Abstract
Preterm birth (PTB), or birth before 37 weeks gestation, is the leading cause of neonatal mortality worldwide. Cervical viral infections have been established as risk factors for PTB in women, although the mechanism leading to increased risk is unknown. Using a mouse model of pregnancy, we determined that intra-vaginal HSV2 infection caused increased rates of preterm birth following an intra-vaginal bacterial infection. HSV2 infection resulted in histological changes in the cervix mimicking cervical ripening, including significant collagen remodeling and increased hyaluronic acid synthesis. Viral infection also caused aberrant expression of estrogen and progesterone receptor in the cervical epithelium. Further analysis using human ectocervical cells demonstrated a role for Src kinase in virus-mediated changes in estrogen receptor and hyaluronic acid expression. In conclusion, HSV2 affects proteins involved in tissue hormone responsiveness, causes significant changes reminiscent of premature cervical ripening, and increases risk of preterm birth. Studies such as this improve our chances of identifying clinical interventions in the future.
Highlights
Preterm birth (PTB), or birth before 37 weeks gestation, affects approximately 12% of pregnancies in the United States[1,2,3,4,5,6,7] and is the leading cause of neonatal mortality worldwide[4, 6, 8]
Because ascending infections are often associated with structural changes in the cervix, like those that occur during cervical ripening, we determined how cervical herpes simplex virus-2 (HSV2) infection affected the tissue organization of the cervix during pregnancy
The infected cervix tissues had higher optical density (OD) compared to the controls, indicating the collagen was less dense in infected tissue (Fig 2C), (a
Summary
Preterm birth (PTB), or birth before 37 weeks gestation, affects approximately 12% of pregnancies in the United States[1,2,3,4,5,6,7] and is the leading cause of neonatal mortality worldwide[4, 6, 8]. Despite its frequency and numerous consequences, PTB rates have increased over the last 30 years[2, 5, 7]. Progress in improving PTB rates has been slow due to its complexity and the lack of understanding of the underlying causes of the condition. PTB is better defined as a syndrome[2], and labor is the clinical outcome that results from an accumulation of risk factors or pathologies[9]. The best characterized risk factor for PTB is inflammation associated with bacterial infection. We are still largely unable to predict or prevent even these cases of PTB[2, 10]. Viruses were relatively uncharacterized in the reproductive tract during pregnancy but, with improved technologies for detection, i.e. PCR, they have recently garnered
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