Ureaplasma parvum lipoproteins, including MB antigen, activate NF-{kappa}B through TLR1, TLR2 and TLR6

Division of Microbiology, Department of Infectious Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Microbiology (Impact Factor: 2.56). 06/2008; 154(Pt 5):1318-25. DOI: 10.1099/mic.0.2007/016212-0
Source: PubMed


Ureaplasma species (Ureaplasma parvum and Ureaplasma urealyticum) are commonly isolated pathogens from the female reproductive tract and are associated with perinatal diseases in humans. Inappropriate induction of inflammatory responses may be involved in the occurrence of such diseases; however, pathogenic agents that induce the inflammatory response have not been identified in ureaplasmas. In this study, we examined the involvement of Toll-like receptors (TLRs) in the activation of the immune response by U. parvum lipoproteins, as well as the U. parvum components responsible for nuclear factor kappaB (NF-kappaB) activation. The Triton X-114 (TX-114) detergent phase of U. parvum was found to induce NF-kappaB through TLR2. The active components of the TX-114 detergent phase were lipoproteins, such as multiple banded (MB) antigen, UU012 and UU016 of U. parvum. The activation of NF-kappaB by these lipoproteins was inhibited by dominant negative (DN) constructs of TLR1 and DN TLR6. Thus, the lipoproteins from U. parvum were found to activate NF-kappaB through TLR1, TLR2 and TLR6. Furthermore, these lipoproteins possessed an ability to induce tumour necrosis factor-alpha (TNF-alpha) in mouse peritoneal macrophages.

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Available from: Koichi Kuwano, Apr 14, 2015
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    • "Zhu et al. [14] in the study of pathogenicity of U. parvum serotypes 1, 3, and 6, and U. urealyticum serotypes 4 and 8 for BALB/c female mice showed that all these serotypes caused morphological changes of the external genitalia associated with infiltration by inflammatory cells and increased tumor necrosis factor-α (TNF-α) expression. Similarly, Shimizu et al. [15] indicated that U. parvum lipoproteins activated nuclear factor NF-κB thus inducing the synthesis of tumor necrosis factor alpha (TNF-α) in mouse peritoneal macrophages. Allam et al. [6] in their study on bladder tissue from animals actively colonized by U. parvum demonstrated significant alterations in actin binding proteins that may influence cell signaling cascades regulating cell motility, differentiation, apoptosis, and inflammation. "
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    ABSTRACT: Genital ureaplasmas are considered opportunistic pathogens of human genitourinary tract involved in adverse pregnancy sequelae and infertility. While association of Ureaplasma urealyticum with urogenital tract infections is well established, the role of Ureaplasma parvum in these infections is still insufficient. In the study, we compared how often cervicovaginal colonization with U. parvum is associated with the presence of these microorganisms in the upper genitourinary tract of fertile and infertile women. We used PCR assay to determine the prevalence of U. parvum and U. urealyticum in pairs of specimens, i.e., vaginal swabs and Douglas' pouch fluid samples from consecutive 40 women with no symptoms of genital tract infection. In total, 19 (47.5 %) of the 40 samples were positive for ureaplasmas. U. parvum was simultaneously detected in pairs of samples in five (55.5 %) of the nine (47.4 %) women positive in PCR assay. As many as 5 (18.5 %) of the 27 infertile women and 1 (7.7 %) of the 13 fertile women showed infection of the upper genital tract with U. parvum. The results of the study demonstrated that colonization of the lower genital tract with U. parvum can produce asymptomatic infection of the upper reproductive system in women. These findings also imply that U. parvum may be present in the upper genital tract at the time of conception and might be involved in adverse pregnancy outcomes.
    Full-text · Article · Dec 2013 · Archives of Gynecology
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    • "Three strains were cultured according to the previous report (Namba et al., 2010). After the centrifugation for 50 min at 12,000 × g at 4 • C, Triton X (TX)-114 (Wako) phase partitioning was performed to obtain MRF (Shimizu et al., 2008), and the pelleted MRF fraction was suspended in dimethyl sulfoxide (DMSO). The protein concentration was measured with a Micro BCA Protein Assay Kit (Thermo Scientific). "
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    ABSTRACT: Ureaplasma spp. are members of the family Mycoplasmataceae and have been considered to be associated with chorioamnionitis and preterm delivery. However, it is unclear whether Ureaplasma spp. have virulence factors related to these manifestations. The purpose of the present study was to determine whether the immunogenic protein multiple-banded antigen (MBA) from Ureaplasma parvum is a virulence factor for preterm delivery. We partially purified MBA from a type strain and clinical isolates of U. parvum, and also synthesized a diacylated lipopeptide derived from U. parvum, UPM-1. Using luciferase assays, both MBA-rich fraction MRF and UPM-1 activated the NF-κB pathway via TLR2. UPM-1 upregulated IL-1β, IL-6, IL-12p35, TNF-α, MIP2, LIX, and iNOS in mouse peritoneal macrophage. MRF or UPM-1 was injected into uteri on day 15 of gestation on pregnant C3H/HeN mice. The intrauterine MRF injection group had a significantly higher incidence of intrauterine fetal death (IUFD; 38.5%) than the control group (14.0%). Interestingly, intrauterine injection of UPM-1 caused preterm deliveries at high concentration (80.0%). In contrast, a low concentration of UPM-1 induced a significantly higher rate of fetal deaths (55.2%) than the control group (14.0%). The placentas of the UPM-1 injection group showed neutrophil infiltration and increased iNOS protein expression. Our data indicate that MBA from the clinical isolate of U. parvum is a potential virulence factor for IUFD and preterm delivery in mice and that the N-terminal diacylated lipopeptide is essential for the initiation of inflammation.
    Full-text · Article · Oct 2013 · Journal of Reproductive Immunology
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    • "The same variable domain is found also in UUR12 and UUR4; however it is not attached to the conserved domain of the mba in these serovars. The MBA is recognized by the Toll-like receptors 1, 2, and 6, and is capable of inducing the cytokine, NF-κB and antibody production [52]. It is conceivable that ureaplasmas would have evolved strategies to vary the MBA in order to evade this response. "
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    ABSTRACT: Background Ureaplasma urealyticum (UUR) and Ureaplasma parvum (UPA) are sexually transmitted bacteria among humans implicated in a variety of disease states including but not limited to: nongonococcal urethritis, infertility, adverse pregnancy outcomes, chorioamnionitis, and bronchopulmonary dysplasia in neonates. There are 10 distinct serotypes of UUR and 4 of UPA. Efforts to determine whether difference in pathogenic potential exists at the ureaplasma serovar level have been hampered by limitations of antibody-based typing methods, multiple cross-reactions and poor discriminating capacity in clinical samples containing two or more serovars. Results We determined the genome sequences of the American Type Culture Collection (ATCC) type strains of all UUR and UPA serovars as well as four clinical isolates of UUR for which we were not able to determine serovar designation. UPA serovars had 0.75−0.78 Mbp genomes and UUR serovars were 0.84−0.95 Mbp. The original classification of ureaplasma isolates into distinct serovars was largely based on differences in the major ureaplasma surface antigen called the multiple banded antigen (MBA) and reactions of human and animal sera to the organisms. Whole genome analysis of the 14 serovars and the 4 clinical isolates showed the mba gene was part of a large superfamily, which is a phase variable gene system, and that some serovars have identical sets of mba genes. Most of the differences among serovars are hypothetical genes, and in general the two species and 14 serovars are extremely similar at the genome level. Conclusions Comparative genome analysis suggests UUR is more capable of acquiring genes horizontally, which may contribute to its greater virulence for some conditions. The overwhelming evidence of extensive horizontal gene transfer among these organisms from our previous studies combined with our comparative analysis indicates that ureaplasmas exist as quasi-species rather than as stable serovars in their native environment. Therefore, differential pathogenicity and clinical outcome of a ureaplasmal infection is most likely not on the serovar level, but rather may be due to the presence or absence of potential pathogenicity factors in an individual ureaplasma clinical isolate and/or patient to patient differences in terms of autoimmunity and microbiome.
    Full-text · Article · May 2012 · BMC Microbiology
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