Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin

ABSTRACT Intra-amniotic infection is strongly associated with adverse pregnancy and neonatal outcomes. Most intra-amniotic infections are due to Ureaplasma species; however, the pathogenic potency of these genital mycoplasmas to induce preterm birth is still controversial. Here, we first laid out a...

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Main Authors: Kenichiro Motomura, Roberto Romero, Yi Xu, Kevin R. Theis, Jose Galaz, Andrew D. Winters, Rebecca Slutsky, Valeria Garcia-Flores, Chengrui Zou, Dustyn Levenson, Robert Para, Madison M. Ahmad, Derek Miller, Chaur-Dong Hsu, Nardhy Gomez-Lopez
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Language:English
Published: American Society for Microbiology 2020-06-01
Series:mBio
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Online Access:https://journals.asm.org/doi/10.1128/mBio.00797-20
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author Kenichiro Motomura
Roberto Romero
Yi Xu
Kevin R. Theis
Jose Galaz
Andrew D. Winters
Rebecca Slutsky
Valeria Garcia-Flores
Chengrui Zou
Dustyn Levenson
Robert Para
Madison M. Ahmad
Derek Miller
Chaur-Dong Hsu
Nardhy Gomez-Lopez
author_facet Kenichiro Motomura
Roberto Romero
Yi Xu
Kevin R. Theis
Jose Galaz
Andrew D. Winters
Rebecca Slutsky
Valeria Garcia-Flores
Chengrui Zou
Dustyn Levenson
Robert Para
Madison M. Ahmad
Derek Miller
Chaur-Dong Hsu
Nardhy Gomez-Lopez
author_sort Kenichiro Motomura
collection DOAJ
description ABSTRACT Intra-amniotic infection is strongly associated with adverse pregnancy and neonatal outcomes. Most intra-amniotic infections are due to Ureaplasma species; however, the pathogenic potency of these genital mycoplasmas to induce preterm birth is still controversial. Here, we first laid out a taxonomic characterization of Ureaplasma isolates from women with intra-amniotic infection, which revealed that Ureaplasma parvum is the most common bacterium found in this clinical condition. Next, using animal models, we provided a causal link between intra-amniotic inoculation with Ureaplasma species and preterm birth. Importantly, the intra-amniotic inoculation of Ureaplasma species induced high rates of mortality in both preterm and term neonates. The in vivo potency of U. parvum to induce preterm birth was not associated with known virulence factors. However, term-derived and preterm-derived U. parvum isolates were capable of inducing an intra-amniotic inflammatory response. Both U. parvum isolates invaded several fetal tissues, primarily the fetal lung, and caused fetal inflammatory response syndrome. This bacterium was also detected in the placenta, reproductive tissues, and most severely in the fetal membranes, inducing a local inflammatory response that was replicated in an in vitro model. Importantly, treatment with clarithromycin, a recently recommended yet not widely utilized antibiotic, prevented the adverse pregnancy and neonatal outcomes induced by U. parvum. These findings shed light on the maternal-fetal immunobiology of intra-amniotic infection. IMPORTANCE Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Multiple etiologies are associated with preterm birth; however, 25% of preterm infants are born to a mother with intra-amniotic infection, most commonly due to invasion of the amniotic cavity by Ureaplasma species. Much research has focused on establishing a link between Ureaplasma species and adverse pregnancy/neonatal outcomes; however, little is known about the taxonomy of and host response against Ureaplasma species. Here, we applied a multifaceted approach, including human samples, in vivo models, and in vitro manipulations, to study the maternal-fetal immunobiology of Ureaplasma infection during pregnancy. Furthermore, we investigated the use of clarithromycin as a treatment for this infection. Our research provides translational knowledge that bolsters scientific understanding of Ureaplasma species as a cause of adverse pregnancy/neonatal outcomes and gives strong evidence for the use of clarithromycin as the recommended treatment for women intra-amniotically infected with Ureaplasma species.
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spelling doaj.art-376ac8970ef1425d8420cfdeec6b82f62022-12-21T19:28:19ZengAmerican Society for MicrobiologymBio2150-75112020-06-0111310.1128/mBio.00797-20Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with ClarithromycinKenichiro Motomura0Roberto Romero1Yi Xu2Kevin R. Theis3Jose Galaz4Andrew D. Winters5Rebecca Slutsky6Valeria Garcia-Flores7Chengrui Zou8Dustyn Levenson9Robert Para10Madison M. Ahmad11Derek Miller12Chaur-Dong Hsu13Nardhy Gomez-Lopez14Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USADepartment of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAPerinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland, and Detroit, Michigan, USAABSTRACT Intra-amniotic infection is strongly associated with adverse pregnancy and neonatal outcomes. Most intra-amniotic infections are due to Ureaplasma species; however, the pathogenic potency of these genital mycoplasmas to induce preterm birth is still controversial. Here, we first laid out a taxonomic characterization of Ureaplasma isolates from women with intra-amniotic infection, which revealed that Ureaplasma parvum is the most common bacterium found in this clinical condition. Next, using animal models, we provided a causal link between intra-amniotic inoculation with Ureaplasma species and preterm birth. Importantly, the intra-amniotic inoculation of Ureaplasma species induced high rates of mortality in both preterm and term neonates. The in vivo potency of U. parvum to induce preterm birth was not associated with known virulence factors. However, term-derived and preterm-derived U. parvum isolates were capable of inducing an intra-amniotic inflammatory response. Both U. parvum isolates invaded several fetal tissues, primarily the fetal lung, and caused fetal inflammatory response syndrome. This bacterium was also detected in the placenta, reproductive tissues, and most severely in the fetal membranes, inducing a local inflammatory response that was replicated in an in vitro model. Importantly, treatment with clarithromycin, a recently recommended yet not widely utilized antibiotic, prevented the adverse pregnancy and neonatal outcomes induced by U. parvum. These findings shed light on the maternal-fetal immunobiology of intra-amniotic infection. IMPORTANCE Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Multiple etiologies are associated with preterm birth; however, 25% of preterm infants are born to a mother with intra-amniotic infection, most commonly due to invasion of the amniotic cavity by Ureaplasma species. Much research has focused on establishing a link between Ureaplasma species and adverse pregnancy/neonatal outcomes; however, little is known about the taxonomy of and host response against Ureaplasma species. Here, we applied a multifaceted approach, including human samples, in vivo models, and in vitro manipulations, to study the maternal-fetal immunobiology of Ureaplasma infection during pregnancy. Furthermore, we investigated the use of clarithromycin as a treatment for this infection. Our research provides translational knowledge that bolsters scientific understanding of Ureaplasma species as a cause of adverse pregnancy/neonatal outcomes and gives strong evidence for the use of clarithromycin as the recommended treatment for women intra-amniotically infected with Ureaplasma species.https://journals.asm.org/doi/10.1128/mBio.00797-20Ureaplasmaantibioticsbacterial burdenintra-amniotic infectionneonatepregnancy
spellingShingle Kenichiro Motomura
Roberto Romero
Yi Xu
Kevin R. Theis
Jose Galaz
Andrew D. Winters
Rebecca Slutsky
Valeria Garcia-Flores
Chengrui Zou
Dustyn Levenson
Robert Para
Madison M. Ahmad
Derek Miller
Chaur-Dong Hsu
Nardhy Gomez-Lopez
Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin
mBio
Ureaplasma
antibiotics
bacterial burden
intra-amniotic infection
neonate
pregnancy
title Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin
title_full Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin
title_fullStr Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin
title_full_unstemmed Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin
title_short Intra-Amniotic Infection with <italic toggle="yes">Ureaplasma parvum</italic> Causes Preterm Birth and Neonatal Mortality That Are Prevented by Treatment with Clarithromycin
title_sort intra amniotic infection with italic toggle yes ureaplasma parvum italic causes preterm birth and neonatal mortality that are prevented by treatment with clarithromycin
topic Ureaplasma
antibiotics
bacterial burden
intra-amniotic infection
neonate
pregnancy
url https://journals.asm.org/doi/10.1128/mBio.00797-20
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