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Ureaplasma and BPD

https://doi.org/10.1053/j.semperi.2013.01.005Get rights and content

Abstract

Ureaplasma is an organism with low virulence and is a commensal of the lower genito-urinary tract in females. From here, it can gain entry in the amniotic fluid to cause inflammation in the amniotic compartment during pregnancy. Ureaplasma spp. are the most common organisms isolated from women with chorioamnionitis. Ureaplasma spp. are associated with increased risk for preterm labor and morbidity in the preterm neonate. However, there is some controversy regarding the importance of Ureaplasma in the pathogenesis of bronchopulmonary dysplasia (BPD). This article will review the microbiology of Ureaplasma, host innate immune responses, and the pathology of lung injury in animal models of Ureaplasma chorioamnionitis. We will review epidemiological studies of Ureaplasma and BPD in preterm infants and efficacy of antibiotics in preventing preterm labor and BPD.

Section snippets

Microbiology of Ureaplasma species

Ureaplasma spp. are among the smallest free-living, self-replicating microorganisms. They have an extremely low G+C content of 25.5% (or the highest A+T composition) within open reading frames of any prokaryotes sequenced to date. Ureaplasma spp. have evolved from Gram-positive bacteria by degenerative evolution to lose the peptidoglycan cell wall.4 As their name suggests, Ureaplasma spp. utilize urea as their sole source of carbon, producing ammonia as a metabolic product.5 Currently, there

Virulence of Ureaplasma species

Several proteins have been proposed as virulence factors. The mba gene encodes for MBA, the major surface-exposed lipoprotein. MBA is thought to be the major virulence factor of Ureaplasma spp. and is the predominant antigen recognized by the host immune system during infection.4 Ureaplasma spp. can alter the expression of their MBA in order to evade host immune responses and maintain chronicity of infection.8., 9., 10. Ureaplasma phospholipase A and C activities were identified by in vitro

Ureaplasma spp. perinatal pathogens causing preterm birth

The microbial invasion of amniotic cavity associated with preterm birth is relatively unique among infectious diseases in humans. The microbes are mostly opportunistic commensal vaginal organisms of low pathogenicity in otherwise healthy women. Polymicrobial growth is common from amniotic fluid from chorioamnionitis, and Ureaplasma spp. are the organisms most frequently isolated, although they rarely cause infections elsewhere.13., 17. The strongest evidence that Ureaplasma can cause preterm

Host response to Ureaplasma infection

Microbial recognition by innate immune systems can be mediated by a variety of germline-encoded receptors, including Toll-like receptors (TLRs), RIG-like receptors (RLRs), Nod-like receptors (NLRs), and cytosolic DNA sensors such as the HIN-200 family member AIM2.24 Ureaplasma spp. lack a gram-negative or gram-positive bacterial cell wall, thus are devoid of lipopolysaccharides or peptidoglycans—the microbial products that are potent activators of TR4 (lipopolysaccharide or LPS) and the TLR2 or

Ureaplasma and immune modulation

Chronic infections can induce a state of immune paralysis called endotoxin tolerance. Thus leukocytes from patients with sepsis or recovering from typhoid fever can have endotoxin tolerance.32., 33. We reported that in sheep repeated intra-amniotic injections of lipopolysaccharide (LPS endotoxin), a constituent of cell wall of gram-negative bacteria, induces tolerance to a variety of toll-like receptor agonists in the preterm fetus.34., 35., 36. Interestingly, chronic intra-amniotic

Ureaplasma species and inflammation in the developing lung—animal studies

Ureaplasma infection of the developing lung has been studied primarily in sheep and non-human primates. Intra-amniotic injection of Ureaplasma in early gestation sheep resulted in efficient colonization and a 5-log increase in the Ureaplasma in amniotic fluid counts that persisted for 3 months to term with very little overt adverse effects in the ewe, consistent with a commensal-like host response.15 Interestingly, after a chronic exposure to intra-amniotic Ureaplasma, all of the fetal lungs

Ureaplasma species and lung inflammation in the developing lung—Human studies

The lung pathology of archived autopsy specimens from Ureaplasma infected preterm infants demonstrated increased lung fibrosis, elastic fiber accumulation, smooth muscle actin, and increased tumor necrosis factor alpha (TNFα) and transforming growth factor beta 1 (TGFβ1) immunoreactivity.45., 46. Elevated maternal and fetal or newborn antibody titers to Ureaplasma correlated with an increased incidence of stillbirth and infants with fatal neonatal respiratory disease.29 The findings from these

Pathogenesis of BPD

The most predictive risk factors for development of BPD are gestational age, birth weight, duration of respiratory support, fraction of inspired oxygen (FiO2), race and gender.47 Although these risk factors hold true on a population basis, individual infants who develop BPD have different trajectories toward developing BPD. For instance, if the need for supplemental oxygen is used as a proxy for lung injury, then 3 patterns (or subsets) of BPD are discernible.48., 49. In a study of preterm

Clinical and epidemiological studies of Ureaplasma and BPD

Ureaplasma spp. are the organisms most frequently associated with chorioamnionitis and very preterm delivery.53 However, the contribution of Ureaplasma or chorioamnionitis to BPD is less clear. Several single center studies reported the association of Ureaplasma in the respiratory secretions of newborns with the development of BPD.54., 55., 56., 57., 58. Some studies used the BPD definition of oxygen supplementation at 28 days, while others used the more current definition of BPD as the need

Treatment with antimicrobial agents

Since Ureaplasma is the most common organism isolated in women with chorioamnionitis it is instructive to review antibiotic trials for chorioamnionitis. Antenatal trials of antimicrobial use in the setting of preterm labor have yielded mixed results. Mercer et al.75 randomized 614 women with preterm premature rupture of membranes between 24 and 32 weeks to ampicillin plus erythromycin or placebo for a 7 day treatment course.75 The women randomized to antibiotics had a higher latency and the

Summary and conclusions

Ureaplasma species are the organisms most associated with chorioamnionitis and preterm delivery. Although there is controversy regarding the role of Ureaplasma in BPD, experimental evidence and clinical/epidemiological data demonstrate that Ureaplasma species can increase the risk for BPD in preterm infants. Antenatal exposure to Ureaplasma increases surfactant production, increases lung volumes and induces pulmonary inflammation with disordered alveolar development in preterm sheep.

References (88)

  • S.G. Kallapur et al.

    Antenatal factors that influence postnatal lung development and injury

  • S.M. Garland et al.

    Role of Ureaplasma urealyticum and Chlamydia trachomatis in lung disease in low birth weight infants

    Pathology

    (1996)
  • L.J. Van Marter et al.

    Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants

    J Pediatr

    (2002)
  • W.W. Andrews et al.

    The Alabama preterm birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants

    Am J Obstet Gynecol

    (2006)
  • S.L. Kenyon et al.

    Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE Collaborative Group

    Lancet

    (2001)
  • S.L. Kenyon et al.

    Broad-spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE Collaborative Group

    Lancet

    (2001)
  • S. Kenyon et al.

    Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial

    Lancet

    (2008)
  • V.S. Kuppala et al.

    Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants

    J Pediatr

    (2011)
  • G.H. Cassell et al.

    Ureaplasma urealyticum intrauterine infection: role in prematurity and disease in newborns

    Clin Microbiol Rev

    (1993)
  • J.I. Glass et al.

    The complete sequence of the mucosal pathogen Ureaplasma urealyticum

    Nature

    (2000)
  • J.V. Ligon et al.

    Virulence of ureaplasmal urease for mice

    Infect Immun

    (1991)
  • F. Echahidi et al.

    Development of monoclonal antibodies against Ureaplasma urealyticum serotypes and their use for serotyping clinical isolates

    Clin Diagn Lab Immunol

    (2000)
  • J.A. Robertson et al.

    Proposal of Ureaplasma parvum sp. nov. and emended description of Ureaplasma urealyticum (Shepard et al. 1974) Robertson et al. 2001

    Int J Syst Evol Microbiol

    (2002)
  • C.U. Zimmerman et al.

    Ureaplasma antigenic variation beyond MBA phase variation: DNA inversions generating chimeric structures and switching in expression of the MBA N-terminal paralogue UU172

    Mol Microbiol

    (2011)
  • C.L. Knox et al.

    The severity of chorioamnionitis in pregnant sheep is associated with in vivo variation of the surface-exposed multiple-banded antigen/gene of Ureaplasma parvum

    Biol Reprod

    (2010)
  • N.S. De Silva et al.

    Localization of endogenous activity of phospholipases A and C in Ureaplasma urealyticum

    J Clin Microbiol

    (1991)
  • M. Kilian et al.

    Immunoglobulin A1 protease activity in strains of Ureaplasma urealyticum

    Acta Pathol Microbiol Immunol Scand B

    (1984)
  • V. Paralanov et al.

    Comparative genome analysis of 19 Ureaplasma urealyticum and Ureaplasma parvum strains

    BMC Microbiol

    (2012)
  • L. Xiao et al.

    Extensive horizontal gene transfer in Ureaplasmas from humans questions the utility of serotyping for diagnostic purposes

    J Clin Microbiol

    (2011)
  • S.J. Dando et al.

    The role of the multiple banded antigen of Ureaplasma parvum in intra-amniotic infection: major virulence factor or decoy?

    PLoS One

    (2012)
  • Pandelidis K, McCarthy A, Chesko, K.L, Viscardi R.M Role of biofilm formation in Ureaplasma antibiotic susceptibility...
  • M.J. Novy et al.

    Ureaplasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, preterm delivery, and fetal pneumonia in rhesus macaques

    Reprod Sci

    (2009)
  • S. Gerber et al.

    Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery

    J Infect Dis

    (2003)
  • F. Namba et al.

    Placental features of chorioamnionitis colonized with Ureaplasma species in preterm delivery

    Pediatr Res

    (2010)
  • H. Kumar et al.

    Pathogen recognition by the innate immune system

    Int Rev Immunol

    (2011)
  • G. Estrada-Gutierrez et al.

    Interaction between pathogenic bacteria and intrauterine leukocytes triggers alternative molecular signaling cascades leading to labor in women

    Infect Immun

    (2010)
  • W.M. Manimtim et al.

    Ureaplasma urealyticum modulates endotoxin-induced cytokine release by human monocytes derived from preterm and term newborns and adults

    Infect Immun

    (2001)
  • T. Shimizu et al.

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

    Microbiology

    (2008)
  • M.R. Peltier et al.

    Characterization of the macrophage-stimulating activity from Ureaplasma urealyticum

    Am J Reprod Immunol

    (2007)
  • P.A. Quinn

    Evidence of an immune response to Ureaplasma urealyticum in perinatal morbidity and mortality

    Pediatr Infect Dis

    (1986)
  • M.E. Famuyide et al.

    Surfactant protein-A limits Ureaplasma-mediated lung inflammation in a murine pneumonia model

    Pediatr Res

    (2009)
  • G. Monneret et al.

    Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony

    Mol Med

    (2008)
  • J.S. Lehman et al.

    Endotoxin tolerance in patients with chronic bacteremia and bacteriuria due to Salmonella

    J Infect Dis

    (1971)
  • S.G. Kallapur et al.

    Pulmonary and systemic endotoxin tolerance in preterm fetal sheep exposed to chorioamnionitis

    J Immunol

    (2007)
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