The Yop virulon of Yersinia: a bacterial weapon to kill host cells

Abstract

The genus Yersinia includes three species that are pathogenic for rodents and humans. Yersinia pestis, the agent of black death, is generally inoculated by a flea bite. I.: pseudotuberculosis is an agent of mesenteric adenitis and septicemia, and Y enterocolitica, the most prevalent species in humans, causes gastrointestinal syndromes, ranging from an acute enteritis to mesenteric lymphadenitis. Although these three Yersinia species infect their hosts by different routes and cause diseases of different severity, they present a common tropism for lymphoid tissues and a common capacity to resist the non-specific immune response 111. The Yersinia Yop (Yersinia outer protein) virulon (integrated virulence system) is the archetype of a new virulence mechanism, sometimes referred to as ‘type 111’ secretion. This mechanism allows extracellular bacteria which are in close contact with the surface of eukaryotic cells to inject virulence proteins into the cytosol of these cells in order to disarm them or disrupt their communication systems. This kind of mechanism is encountered in other animal pathogens, such as Salmonella spp., Shigella spp., enteropathogenic Esckerichia coli (EPEC) and Pseudoinonas aeruginosa, and also in the bacterial plant pathogens that elicit the ‘hypersensitive response’ (for review, see [2]). The Yop virulon of Yersinia is encoded by a 70-kb plasmid called pYV for ‘plasmid involved in Yersinia virulence’. It consists basically of a dozen secreted proteins, called Yop proteins, and their ‘contact’-or ‘type 111’-secretion apparatus, called Ysc. The Yop proteins form two distinct groups. The first group includes YopE, YopH, YopM, YopO, YopP and YopT, which are intracellular effectors, while the second one, including at least YopB, YopD and low calcium response virulence gene (LcrV), forms the translocation apparatus that is deployed at the bacterial surface to deliver the effectors into the target cell. The assembly of this translocation machinery is triggered by the contact between the bacterium and eukaryotic cell and controlled by proteins of the virulon, including YopN. Our present knowledge of the Yersinia system leads to the model presented in Figure 1 and described in this short paper. At 37”C, the host body temperature, the system is switched on. In these conditions, transcription of the yop genes is activated by VirF, a transcriptional activator of the AraC family [3,4]. The Ysc secretion machinery is synthesized and assembled in the bacterial membranes. It contains a putative ATPase, called YscN, which is probably the energizer of the system 151, and a set of integral membrane proteins. Among these, the YscC protein, an outer-membrane protein, forms a multimeric complex with a ring-shaped structure with an external diameter of about 200 A and an apparent central pore of about 50 A. This structure allows the passage of the Yop proteins across the external membrane of the bacterium [6]. Secretion of Yop proteins also requires some individual cytosolic chaperones, named Syc for ‘specific Yop chaperone’. These small acidic proteins bind to their cognate Yop proteins to prevent premature associations, to limit their toxicity and also to pilot them to the secretion machinery 171. Secretion of Yop proteins does not involve the cleavage of an N-terminal signal sequence, as is usually observed for secretion in bacteria. The secretion signal is nevertheless located in the N-terminal part of the Yop [8]. Recently, it has been suggested that the signal could be in the 5’ mRNA rather than in the N-terminus, but more information is needed to characterize this signal 191. The actual model for secretion of Yop proteins is