Manipulation of the host actin cytoskeleton by Salmonella — all in the name of entry
Introduction
Salmonella enterica comprise a family of pathogenic Gram-negative bacteria adept at targeting a variety of eukaryotic hosts [1, 2]. In humans, Salmonella spp. are believed to cause over one billion infections annually, with consequences ranging from acute gastroenteritis (food poisoning) to systemic, often fatal, typhoid fever. Central to their pathogenicity is their ability to enter non-phagocytic cells within the intestinal wall to reach a sheltered niche permissive for replication. Similar to other enteric pathogens, such as Yersinia spp. and Shigella spp., Salmonella has evolved a specialized protein secretion system, termed type III secretion system (TTSS), which delivers several bacterial ‘effector’ proteins directly into the host cell [3]. These virulence factors function in concert to engage host-cell proteins and orchestrate a remarkable series of events that culminate in bacterial entry.
In this review, we discuss recent advances in the understanding of Salmonella invasion into non-phagocytic cells. In particular, we focus on the mechanisms by which bacterial effectors coerce the cytoskeletal machinery of the host cell to facilitate internalization.
Section snippets
Cytoskeletal remodeling: Salmonella style
One of the hallmarks of Salmonella invasion is the profuse rearrangement of actin at the site of entry (Figure 1) [4, 5, 6]. This cytoskeletal remodeling drives localized membrane ruffling and lamellapodial extensions that envelop bacteria and trigger their internalization into membrane bound vacuoles. To date, the coordinated function of at least five distinct effectors (Table 1) are known to contribute to efficient Salmonella entry.
Rho GTPase activation: turning on the switch
Small GTPases of the Rho family are key regulators of eukaryotic cellular architecture [7]. They function as binary switches, cycling between inactive GDP- and active GTP-bound conformations. The cycle is largely controlled by two families of regulatory proteins, the guanine nucleotide exchange factors (GEFs), which catalyze GTP loading, and the GTPase activating proteins (GAPs), which accelerate GTP hydrolysis [8, 9]. Many bacterial pathogens have evolved intricate strategies to flip these
Actin nucleation and manipulation
The activation of RhoGTPases by Salmonella initiates a complex signaling cascade aimed at altering actin dynamics to promote invasion. This involves the coordinated function of multiple downstream effectors, in a specific temporal and spatial manner, to polymerize the monomeric globular actin (G-actin) into the highly ordered filamentous actin (F-actin) necessary to drive engulfment (Figure 2) [22]. An obvious downstream candidate is the heptameric Arp2/3 complex. This is a ubiquitous,
Regaining cytoskeletal composure: covering ones tracks
The cytoskeletal remodeling events that accompany Salmonella invasion are transient and typically reversed 2–3 hours post entry. Remarkably, Salmonella actively participates in this recovery process through the function of another type III effector protein called SptP [43]. This modular effector comprises two distinct biochemical activities, both designed to avert potential host cell damage. Its amino terminus encodes a GAP with specific activity towards Cdc42 and Rac. This GAP domain mimics its
Host degradation of translocated effectors: a new paradigm for regulating invasion
To synchronize invasion, multiple Salmonella effectors must engage their cellular targets in a precise, temporal and spatial manner. The spatial localization is inherent, given the restricted nature of the intimate contact between bacteria and their host. However, mechanisms governing the temporal regulation of effectors, especially those with directly opposing functions such as SopE and SptP, are less obvious. Recently, it was demonstrated that although SopE and SptP are delivered equally
Temporary residence: establishing the Salmonella containing vacuole
The entry process concludes with Salmonella inhabiting a spacious vacuole within the host [48, 49]. SopB plays a key role in assembling this Salmonella containing vacuole (SCV) by inducing profuse macropinocytosis events to accompany bacterial uptake. Indeed, Salmonella mutants lacking SopB activity invade with minimal macropinocytosis and occupy constricted vacuoles that undergo delayed maturation. Hernandez et al. [20••] showed that the inositol phosphatase activity of SopB is necessary to
Conclusions
The association between Salmonella enterica and their hosts has been shaped by extensive co-evolution and offers a fascinating example of how pathogens employ intricate strategies to subvert host cell function. During the past few years we have witnessed remarkable progress in our understanding of the complex interaction between Salmonella and its host cells. The knowledge that has been gained by studying these fascinating close encounters promises to enhance our understanding of the eukaryotic
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors apologize to those whose work could not be cited owing to space limitations. We are grateful to Olivia Rossanese and Jude Wilson for the critical reading of this manuscript and to Kirit Patel for help with the figures.
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