients and is protected from host immune killing. However, if this were the case, then it might be expected that many more bacteria would exploit the cytosol as a habitat for growth and replication. Instead, only a select number of bacteria are adapted for growthwithin the cytosol. Here, we discuss our current understanding of the intracellular lifestyle of cytosolic bacteria by focusing on Shigella flexneri, Burkholderia pseudomallei, Listeria monocytogenes, Francisella tularensis and Rickettsia species. The life cycle of cytosolic bacteria can be divided into three stages: escape from the vacuole, replication within the cytosol and manipulation of theinnate immune responses triggered in the cytosol. We describe the bacterial adaptations that contribute to the success of pathogens during each of these stages and how this information contributes to our knowledge of the nutrients in the cytosol that sustain the replication of microorganisms.

Escape from the vacuole Escape from the vacuole is the crucial first step in the life cycle of cytosolicpathogens. This occurs rapidly following invasion, and most pathogens are detected free in the cytosol within 30 minutes of invasion5–13 (TABLE 1). The speed of vacuole lysis suggests that the bacteria are in a race for survival. The vacuole acidifies rapidly, within 15 minutes of forming 14, and bacteria must escape before the nascent vacuole fuses with lysosomes, which contain various potent...