Geographical heterogeneity between Far Eastern and Western countries in prevalence of the virulence plasmid, the superantigen Yersinia pseudotuberculosis-derived mitogen, and the high-pathogenicity island among Yersinia pseudotuberculosis strains.

Yersinia pseudotuberculosis has a wide distribution in most countries with cold climates and is recognized as an important causal agent of sporadic and epidemic human enteric disease (45). Yersiniae pathogenic to humans are known either as the causative agent of plague (Y. pestis) or as food-borne pathogens that cause intestinal diseases (Y. enterocolitica) (8). The pathogenicity of each of these species depends on the presence of 70-kb virulence plasmid pYV (for plasmid associated with Yersinia virulence) (4, 13, 25, 33). This plasmid is essential for virulence, and its presence differentiates pathogenic from nonpathogenic Yersinia. Additionally, Y. pestis, Y. enterocolitica biotype 1B, and almost all European strains of Y. pseudotuberculosis serotype O1 have a pathogenicity island termed the high-pathogenicity island (HPI) on the chromosome (7), and almost all Far Eastern strains of Y. pseudotuberculosis produce a novel superantigenic toxin designated Y. pseudotuberculosis-derived mitogen (YPM) encoded by a gene on the chromosome (1, 46). Y. pseudotuberculosis has been classified into serotypes O1 to O14 (43); serotypes O1 to O5 have been isolated in Europe and the Far East and almost all are pathogenic, while serotypes O6 to O14 have been isolated only from wild animals and environments in the Far East but never from clinical samples (1, 13, 17, 20, 21, 43). There are numerous reports of each virulence factor of Y. pseudotuberculosis (1, 5, 7, 14, 19, 34, 45, 46); however, comparisons of the prevalences of above virulence factors in the wild Y. pseudotuberculosis strains have not been documented. Pathogenic Yersinia can be further subdivided into low-pathogenicity strains, i.e., strains that induce a mild intestinal infection in humans and at low doses are not lethal for mice, and high-pathogenicity strains, which cause severe systemic infection in humans and at low doses kill mice (7). This difference in the level of virulence correlates with the presence of a large chromosomal fragment with characteristics of an HPI, because its presence is essential for expression of a high-virulence phenotype (7). This chromosomal segment is involved in biosynthesis, regulation, and transport of the siderophore yersiniabactin (24, 35); thus the Yersinia HPI can be considered an iron capture island (7). The presence and size of the HPI within the Y. pseudotuberculosis species correlate with the serotype. At present, a complete island was found only in strains of serotype O1, HPI with a 9-kb truncation in its left-hand part is characteristic of serotype O3 strains, and HPI has not been detected in strains of other serotypes (5, 14, 34). Since data on only 43 strains, all of Y. pseudotuberculosis obtained from Europe (except for one strain of serotype O5a from Russia and two strains of serotype O4b from Japan [34]), have been reported (5, 14, 34), it is difficult to draw any conclusion concerning the definite prevalence of HPI, especially with regard to geographical distribution and the source of infection. Although the main clinical manifestations of Y. pseudotuberculosis infection in Europe are fever, gastroenteric symptoms, and mesenteric lymphadenitis, those in Japan (21, 37), far-eastern Russia (42), and Korea (12) include not only gastrointestinal symptoms but also a variety of systemic manifestations such as fever, scarlatiniform rash, desquamation, erythema nodosum, and arthritis. The clinical pathophysiology of Y. pseudotuberculosis has many similarities to that of infections caused by Staphylococcus aureus and Streptococcus pyogenes, which are each known to produce a superantigen (38). Y. pseudotuberculosis is also known to produce a superantigenic toxin, known as YPM (1, 46) and then YPMa after the discovery of a variant (36). It was experimentally confirmed that YPMa is a virulence factor which exacerbates the toxicity of Y. pseudotuberculosis in systemic but not in gastroenteric infection in mice (11). Superantigen-producing strains could be separated into three clusters which contained YPMa, YPMb, or YPMc encoded by the ypmA, ypmB (36), and ypmC (10) genes, respectively. We and another research group (47, 49) reported that there was a distinct geographical heterogeneity between the Far East and Europe regarding the prevalence of the ypmA gene and that the ypmA gene was absent in strains belonging to serotypes O1a, O1b, and O2b from Europe but was present in almost all strains belonging to serotypes O1b, O2b, O2c, O4a, O4b, O5a, and O5b from the Far East. However, the relationship between the clinical manifestations of Y. pseudotuberculosis infections and the prevalence of HPI and YPMa in Y. pseudotuberculosis has not been demonstrated. We investigated the distribution of virulence factors pYV, YPMs, and HPI among 2,235 wild Y. pseudotuberculosis strains of various serotypes isolated from patients, domestic and wild animals, and natural environments all over the world.