PLA, a surface protease, is an essential virulence factor, exerting multiple effects in the host to achieve the successful dissemination of from peripheral contamination sites by the cleavage of fibrin clots  through the activation of plasminogen to plasmin, and by facilitating adhesion to extracellular matrices and invasion of mammalian endothelial cells [21,22]. to the sporadic nature of plague outbreaks and the hysteria which may surround them. Killed whole cell (KWC) vaccine formulations cannot be exhibited to protect against experimental pneumonic plague [3C5], unlike a live attenuated EV76 vaccine. However, the efficacy data from the clinical use of the EV76 vaccine are more mixed . Here Bovinic acid we review the pathogenicity of species and is a Gram-negative, rod-shaped bacterium belonging to the species within the Enterobacteriaceae family . Since its discovery and isolation by Yersin in 1894 , this organism has been the focus of study and interest for many scientists and has become a paradigm of bacterial evolution. is thought to have evolved over the last 1500C20 000 years from the enteropathogen, , to become a flea-vectored pathogen lethal to man [9,10]. The flea acquires from an infected rodent and the bacteria multiply in the mid-gut, extending eventually into the flea’s oesophagus and proventriculus. The flea reaches a blocked stage in which it can bite but cannot feed without first regurgitating the bacterial meal into a new host . Additionally, in the context of the rapid spread of disease, it is thought that unblocked fleas can achieve early-phase transmission of bacteria to new hosts . has been categorized as a facultative intracellular pathogen because on mammalian contamination it gains entry to and grows in host macrophages, in which it is transported to draining lymph nodes . On apoptosis of the infected macrophage, becomes extracellular, colonizing major organs and causing fatal systemic disease through the deployment of a range of virulence mechanisms and immune evasion strategies. Expression of virulence factors and evasion of host innate immunity In common with the enteropathogenic yersiniae, and possesses a 70 kb plasmid (pYV/pCD1) which encodes for the V-antigen and type III secretion system (T3S); unlike the other yersiniae, however, has also acquired a larger plasmid (100 kb) termed pFra/pMT1 and a small plasmid (95 kb) termed pPst/pPCP1/pPla [13C15]. These plasmids encode for a range of virulence factors which, collectively, further the survival and dissemination of in the mammalian host. Additionally, deploys a range Bovinic acid of mechanisms to escape the host’s innate defences. The pFra/pMT1 plasmid encodes for two proteins, Fraction 1 antigen (F1-antigen) and a phospholipase D, known as murine toxin (MT), while the pPst/pPCP1/pPla plasmid encodes for a collection of proteins which facilitate the dissemination of insect-transmitted in the mammalian host [16C19]. These factors include pesticin, coagulase and plasminogen activator (PLA) and are involved collectively at the interface of successful transmission of by the flea (pesticin, coagulase) and the subsequent breaking-down of physical barriers (endothelial and cell membrane) in the host to achieve dissemination. PLA, a surface protease, is an essential virulence factor, exerting multiple effects in the host to Bovinic acid achieve the successful dissemination of from peripheral contamination sites by the cleavage of fibrin clots  through Bovinic acid the activation of plasminogen to plasmin, and Bovinic acid by facilitating adhesion to extracellular matrices and invasion of mammalian endothelial cells [21,22]. When a Pla deletion mutant of was delivered intranasally to mice it established a local pulmonary contamination, but did not disseminate from the lungs, due possibly to the entrapment of bacteria in fibrin clots . Further, there is evidence that PLA inactivates innate defence mechanisms deployed by the host, such Tmem1 as the production of cationic anti-microbial peptides . In contrast, and despite its name, the major virulence role ascribed to murine toxin is usually to protect bacteria in the flea gut from degradation by digestive enzymes . F1-antigen is usually a capsule-associated protein which is expressed under the influence of the operon around the bacterial cell surface at 37C . Synthesized as a 15k Da monomer, it forms a large homopolymer ( 200 kDa) around the bacterial cell surface in a stacked ring structure composed of heptamers . The physical structure of F1-antigen alone was thought to deter phagocytosis of the bacteria by macrophages, thus protecting from the host’s innate immune system . However, it is now thought that F1-antigen inhibits bacterial adhesion to epithelial cells, thus assuming a role in bacterial transmission in addition to, or instead of, its anti-phagocytic effect [29C31]. Unlike PLA, however, F1-antigen is not strictly an essential virulence factor in has also lost or inactivated genes which are associated with its initial enteropathogenic lifestyle; for example, and genes (involved with invasion and colonization).