The Human Ureaplasma Species as Causative Agents of Chorioamnionitis

Abstract

The human Ureaplasma species are the most frequently isolated microorganisms from the amniotic fluid and placentae of women who deliver preterm and are also associated with spontaneous abortions or miscarriages, neonatal respiratory diseases, and chorioamnionitis. Despite the fact that these microorganisms have been habitually found within placentae of pregnancies with chorioamnionitis, the role of Ureaplasma species as a causative agent has not been satisfactorily explained. There is also controversy surrounding their role in disease, particularly as not all women infected with Ureaplasma spp. develop chorioamnionitis. In this review, we provide evidence that Ureaplasma spp. are associated with diseases of pregnancy and discuss recent findings which demonstrate that Ureaplasma spp. are associated with chorioamnionitis, regardless of gestational age at the time of delivery. Here, we also discuss the proposed major virulence factors of Ureaplasma spp., with a focus on the multiple-banded antigen (MBA), which may facilitate modulation/alteration of the host immune response and potentially explain why only subpopulations of infected women experience adverse pregnancy outcomes. The information presented within this review confirms that Ureaplasma spp. are not simply "innocent bystanders" in disease and highlights that these microorganisms are an often underestimated pathogen of pregnancy.

Keywords: Ureaplasma; amniotic fluid; chorioamnionitis; multiple-banded antigen; neonate/fetus; pregnancy; virulence factors.

FIG 1

Comparison of key events involved in normal parturition and inflammation-induced parturition. Normal parturition is initiated by the increased placental synthesis of CRH at term, which causes the production of cortisol. Cortisol induces the production of prostaglandin E2 and prostaglandin F2α and works in a positive-feedback loop to further stimulate placental CRH production. Prostaglandins induce the production of matrix metalloproteases, which facilitate membrane rupture and cervical remodeling. In concert, activation of the fetal HPA axis leads to a functional progesterone withdrawal and production of contraction-associated proteins, which cause myometrial activation and uterine contractility. During chorioamnionitis, inflammatory cytokines and chemokines produced in response to microbial invasion of the chorioamnion and/or amniotic fluid stimulate prostaglandin production and neutrophil infiltration, leading to the synthesis of matrix metalloproteases and subsequent membrane weakening. Recognition of pathogen-associated molecular patterns by pattern recognition receptors (such as TLRs) is critical for the initiation of inflammation-induced parturition. CAPs, contraction-associated proteins; CRH, corticotropin-releasing hormone; HPA, hypothalamic-pituitary-adrenal; MMPs, matrix metalloproteases; NF-κB, nuclear factor kappa B; PGDH, prostaglandin dehydrogenase; PGs, prostaglandins; PGS2, prostaglandin-endoperoxide synthase 2; TLR, Toll-like receptor. The direction of the arrows within boxes represents either an increase or a decrease in expression.

FIG 2

Differences in the presence of chorioamnionitis in Ureaplasma-infected women. Hematoxylin-and-eosin-stained chorioamnion tissue demonstrates that some women whose placentae are colonized with Ureaplasma spp. have no evidence of chorioamnionitis (A and B), while other women have mild/moderate (C and D) or severe (E and F) evidence of inflammation (demonstrated by neutrophil influx [arrows]) within their chorioamnion, despite high numbers of Ureaplasma spp. present within the tissue. Images are shown at ×200 (A, C, and E) and ×400 (B, D, and F) total magnifications; boxed areas in panels A, C, and E are shown in panels B, D, and F, respectively.