Purification, characterization and cloning of a novel variant of the superantigen <i>Yersinia pseudotuberculosis</i>‐derived mitogen

Ramamurthy, T.; Yoshino, Ken‐ichi; Abe, Jun; Ikeda, Norikazu; Takeda, Tae

doi:10.1016/s0014-5793(97)00909-5

Cited by 22 publications

(17 citation statements)

References 18 publications

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“…We reported that YPM was detected in all clinical strains belonging to serotypes O1b, -2a, -2b, -2c, -3, -4a, -4b, -5a, and -5b, of which serotypes O1b, -2b, -4b, and -5b were dominant, in the Far East but never in European clinical isolates belonging to serotypes O1a and -1b, although it was found in serotype O3 (49). It was confirmed that YPM-producing strains could be separated into three clusters of strains which produce YPMa, YPMb, or YPMc encoded by the ypmA, ypmB (36), and ypmC (10) genes, respectively. In the present study, YPMa was detected in 98% of Far Eastern clinical strains belonging to serotypes O1b, -2a, -2b, -2c, -3, -4a, -4b, -5a, -5b, and UT and YPMc was detected in five strains of serotype O3 from Western countries and Japan (28), while YPMb was never detected in clinical strains.…”

Section: Discussionmentioning

confidence: 84%

“…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.…”

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confidence: 94%

“…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).…”

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confidence: 99%

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Geographical Heterogeneity between Far Eastern and Western Countries in Prevalence of the Virulence Plasmid, the SuperantigenYersinia pseudotuberculosis-Derived Mitogen, and the High-Pathogenicity Island amongYersinia pseudotuberculosisStrains

et al. 2001

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Yersinia pseudotuberculosis produces novel superantigenic toxins designated YPMa ( Y. pseudotuberculosis -derived mitogen), YPMb, and YPMc and has a pathogenicity island termed HPI (high-pathogenicity island) and R-HPI (the right-hand part of the HPI with truncation in its left-hand part) on the chromosome. Analysis of the distribution of these virulence factors allowed for differentiation of species Y. pseudotuberculosis into six subgroups, thus reflecting the geographical spread of two main clones: the YPMa + HPI − Far Eastern systemic pathogenic type belonging to serotypes O1b, -2a, -2b, -2c, -3, -4a, -4b, -5a, -5b, -6, -10, and UT (untypeable) and the YPMs − HPI + European gastroenteric pathogenic type belonging to serotypes O1a and -1b. The YPMa + HPI + pathogenic type belonging to serotypes O1b, -3, -5a, -5b, and UT and the YPMb + HPI − nonpathogenic type belonging to non-melibiose-fermenting serotypes O1b, -5a, -5b, -6, -7, -9, -10, -11, and -12 were prevalent in the Far East. The YPMc + R-HPI + European low-pathogenicity type belonging to non-melibiose-fermenting serotype O3 and the YPMs − HPI − pathogenic type belonging to 15 serotypes were found to be prevalent all over the world. This new information is useful for a better understanding of the evolution and spread of Y. pseudotuberculosis.

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Section: Discussionmentioning

confidence: 84%

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confidence: 94%

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confidence: 99%

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Geographical Heterogeneity between Far Eastern and Western Countries in Prevalence of the Virulence Plasmid, the SuperantigenYersinia pseudotuberculosis-Derived Mitogen, and the High-Pathogenicity Island amongYersinia pseudotuberculosisStrains

et al. 2001

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“…To date, three YPM variants (YPMa, YPMb, and YPMc) have been described. YPMa displays 83% identity with YPMb (11,50) and differs from YPMc only by a single substitution at position 51 of the mature protein (12). A phylogenetic analysis based on the amino acid sequences of various bacterial superantigenic toxins indicated that the YPM variants belong to a new type of bacterial superantigen family (12,46).…”

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The Superantigen GeneypmIs Located in an Unstable Chromosomal Locus ofYersinia pseudotuberculosis

et al. 2002

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Yersinia pseudotuberculosis produces YPM (Y. pseudotuberculosis-derived mitogen), a superantigenic toxin that exacerbates the virulence of the bacterium in vivo. To date, three alleles of the superantigen gene (ypmA, ypmB, and ypmC) have been described. These genes are not found in all Y. pseudotuberculosis strains and have a low GC content, suggesting their location on mobile genetic elements. To elucidate this question, the genetic environment of the superantigen-encoding genes was characterized and 11 open reading frames (ORFs) were defined. Sequence analysis revealed that the ypm genes were not associated with plasmids, phages, transposons, or pathogenicity islands and that the superantigen genes were always located in the chromosome between ORF3 and ORF4. Nonsuperantigenic strains exhibited the same genetic organization of the locus but lacked the ypm gene between ORF3 and ORF4. A new insertion sequence, designated IS1398, which displays features of the Tn3 family, was characterized downstream of the ypmA and ypmC genes. A 13.3-kb region containing the ypm genes was not found in the genome of Y. pestis (CO92 and KIM 5 strains). We experimentally induced deletion of the ypm gene from a superantigen-expressing Y. pseudotuberculosis: using the association of aph(3)-IIIa and sacB genes, we demonstrated that when these reporter genes were present in the ypm locus, deletion of these genes was about 250 times more frequent than when they were located in another region of the Y. pseudotuberculosis chromosome. These results indicate that unlike other superantigenic toxin genes, the Yersinia ypm genes are not associated with mobile genetic elements but are inserted in an unstable locus of the genome.Yersinia pseudotuberculosis, a microorganism causing gastrointestinal diseases and immunopathological complications such as reactive arthritis and erythema nodosum (10,47,59,60), is at present the only gram-negative bacteria known to produce a superantigenic toxin. This molecule (designated YPM for Y. pseudotuberculosis-derived mitogen) is a 14.5-kDa protein able to induce proliferation of human T lymphocytes bearing V␤3, V␤9, V␤13.1, and V␤13.2 T-cell receptor variable regions (1, 61). In vivo, YPM induces lethal shock in mice (44) and exacerbates the virulence of Y. pseudotuberculosis in a murine experimental model of systemic infection (13). To date, three YPM variants (YPMa, YPMb, and YPMc) have been described. YPMa displays 83% identity with YPMb (11, 50) and differs from YPMc only by a single substitution at position 51 of the mature protein (12). A phylogenetic analysis based on the amino acid sequences of various bacterial superantigenic toxins indicated that the YPM variants belong to a new type of bacterial superantigen family (12, 46). The ypm genes encoding the YPM toxins have not been found in the genome of Yersinia pestis, a genetically related species (49). Yersinia enterocolitica, another pathogenic Yersinia species, has been described as a mitogen-producing microorganism (57, 58); however, the Tcell speci...

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“…A few years ago, Y. pseudotuberculosis strains producing a mitogen activity were isolated from a mass outbreak in Japan (48) and from a patient with Kawasaki-like symptoms (1,51). The substance, purified from bacterial lysates and exhibiting a mitogenic activity on human peripheral blood mononuclear cells (PBMC), was first designated YPM, for Y. pseudotuberculosis-derived mitogen (30), and then YPMa after the discovery of a variant (36). YPMa was characterized as a 14.5-kDa superantigenic toxin activating human T lymphocytes bearing T-cell receptors exhibiting the V␤3, V␤9, V␤13.1, and V␤13.2 variable regions (1,48).…”

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Superantigen YPMa Exacerbates the Virulence ofYersinia pseudotuberculosisin Mice

et al. 2000

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The gram-negative bacterium Yersinia pseudotuberculosis is widely spread in nature and is responsible for sporadic infection in many animal species (10). Humans are commonly infected after ingestion of food or water contaminated with excreta of infected animals. Y. pseudotuberculosis causes acute ileitis and mesenteric lymphadenitis, sometimes complicated by septicemia (10, 26), but is also responsible for the occurrence of postinfection complications such as reactive arthritis and erythema nodosum (10,35,45,46). This microorganism has been suggested as one of the causative agents of Kawasaki syndrome, an acute, self-limited vasculitis affecting predominantly infants and young children (4,25,39). A few years ago, Y. pseudotuberculosis strains producing a mitogen activity were isolated from a mass outbreak in Japan (48) and from a patient with Kawasaki-like symptoms (1, 51). The substance, purified from bacterial lysates and exhibiting a mitogenic activity on human peripheral blood mononuclear cells (PBMC), was first designated YPM, for Y. pseudotuberculosis-derived mitogen (30), and then YPMa after the discovery of a variant (36). YPMa was characterized as a 14.5-kDa superantigenic toxin activating human T lymphocytes bearing T-cell receptors exhibiting the V␤3, V␤9, V␤13.1, and V␤13.2 variable regions (1, 48). The geographic distribution of the 456-bp superantigenencoding gene ypmA is rather heterogeneous, being present in most Y. pseudotuberculosis strains from the Far East but only in about 20% of European clinical isolates (13,52).A recent study showed that 61% of patients acutely infected with Y. pseudotuberculosis, especially those with systemic complications, had elevated anti-YPM immunoglobulin G level in blood, thereby demonstrating the production of YPMa in vivo (2). Furthermore, V␤3-bearing T cells were increased in patients during the acute phase of the disease (2). Additionally, Miyoshi-Akiyama et al. (32) found that purified YPMa was able to induce lethal shock in a murine experimental model, demonstrating the toxicity of the Y. pseudotuberculosis superantigenic toxin in vivo. The toxin was also found to alter in vitro epithelial function by reducing active ion transport and increasing epithelial permeability (16). Altogether, these data suggest a role of YPMa in the pathogenesis of Y. pseudotuberculosis infections, but experimental evidence necessary to confirm this hypothesis is lacking. In this study, we constructed a superantigen-deficient mutant of Y. pseudotuberculosis and tested its virulence in a mouse experimental model of infection. Rodents have been extensively used as the animal model to study Yersinia infections since they develop a disease resembling yersiniosis in humans (22). We found that inactivation of ypmA reduced the virulence of Y. pseudotuberculosis after intravenous (i.v.) challenge but not after intragastric (i.g.) inoculation, demonstrating an exacerbated toxicity of YPMa-producing Y. pseudotuberculosis in systemic infection. MATERIALS AND METHODSBacterial strains, growth ...

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Purification, characterization and cloning of a novel variant of the superantigen Yersinia pseudotuberculosis‐derived mitogen

Cited by 22 publications

References 18 publications

Geographical Heterogeneity between Far Eastern and Western Countries in Prevalence of the Virulence Plasmid, the SuperantigenYersinia pseudotuberculosis-Derived Mitogen, and the High-Pathogenicity Island amongYersinia pseudotuberculosisStrains

Geographical Heterogeneity between Far Eastern and Western Countries in Prevalence of the Virulence Plasmid, the SuperantigenYersinia pseudotuberculosis-Derived Mitogen, and the High-Pathogenicity Island amongYersinia pseudotuberculosisStrains

The Superantigen GeneypmIs Located in an Unstable Chromosomal Locus ofYersinia pseudotuberculosis

Superantigen YPMa Exacerbates the Virulence ofYersinia pseudotuberculosisin Mice

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