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Alan H Jobe - One of the best experts on this subject based on the ideXlab platform.
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prophylactic intra uterine β cyclodextrin administration during intra uterine Ureaplasma parvum infection partly prevents liver inflammation without interfering with the enterohepatic circulation of the fetal sheep
Nutrients, 2020Co-Authors: Cathelijne Heymans, Owen Bradley Spiller, Sarah J Stock, Michael L Beeton, Kaatje Lenaerts, Lara R Heij, Marcel Den Dulk, Mhamed Hadfoune, Chantal Van Heugten, Alan H JobeAbstract:Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects.
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pulmonary vascular changes in extremely preterm sheep after intra amniotic exposure to Ureaplasma parvum and lipopolysaccharide
PLOS ONE, 2017Co-Authors: Monique G M Willems, John P Newnham, Suhas G Kallapur, Matthew S Payne, Owen Bradley Spiller, Matthew W. Kemp, Laura A Fast, Nick M M Wagemaker, Leon E W Janssen, Alan H JobeAbstract:Background Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes. Methods Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed. Results LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone. Conclusion Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals. Figures
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intra amniotic Ureaplasma parvum induced maternal and fetal inflammation and immune responses in rhesus macaques
The Journal of Infectious Diseases, 2016Co-Authors: Paranthaman Senthamaraikannan, Alan H Jobe, Ken B Waites, Pietro Presicce, Cesar M Rueda, Gunlawadee Maneenil, Augusto F Schmidt, Lisa A Miller, Suhas G KallapurAbstract:BACKGROUND: Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized. METHODS: Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 107 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues. RESULTS: Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor. CONCLUSIONS: U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype.
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repeated maternal intramuscular or intraamniotic erythromycin incompletely resolves intrauterine Ureaplasma parvum infection in a sheep model of pregnancy
American Journal of Obstetrics and Gynecology, 2014Co-Authors: Matthew W. Kemp, Suhas G Kallapur, Alan H Jobe, Matthew S Payne, Rory Watts, Yuichiro Miura, Smruthi Megharaj, Masatoshi SaitoAbstract:Objective: Ureaplasma spp are the most commonly isolated microorganisms in association with preterm birth. Maternal erythromycin administration is a standard treatment for preterm prelabor rupture of membranes. There is little evidence of its effectiveness in eradicating Ureaplasma spp from the intrauterine cavity and fetus. We used a sheep model of intrauterine Ureaplasma spp infection to investigate the efficacy of repeated maternal intramuscular and intraamniotic erythromycin treatment to eradicate such an infection. Study Design: Thirty ewes with singleton pregnancies received an intraamniotic injection of 107 color change units of erythromycin-sensitive Ureaplasma parvum serovar 3 at 55 days' gestation. At 116 days' gestation, 28 ewes with viable fetuses were randomized to receive (1) intraamniotic and maternal intramuscular saline solution treatment (n = 8), (2) single intraamniotic and repeated maternal intramuscular erythromycin treatment (n = 10), or (3) single maternal intramuscular and repeated intraamniotic erythromycin treatment (n = 10). Fetuses were surgically delivered at 125 days' gestation. Treatment efficacy was assessed by culture, quantitative polymerase chain reaction, and histopathologic evaluation. Results: Animals treated with intraamniotic erythromycin had significantly less viable U parvum serovar 3 in the amniotic fluid at delivery. However, neither combination of maternal intramuscular and intraamniotic erythromycin treatment successfully cleared U parvum serovar 3 from the amniotic fluid or fetal tissues. Three de novo erythromycin-resistant U parvum isolates were identified in erythromycin-treated animals. Conclusion: Erythromycin treatment, given both to the ewe and into the amniotic cavity, fails to eradicate intrauterine and fetal U parvum serovar 3 infection and may lead to development of erythromycin resistant U parvum.
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Ureaplasma parvum undergoes selection in utero resulting in genetically diverse isolates colonizing the chorioamnion of fetal sheep
Biology of Reproduction, 2014Co-Authors: Samantha J Dando, Graeme R Polglase, Ilias Nitsos, John P Newnham, Alan H Jobe, Christine L KnoxAbstract:Ureaplasmas are the microorganisms most frequently isolated from the amniotic fluid of pregnant women and can cause chronic intrauterine infections. These tiny bacteria are thought to undergo rapid evolution and exhibit a hypermutatable phenotype; however, little is known about how Ureaplasmas respond to selective pressures in utero. Using an ovine model of chronic intraamniotic infection, we investigated if exposure of Ureaplasmas to subinhibitory concentrations of erythromycin could induce phenotypic or genetic indicators of macrolide resistance. At 55 days gestation, 12 pregnant ewes received an intraamniotic injection of a nonclonal, clinical Ureaplasma parvum strain followed by (i) erythromycin treatment (intramuscularly, 30 mg/kg/day, n = 6) or (ii) saline (intramuscularly, n = 6) at 100 days gestation. Fetuses were then delivered surgically at 125 days gestation. Despite injecting the same inoculum into all the ewes, significant differences between amniotic fluid and chorioamnion Ureaplasmas were detected following chronic intraamniotic infection. Numerous polymorphisms were observed in domain V of the 23S rRNA gene of Ureaplasmas isolated from the chorioamnion (but not the amniotic fluid), resulting in a mosaiclike sequence. Chorioamnion isolates also harbored the macrolide resistance genes erm(B) and msr(D) and were associated with variable roxithromycin minimum inhibitory concentrations. Remarkably, this variability occurred independently of exposure of Ureaplasmas to erythromycin, suggesting that low-level erythromycin exposure does not induce Ureaplasmal macrolide resistance in utero. Rather, the significant differences observed between amniotic fluid and chorioamnion Ureaplasmas suggest that different anatomical sites may select for Ureaplasma subtypes within nonclonal, clinical strains. This may have implications for the treatment of intrauterine Ureaplasma infections.
Suhas G Kallapur - One of the best experts on this subject based on the ideXlab platform.
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pulmonary vascular changes in extremely preterm sheep after intra amniotic exposure to Ureaplasma parvum and lipopolysaccharide
PLOS ONE, 2017Co-Authors: Monique G M Willems, John P Newnham, Suhas G Kallapur, Matthew S Payne, Owen Bradley Spiller, Matthew W. Kemp, Laura A Fast, Nick M M Wagemaker, Leon E W Janssen, Alan H JobeAbstract:Background Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes. Methods Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed. Results LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone. Conclusion Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals. Figures
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intra amniotic Ureaplasma parvum induced maternal and fetal inflammation and immune responses in rhesus macaques
The Journal of Infectious Diseases, 2016Co-Authors: Paranthaman Senthamaraikannan, Alan H Jobe, Ken B Waites, Pietro Presicce, Cesar M Rueda, Gunlawadee Maneenil, Augusto F Schmidt, Lisa A Miller, Suhas G KallapurAbstract:BACKGROUND: Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized. METHODS: Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 107 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues. RESULTS: Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor. CONCLUSIONS: U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype.
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repeated maternal intramuscular or intraamniotic erythromycin incompletely resolves intrauterine Ureaplasma parvum infection in a sheep model of pregnancy
American Journal of Obstetrics and Gynecology, 2014Co-Authors: Matthew W. Kemp, Suhas G Kallapur, Alan H Jobe, Matthew S Payne, Rory Watts, Yuichiro Miura, Smruthi Megharaj, Masatoshi SaitoAbstract:Objective: Ureaplasma spp are the most commonly isolated microorganisms in association with preterm birth. Maternal erythromycin administration is a standard treatment for preterm prelabor rupture of membranes. There is little evidence of its effectiveness in eradicating Ureaplasma spp from the intrauterine cavity and fetus. We used a sheep model of intrauterine Ureaplasma spp infection to investigate the efficacy of repeated maternal intramuscular and intraamniotic erythromycin treatment to eradicate such an infection. Study Design: Thirty ewes with singleton pregnancies received an intraamniotic injection of 107 color change units of erythromycin-sensitive Ureaplasma parvum serovar 3 at 55 days' gestation. At 116 days' gestation, 28 ewes with viable fetuses were randomized to receive (1) intraamniotic and maternal intramuscular saline solution treatment (n = 8), (2) single intraamniotic and repeated maternal intramuscular erythromycin treatment (n = 10), or (3) single maternal intramuscular and repeated intraamniotic erythromycin treatment (n = 10). Fetuses were surgically delivered at 125 days' gestation. Treatment efficacy was assessed by culture, quantitative polymerase chain reaction, and histopathologic evaluation. Results: Animals treated with intraamniotic erythromycin had significantly less viable U parvum serovar 3 in the amniotic fluid at delivery. However, neither combination of maternal intramuscular and intraamniotic erythromycin treatment successfully cleared U parvum serovar 3 from the amniotic fluid or fetal tissues. Three de novo erythromycin-resistant U parvum isolates were identified in erythromycin-treated animals. Conclusion: Erythromycin treatment, given both to the ewe and into the amniotic cavity, fails to eradicate intrauterine and fetal U parvum serovar 3 infection and may lead to development of erythromycin resistant U parvum.
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Inflammation of the Fetal Ovine Skin Following in utero Exposure to Ureaplasma parvum
Reproductive Sciences, 2011Co-Authors: Matthew W. Kemp, Suhas G Kallapur, Alan H Jobe, Jeffrey A Keelan, Masatoshi Saito, Shaofu Li, Boris Kramer, Li Zhang, Christine Knox, Nobuo YaegashiAbstract:There is increasing evidence linking in utero infection and inflammation to preterm birth. Many commensal urogenital tract microorganisms, including the Mycoplasmas and Ureaplasmas , are commonly detected in association with preterm birth. Using an ovine model of sterile fetal inflammation, we demonstrated previously that the fetal skin generates a robust inflammatory response following in utero exposure to lipopolysaccharides from Escherichia coli . The fetal skin’s response to colonization of the amniotic fluid by viable microorganisms remains unstudied. We hypothesised that in utero infection with Ureaplasma parvum serovar 3 would induce a proinflammatory response in the fetal skin. We found that (1) cultured fetal keratinocytes (the primary cellular constituent of the epidermis) respond to U. parvum exposure in vitro by increasing the expression of the chemotactant monocyte chemoattractant protein 1 (MCP-1) but not interleukin 1β (IL-1β), IL-6, IL-8, or tumor necrosis factor-α (TNF-α); (2) the fetal skin’s response to 7 days of U. parvum exposure is characterized by elevated expression of MCP-1, TNF-α, and IL-10; and (3) the magnitude of inflammatory cytokine/chemokine expression in the fetal skin is dependent on the duration of U parvum exposure. These novel findings provide further support for the role of the fetal skin in the development of fetal inflammation and the preterm birth that may follow.
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chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep
Journal of Immunology, 2011Co-Authors: Suhas G Kallapur, Graeme R Polglase, Ilias Nitsos, Christine L Knox, Matthew W. Kemp, Boris W Kramer, Clare A Berry, Jennifer J P Collins, James W Robinson, Noah H HillmanAbstract:The chorioamnionitis associated with preterm delivery is often polymicrobial with Ureaplasma being the most common isolate. To evaluate interactions between the different proinflammatory mediators, we hypothesized that Ureaplasma exposure would increase fetal responsiveness to LPS. Fetal sheep were given intra-amniotic (IA) injections of media (control) or Ureaplasma parvum serovar 3 either 7 or 70 d before preterm delivery. Another group received an IA injection of Escherichia coli LPS 2 d prior to delivery. To test for interactions, IA U. parvum-exposed animals were challenged with IA LPS and delivered 2 d later. All animals were delivered at 124 ± 1-d gestation (term = 150 d). Compared with the 2-d LPS exposure group, the U. parvum 70 d + LPS group had 1) decreased lung pro- and anti-inflammatory cytokine expression and 2) fewer CD3+ T lymphocytes, CCL2+, myeloperoxidase+, and PU.1+ cells in the lung. Interestingly, exposure to U. parvum for 7 d did not change responses to a subsequent IA LPS challenge, and exposure to IA U. parvum alone induced mild lung inflammation. Exposure to U. parvum increased pulmonary TGF-β1 expression but did not change mRNA expression of either the receptor TLR4 or some of the downstream mediators in the lung. Monocytes from fetal blood and lung isolated from U. parvum 70 d + LPS but not U. parvum 7 d + LPS animals had decreased in vitro responsiveness to LPS. These results are consistent with the novel finding of downregulation of LPS responses by chronic but not acute fetal exposures to U. parvum. The findings increase our understanding of how chorioamnionitis-exposed preterm infants may respond to lung injury and postnatal nosocomial infections.
Mary B Brown - One of the best experts on this subject based on the ideXlab platform.
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immune profiling of balb c and c57bl 6 mice reveals a correlation between Ureaplasma parvum induced fetal inflammatory response syndrome like pathology and increased placental expression of tlr2 and cd14
American Journal of Reproductive Immunology, 2014Co-Authors: Ayman B. Allam, Maria Von Chamier, Mary B Brown, Leticia ReyesAbstract:Problem Both BALB/c and C57BL/6 mice are susceptible to intrauterine infection with Ureaplasma parvum, but only protypical TH2/M2 BALB/c mice develop severe chorioamnionitis, fetal infection, and fetal inflammatory response syndrome-like (FIRS) pathology. Method of study Microscopy, gene expression analysis, and ELISA were used to identify placental innate immune responses relevant to macrophage polarity, severe chorioamnionitis, and fetal infection. Results Both mouse strains exhibited a pro-M2 cytokine profile at the maternal/fetal interface. In BALB/c mice, expression of CD14 and TLRs 1, 2, 6 was increased in infected placentas; TLR2 and CD14 were localized to neutrophils. Increased TLR2/CD14 was also observed in BALB/c syncytiotrophoblasts in tissues with pathological evidence of FIRS. In contrast, expression in C57BL/6 placentas was either unchanged or down-regulated. Conclusion Our findings show a link between increased syncytiotrophoblast expression of CD14/TLR2 and FIRS-like pathology in BALB/c mice. Functional studies are required to determine if CD14 is contributing to fetal morbidity during chorioamnionitis.
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Immune Profiling of BALB/C and C57BL/6 Mice Reveals a Correlation Between Ureaplasma parvum-Induced Fetal Inflammatory Response Syndrome-Like Pathology and Increased Placental Expression of TLR2 and CD14
American Journal of Reproductive Immunology, 2013Co-Authors: Ayman B. Allam, Maria Von Chamier, Mary B Brown, Leticia ReyesAbstract:Problem Both BALB/c and C57BL/6 mice are susceptible to intrauterine infection with Ureaplasma parvum, but only protypical TH2/M2 BALB/c mice develop severe chorioamnionitis, fetal infection, and fetal inflammatory response syndrome-like (FIRS) pathology. Method of study Microscopy, gene expression analysis, and ELISA were used to identify placental innate immune responses relevant to macrophage polarity, severe chorioamnionitis, and fetal infection. Results Both mouse strains exhibited a pro-M2 cytokine profile at the maternal/fetal interface. In BALB/c mice, expression of CD14 and TLRs 1, 2, 6 was increased in infected placentas; TLR2 and CD14 were localized to neutrophils. Increased TLR2/CD14 was also observed in BALB/c syncytiotrophoblasts in tissues with pathological evidence of FIRS. In contrast, expression in C57BL/6 placentas was either unchanged or down-regulated. Conclusion Our findings show a link between increased syncytiotrophoblast expression of CD14/TLR2 and FIRS-like pathology in BALB/c mice. Functional studies are required to determine if CD14 is contributing to fetal morbidity during chorioamnionitis.
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Host Genetic Background Impacts Disease Outcome During Intrauterine Infection with Ureaplasma parvum
PLOS ONE, 2012Co-Authors: Maria Von Chamier, Mary B Brown, Mary K Reinhard, Ayman B. Allam, Leticia ReyesAbstract:Ureaplasma parvum, an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to U. parvum intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine U. parvum infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or U. parvum was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, in situ detection of U. parvum in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The in situ distribution of U. parvum in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P
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host genetic background impacts disease outcome during intrauterine infection with Ureaplasma parvum
PLOS ONE, 2012Co-Authors: Maria Von Chamier, Mary B Brown, Mary K Reinhard, Ayman B. Allam, Leticia ReyesAbstract:Ureaplasma parvum, an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to U. parvum intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine U. parvum infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or U. parvum was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, in situ detection of U. parvum in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The in situ distribution of U. parvum in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P<0.02). C57BL/6 infected animals predominantly exhibited mild to moderate chorioamnionitis (P<0.0001), and a significant reduction in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 compared to sham controls (P<0.02). Conversely, severe protracted chorioamnionitis with cellular necrosis was the predominant lesion phenotype in BALB/c mice, which also exhibited a significant increase in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 (P<0.01). Fetal pathology in BALB/c was multi-organ and included brain, lung, heart, liver, and intestine, whereas fetal pathology in C57BL/6 was only detected in the liver and intestines. These results confirm that the host genetic background is a major determinant in Ureaplasmal induced chorioamnionitis with fetal infection and fetal inflammatory response.
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different inflammatory responses are associated with Ureaplasma parvum induced uti and urolith formation
BMC Infectious Diseases, 2009Co-Authors: Leticia Reyes, Mary K Reinhard, Mary B BrownAbstract:Background Epidemiologic studies show a strong association between Ureaplasmas and urogenital tract disease in humans. Since healthy humans can be colonized with Ureaplasmas, its role as a pathogen remains controversial. In order to begin to define the role of the host in disease, we developed a rodent model of urinary tract infection (UTI) using Fischer 344 (F344) rats. Animals were inoculated with sterile broth, 101, 103, 105, 107, or 109 log CFU of a rat-adapted strain of Ureaplasma parvum.
Leticia Reyes - One of the best experts on this subject based on the ideXlab platform.
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immune profiling of balb c and c57bl 6 mice reveals a correlation between Ureaplasma parvum induced fetal inflammatory response syndrome like pathology and increased placental expression of tlr2 and cd14
American Journal of Reproductive Immunology, 2014Co-Authors: Ayman B. Allam, Maria Von Chamier, Mary B Brown, Leticia ReyesAbstract:Problem Both BALB/c and C57BL/6 mice are susceptible to intrauterine infection with Ureaplasma parvum, but only protypical TH2/M2 BALB/c mice develop severe chorioamnionitis, fetal infection, and fetal inflammatory response syndrome-like (FIRS) pathology. Method of study Microscopy, gene expression analysis, and ELISA were used to identify placental innate immune responses relevant to macrophage polarity, severe chorioamnionitis, and fetal infection. Results Both mouse strains exhibited a pro-M2 cytokine profile at the maternal/fetal interface. In BALB/c mice, expression of CD14 and TLRs 1, 2, 6 was increased in infected placentas; TLR2 and CD14 were localized to neutrophils. Increased TLR2/CD14 was also observed in BALB/c syncytiotrophoblasts in tissues with pathological evidence of FIRS. In contrast, expression in C57BL/6 placentas was either unchanged or down-regulated. Conclusion Our findings show a link between increased syncytiotrophoblast expression of CD14/TLR2 and FIRS-like pathology in BALB/c mice. Functional studies are required to determine if CD14 is contributing to fetal morbidity during chorioamnionitis.
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Immune Profiling of BALB/C and C57BL/6 Mice Reveals a Correlation Between Ureaplasma parvum-Induced Fetal Inflammatory Response Syndrome-Like Pathology and Increased Placental Expression of TLR2 and CD14
American Journal of Reproductive Immunology, 2013Co-Authors: Ayman B. Allam, Maria Von Chamier, Mary B Brown, Leticia ReyesAbstract:Problem Both BALB/c and C57BL/6 mice are susceptible to intrauterine infection with Ureaplasma parvum, but only protypical TH2/M2 BALB/c mice develop severe chorioamnionitis, fetal infection, and fetal inflammatory response syndrome-like (FIRS) pathology. Method of study Microscopy, gene expression analysis, and ELISA were used to identify placental innate immune responses relevant to macrophage polarity, severe chorioamnionitis, and fetal infection. Results Both mouse strains exhibited a pro-M2 cytokine profile at the maternal/fetal interface. In BALB/c mice, expression of CD14 and TLRs 1, 2, 6 was increased in infected placentas; TLR2 and CD14 were localized to neutrophils. Increased TLR2/CD14 was also observed in BALB/c syncytiotrophoblasts in tissues with pathological evidence of FIRS. In contrast, expression in C57BL/6 placentas was either unchanged or down-regulated. Conclusion Our findings show a link between increased syncytiotrophoblast expression of CD14/TLR2 and FIRS-like pathology in BALB/c mice. Functional studies are required to determine if CD14 is contributing to fetal morbidity during chorioamnionitis.
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Host Genetic Background Impacts Disease Outcome During Intrauterine Infection with Ureaplasma parvum
PLOS ONE, 2012Co-Authors: Maria Von Chamier, Mary B Brown, Mary K Reinhard, Ayman B. Allam, Leticia ReyesAbstract:Ureaplasma parvum, an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to U. parvum intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine U. parvum infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or U. parvum was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, in situ detection of U. parvum in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The in situ distribution of U. parvum in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P
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host genetic background impacts disease outcome during intrauterine infection with Ureaplasma parvum
PLOS ONE, 2012Co-Authors: Maria Von Chamier, Mary B Brown, Mary K Reinhard, Ayman B. Allam, Leticia ReyesAbstract:Ureaplasma parvum, an opportunistic pathogen of the human urogenital tract, has been implicated in contributing to chorioamnionitis, fetal morbidity, and fetal mortality. It has been proposed that the host genetic background is a critical factor in adverse pregnancy outcome as sequela to U. parvum intra-amniotic infection. To test this hypothesis we assessed the impact of intrauterine U. parvum infection in the prototypical TH1/M1 C57BL/6 and TH2/M2 BALB/c mouse strain. Sterile medium or U. parvum was inoculated into each uterine horn and animals were evaluated for intra-amniotic infection, fetal infection, chorioamnionitis and fetal pathology at 72 hours post-inoculation. Disease outcome was assessed by microbial culture, in situ detection of U. parvum in fetal and utero-placental tissues, grading of chorioamnionitis, and placental gene expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9. Placental infection and colonization rates were equivalent in both strains. The in situ distribution of U. parvum in placental tissues was also similar. However, a significantly greater proportion of BALB/c fetuses were infected (P<0.02). C57BL/6 infected animals predominantly exhibited mild to moderate chorioamnionitis (P<0.0001), and a significant reduction in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 compared to sham controls (P<0.02). Conversely, severe protracted chorioamnionitis with cellular necrosis was the predominant lesion phenotype in BALB/c mice, which also exhibited a significant increase in placental expression of IL-1α, IL-1β, IL-6, TNF-α, S100A8, and S100A9 (P<0.01). Fetal pathology in BALB/c was multi-organ and included brain, lung, heart, liver, and intestine, whereas fetal pathology in C57BL/6 was only detected in the liver and intestines. These results confirm that the host genetic background is a major determinant in Ureaplasmal induced chorioamnionitis with fetal infection and fetal inflammatory response.
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different inflammatory responses are associated with Ureaplasma parvum induced uti and urolith formation
BMC Infectious Diseases, 2009Co-Authors: Leticia Reyes, Mary K Reinhard, Mary B BrownAbstract:Background Epidemiologic studies show a strong association between Ureaplasmas and urogenital tract disease in humans. Since healthy humans can be colonized with Ureaplasmas, its role as a pathogen remains controversial. In order to begin to define the role of the host in disease, we developed a rodent model of urinary tract infection (UTI) using Fischer 344 (F344) rats. Animals were inoculated with sterile broth, 101, 103, 105, 107, or 109 log CFU of a rat-adapted strain of Ureaplasma parvum.
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prophylactic intra uterine β cyclodextrin administration during intra uterine Ureaplasma parvum infection partly prevents liver inflammation without interfering with the enterohepatic circulation of the fetal sheep
Nutrients, 2020Co-Authors: Cathelijne Heymans, Owen Bradley Spiller, Sarah J Stock, Michael L Beeton, Kaatje Lenaerts, Lara R Heij, Marcel Den Dulk, Mhamed Hadfoune, Chantal Van Heugten, Alan H JobeAbstract:Chorioamnionitis can lead to inflammation and injury of the liver and gut, thereby predisposing patients to adverse outcomes such as necrotizing enterocolitis (NEC). In addition, intestinal bile acids (BAs) accumulation is causally linked to NEC development. Plant sterols are a promising intervention to prevent NEC development, considering their anti-inflammatory properties in the liver. Therefore, we investigated whether an intra-amniotic (IA) Ureaplasma parvum (UP) infection affected the liver and enterohepatic circulation (EHC) and evaluated whether an IA administered plant sterol mixture dissolved in β-cyclodextrin exerted prophylactic effects. An ovine chorioamnionitis model was used in which liver inflammation and the EHC were assessed following IA UP exposure in the presence or absence of IA prophylactic plant sterols (a mixture of β-sitosterol and campesterol dissolved in β-cyclodextrin (carrier)) or carrier alone. IA UP exposure caused an inflammatory reaction in the liver, histologically seen as clustered and conflated hepatic erythropoiesis in the parenchyma, which was partially prevented by IA administration of sterol + β-cyclodextrin, or β-cyclodextrin alone. In addition, IA administration of β-cyclodextrin prior to UP caused changes in the expression of several hepatic BAs transporters, without causing alterations in other aspects of the EHC. Thereby, the addition of plant sterols to the carrier β-cyclodextrin did not have additional effects.
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cervical epithelial damage promotes Ureaplasma parvum ascending infection intrauterine inflammation and preterm birth induction in mice
Nature Communications, 2020Co-Authors: Ioannis Pavlidis, Owen Bradley Spiller, Gabriella Sammut Demarco, Heather Macpherson, Sarah E M Howie, Jane E Norman, Sarah J StockAbstract:Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth.
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the paradoxical effects of chronic intra amniotic Ureaplasma parvum exposure on ovine fetal brain development
Developmental Neuroscience, 2017Co-Authors: Ruth Gussenhoven, Matthew S Payne, Owen Bradley Spiller, Sarah J Stock, Matthew W. Kemp, Daan R M G Ophelders, Michael L Beeton, Bertha Cilleropastor, Florian P Y Barre, Ron M A HeerenAbstract:Chorioamnionitis is associated with adverse neurodevelopmental outcomes in preterm infants. Ureaplasma spp. are the microorganisms most frequently isolated from the amniotic fluid of women diagnosed with chorioamnionitis. However, controversy remains concerning the role of Ureaplasma spp. in the pathogenesis of neonatal brain injury. We hypothesize that reexposure to an inflammatory trigger during the perinatal period might be responsible for the variation in brain outcomes of preterms following Ureaplasma-driven chorioamnionitis. To investigate these clinical scenarios, we performed a detailed multimodal study in which ovine neurodevelopmental outcomes were assessed following chronic intra-amniotic Ureaplasma parvum (UP) infection either alone or combined with subsequent lipopolysaccharide (LPS) exposure. We show that chronic intra-amniotic UP exposure during the second trimester provoked a decrease in astrocytes, increased oligodendrocyte numbers, and elevated 5-methylcytosine levels. In contrast, short-term LPS exposure before preterm birth induced increased microglial activation, myelin loss, elevation of 5-hydroxymethylcytosine levels, and lipid profile changes. These LPS-induced changes were prevented by chronic preexposure to UP (preconditioning). These data indicate that chronic UP exposure has dual effects on preterm brain development in utero. On the one hand, prolonged UP exposure causes detrimental cerebral changes that may predispose to adverse postnatal clinical outcomes. On the other, chronic intra-amniotic UP exposure preconditions the brain against a second inflammatory hit. This study demonstrates that microbial interactions and the timing and duration of the inflammatory insults determine the effects on the fetal brain. Therefore, this study helps to understand the complex and diverse postnatal neurological outcomes following UP driven chorioamnionitis.
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pulmonary vascular changes in extremely preterm sheep after intra amniotic exposure to Ureaplasma parvum and lipopolysaccharide
PLOS ONE, 2017Co-Authors: Monique G M Willems, John P Newnham, Suhas G Kallapur, Matthew S Payne, Owen Bradley Spiller, Matthew W. Kemp, Laura A Fast, Nick M M Wagemaker, Leon E W Janssen, Alan H JobeAbstract:Background Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes. Methods Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed. Results LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone. Conclusion Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals. Figures
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antimicrobial activity of manuka honey against antibiotic resistant strains of the cell wall free bacteria Ureaplasma parvum and Ureaplasma urealyticum
Letters in Applied Microbiology, 2017Co-Authors: K L Hillitt, Owen Bradley Spiller, Ron Jenkins, Michael L BeetonAbstract:The susceptibility of the cell-wall free bacterial pathogens Ureaplasma spp. to Manuka honey was examined. The minimum inhibitory concentration (MIC) of Manuka honey for four Ureaplasma urealyticum and four Ureaplasma parvum isolates was determined. Sensitivity to honey was also compared to clinical isolates with resistance to tetracycline, macrolide and fluoroquinolone antibiotics. Finally step-wise resistance training was utilised in an attempt to induce increased tolerance to honey. The MIC was dependent on the initial bacterial load with 7.5 % and 18.0 % w/v honey required to inhibit U. urealyticum at 1 and 10 6 colour changing units (CCU), respectively, and 4.8 % and 15.3 % w/v required to inhibit U. parvum at 1 and 10 6 CCU, respectively. MIC values were consistently lower for U. parvum compared with U. urealyticum. Antimicrobial activity was seen against tetracycline resistant, erythromycin resistant and ciprofloxacin resistant isolates at 10 5 CCU. No resistance to honey was observed with fifty consecutive challenges at increasing concentrations of honey. This is the first report of the antimicrobial activity of Manuka honey against a cell-wall free bacterial pathogen. The antimicrobial activity was retained against antibiotic resistant strains and it was not possible to generate resistant mutants.
