Host Genetic Background Impacts Disease Outcome During Intrauterine Infection with Ureaplasma parvum

Abstract

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.

The Human Ureaplasma Species as Causative Agents of Chorioamnionitis

“…experience adverse pregnancy outcomes while others do not, some researchers have attributed these differences in sequelae to the virulence of the infecting serovar (200), the bacterial load present (201,202), or genetic background/ethnicity (203,204). However, these findings are not always consistent, with a recent study by our group demonstrating no correlation between the numbers of Ureaplasma present within placentae, the species/serovar present, or the ethnicity of women infected with Ureaplasma and the incidence or severity of histological chorioamnionitis (62).…”

“…BALB/c mice typically display a Th1/M1-dominant immune profile, whereas the immune profile of C57BL/6 mice is consistent with a Th2/M2 bias (203). These differences have enabled researchers to examine the immunopathogenic role of a skewed Th1/M1 or Th2/M2 response in Ureaplasma chorioamnionitis.…”

“…These differences have enabled researchers to examine the immunopathogenic role of a skewed Th1/M1 or Th2/M2 response in Ureaplasma chorioamnionitis. In a model of experimental intra-uterine infection, von Chamier et al injected 10 7 CFU of U. parvum into the uterine horns of pregnant BALB/c and C57BL/6 mice at 14 days (203). Examination of the fetal membranes at 72 h postinfection demonstrated that C57BL/6 mice exhibited mildmoderate chorioamnionitis, whereas BALB/c mice displayed severe necrotizing chorioamnionitis and extensive neutrophil infiltration.…”

“…Examination of the fetal membranes at 72 h postinfection demonstrated that C57BL/6 mice exhibited mildmoderate chorioamnionitis, whereas BALB/c mice displayed severe necrotizing chorioamnionitis and extensive neutrophil infiltration. These differences could not be attributed to differences in bacterial load; however, the placental expression levels of cytokines and calgranulins were markedly different between the strains (203). In a separate study, it was demonstrated that intrauterine U. parvum infection increased the expression of TLR2 and CD14 on neutrophils in BALB/c but not C57BL/6 mice (56).…”

Intra-uterine experimental infection by Ureaplasma diversum induces TNF-α mediated womb inflammation in mice

“…However, the observed leukocytosis is associated with low immunity (Tegtmeier et al 1999, Ohlsson et al 1993, Honma et al 2007). Von Chamier et al (2012) reported that intra-uterine experimental infection in mice with U. parvum was able to induce sepsis with severe fetal infl ammatory response. Thus, the host immune response could be a determinant factor in the severity of disease, since immunosuppressed animals are more likely to develop a systemic response (Famuyide et al 2009, Peng et al 2013.…”