Salmonella - at home in the host cell.

REVIEW ARTICLE published: 03 June 2011 doi: 10.3389/fmicb.2011.00125 Salmonella – at home in the host cell Preeti Malik-Kale, Carrie E. Jolly, Stephanie Lathrop, Seth Winfree, Courtney Luterbach and Olivia Steele-Mortimer* Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institutes of Allergy and Infectious Disease, National Institute of Health, Hamilton, MT, USA Edited by: John S. Gunn, The Ohio State University, USA Reviewed by: Gregory Plano, University of Miami Miller School of Medicine, USA Tim Yahr, University of Iowa, USA *Correspondence: Olivia Steele-Mortimer, Rocky Mountain Laboratories, National Institutes of Allergy and Infectious Disease, National Institute of Health, 903 South 4th Street, Hamilton, MT 59840, USA. e-mail: The Gram-negative bacterium Salmonella enterica has developed an array of sophisticated tools to manipulate the host cell and establish an intracellular niche, for successful propagation as a facultative intracellular pathogen. While Salmonella exerts diverse effects on its host cell, only the cell biology of the classic “trigger”-mediated invasion process and the subsequent development of the Salmonella-containing vacuole have been investigated extensively. These processes are dependent on cohorts of effector proteins translocated into host cells by two type III secretion systems (T3SS), although T3SS-independent mechanisms of entry may be important for invasion of certain host cell types. Recent studies into the intracellular lifestyle of Salmonella have provided new insights into the mechanisms used by this pathogen to modulate its intracellular environment. Here we discuss current knowledge of Salmonella-host interactions including invasion and establishment of an intracellular niche within the host. Keywords: effectors, invasion, membrane tubules, phagosome, type III secretion system, vacuole INTRODUCTION Salmonella enterica are facultative intracellular pathogens that are found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. These Gram-negative bacteria are highly versatile and can adapt to a wide range of conditions both in the natural environment and within host organisms. While there are more than 2,500 S. enterica serovars only a few are commonly associated with disease in mammals. In humans, Salmonella are primarily associated with either localized intestinal infection or severe systemic disease. Salmonella gastroenteritis is usually self-resolving in healthy adults. It is one of the most common causes of foodborne disease, possibly affecting over 90 million people globally each year (Majowicz et al., 2010), and can be caused by many serovars although the most common are serovars Typhimurium and Enteritidis. Systemic disease in healthy humans (typhoid) is caused by serovar Typhi and a handful of other serovars that are strictly adapted to humans and higher primates. Immunocompromised individuals, such as those with AIDS or cancer, often develop systemic salmonellosis when infected with non-typhoidal Salmonella serovars (Gordon, 2008). The interplay between Salmonella and its vertebrate hosts is complex and involves a variety of virulence factors, although two of the most important are the type III secretion systems 1 and 2 (T3SS1 and T3SS2). Together these are used to inject over 30 effector proteins into the cytoplasm of host cells where they act on a variety of pathways. In epithelial cells, T3SS effectors are essential for both invasion and the subsequent establishment of the intracellular niche by Salmonella (Figure 1). The intracellular niche is a modified phagosome, known as the Salmonella-containing vacuole (SCV), which undergoes extensive T3SS effector-dependent membrane remodeling. This review focuses on how Salmonella establish their intracellular niche in epithelial cells with particular emphasis on invasion and SCV biogenesis. www.frontiersin.org SALMONELLA TYPE III SECRETION SYSTEMS Type III secretion systems are sophisticated contact-dependent delivery systems used by many Gram-negative bacterial pathogens to inject bacterial effector proteins into host cells. These nanoinjection systems consist of 20–30 proteins, many of which have homology to proteins in the flagellar export apparatus [for review (Marlovits and Stebbins, 2010)]. While all T3SSs are structurally similar, the effectors secreted by these delivery systems are extremely diverse (Samudrala et al., 2009). T3SS1 and T3SS2 are encoded on different regions of the chromosome, known as Salmonella pathogenicity islands 1 and 2 (SPI1 and SPI2) respectively, and are functionally and temporally distinct. The SPI1-encoded T3SS1 translocates a cohort of effectors that drive “trigger”mediated invasion of host cells whereas the SPI2-encoded T3SS2 is induced after invasion and is required for modulation of the intracellular environment. Nevertheless, it is now apparent that some overlap exists and effectors from both systems mediate biogenesis of the SCV (Hernandez et al., 2004; Drecktrah et al., 2005; Lawley et al., 2006; Brawn et al., 2007). SALMONELLA ENTRY In vivo, Salmonella can be found in a variety of phagocytic and non-phagocytic cells, including macrophages, dendritic cells, neutrophils, M cells, and enterocytes (Wallis et al., 1986; Jones et al., 1994; Richter-Dahlfors et al., 1997; Rescigno et al., 2001; Salcedo et al., 2001; Meyerholz et al., 2002; Geddes et al., 2007). Bacterial internalization, whether by phagocytosis or Salmonella-mediated invasion, involves actin remodeling at its core, which results in formation of plasma membrane extensions and ingestion of the target particle into the membrane bound phagosome. Common features of this process are the involvement of Rho family GTPases and phosphoinositides, which are instrumental in actin remodeling, membrane trafficking and signal transduction. The Rho June 2011 | Volume 2 | Article 125 | 1 Malik-Kale et al. Invasion and the Salmonella-containing vacuole in membrane phospholipid composition can also affect the net charge on the cytoplasmic surface of membranes resulting in the selective recruitment of proteins such as members of the Rho family of GTPases (Magalhaes and Glogauer, 2010). Bacterial internalization is accompanied by changes in host cell signaling pathways, affecting a number of vital cellular processes, including membrane trafficking, cell division, apoptosis, microbial killing, cytokine production, and antigen presentation. The ultimate fate of intracellular Salmonella is determined by a complex interplay of both host and bacterial factors. Here we focus on the entry methods employed by Salmonella invasion of non-phagocytic epithelial cells. FIGURE 1 | Biogenesis of the SCV. Invasive Salmonella use T3SS1 to translocate effector proteins into host cells. Several of these effectors drive actin-mediated ruffling and internalization of the bacteria into a modified phagosome or SCV. T3SS1 effectors are also present on the SCV memb (...truncated)