Multiplicity of Salmonella entry mechanisms, a new paradigm for Salmonella pathogenesis

Abstract

The Salmonella enterica species includes about 2600 diverse serotypes, most of which cause a wide range of food- and water-borne diseases ranging from self-limiting gastroenteritis to typhoid fever in both humans and animals. Moreover, some serotypes are restricted to a few animal species, whereas other serotypes are able to infect plants as well as cold- and warm-blooded animals. An essential feature of the pathogenicity of Salmonella is its capacity to cross a number of barriers requiring invasion of a large variety of phagocytic and nonphagocytic cells. The aim of this review is to describe the different entry pathways used by Salmonella serotypes to enter different nonphagocytic cell types. Until recently, it was accepted that Salmonella invasion of eukaryotic cells required only the type III secretion system (T3SS) encoded by the Salmonella pathogenicity island-1. However, recent evidence shows that Salmonella can cause infection in a T3SS-1-independent manner. Currently, two outer membrane proteins Rck and PagN have been clearly identified as Salmonella invasins. As Rck mediates a Zipper-like entry mechanism, Salmonella is therefore the first bacterium shown to be able to induce both Zipper and Trigger mechanisms to invade host cells. In addition to these known entry pathways, recent data have shown that unknown entry routes could be used according to the serotype, the host and the cell type considered, inducing either Zipper-like or Trigger-like entry processes. The new paradigm presented here should change our classic view of Salmonella pathogenicity. It could also modify our understanding of the mechanisms leading to the different Salmonella-induced diseases and to Salmonella-host specificity.

Keywords: Adhesion; Salmonella; Trigger; Zipper; invasin; invasion; type III secretion system.

Figure 1

Trigger and Zipper mechanisms used by Salmonella to enter cells. (A) Schematic representation of the Trigger mechanism: Using a type III secretion system (T3SS), Salmonella bacterial effectors (SipA, SipC, SopB, SopE, SopE2) are directly injected into eukaryotic cells. SopE, SopE2, and SopB activate the RhoGTPases Rac/Cdc42/RhoG to allow actin cytoskeleton remodeling via cellular proteins, such as WASP/Scar/WAVE/WASH, which activate the Arp2/3 complex. In contrast, SipA and SipC bind directly to actin. To induce the formation of membrane ruffles and internalization, the recruitment of the exocyst complex is required and is manipulated by SipC and by SopE via the Ras-related protein RalA. (B) Scanning electron microscopy of Salmonella entering into cells via a Trigger mechanism, which is characterized by the apparition of large membrane ruffles at the bacterial entry site. (C) Schematic representation of the Zipper mechanism: the Rck invasin expressed on Salmonella outer membrane interacts with its receptor on the host cell membrane, leading to phosphorylation of at least one tyrosine kinase. Activation of the class I PI 3-kinase induces PI (3,4,5)P3 formation, participating to Akt activation. The activation of the GTPase Rac1, downstream of the Akt/PI 3-kinase activation, and the GTPase Cdc42 trigger actin polymerization via the Arp2/3 nucleator complex. The mechanism controlling Cdc42 during Rck-induced signaling pathway is still unknown. Dotted arrows represent possible signaling events and/or interactions. (D) Scanning electron microscopy of Salmonella entering into cells via a Zipper mechanism, which is characterized by weak membrane rearrangements.