Inflammatory response elicited by Ureaplasma parvum colonization in human cervical epithelial, stromal, and immune cells

Abstract

Ureaplasma parvum is a commensal bacterium in the female reproductive tract but has been associated with pregnancy complications such as preterm prelabor rupture of membranes and preterm birth (PTB). However, the pathologic effects of U. parvum in the cervix, that prevents ascending infections during pregnancy, are still poorly understood. To determine the impact of U. parvum on the cervix, ectocervical (ecto) and endocervical (endo) epithelial and stromal cells were incubated with U. parvum. Macrophages were also tested as a proxy for cervical macrophages to determine the antigenicity of U. parvum. The effects of U. parvum, including influence on cell cycle and cell death, antimicrobial peptide production, epithelial-to-mesenchymal transition (EMT), and inflammatory cytokine levels, were assessed. U. parvum colonized cervical epithelial and stromal cells 4 hours post-infection. Like uninfected control, U. parvum neither inhibited cell cycle progression and nor caused cell death in cervical epithelial and stromal cells. U. parvum increased the production of the antimicrobial peptides (AMPs) cathelicidin and human β-defensin 3 and exhibited weak signs of EMT evidenced by decreased cytokeratin 18 and increased vimentin expression in cervical epithelial cells. U. parvum induced a pro-inflammatory environment (cytokines) and increased MMP-9 in cervical epithelial cells but promoted pro- and anti-inflammatory responses in cervical stromal cells and macrophages. U. parvum may colonize the cervical epithelial layer, but induction of AMPs and anti-inflammatory response may protect the cervix and may prevent ascending infections that can cause PTB. These findings suggest that U. parvum is a weak inducer of inflammation in the cervix.

Genital Mycoplasmas and Biomarkers of Inflammation and Their Association With Spontaneous Preterm Birth and Preterm Prelabor Rupture of Membranes: A Systematic Review and Meta-Analysis

“…This was also supported by various in vitro and in vivo studies showing a dose-dependent increase in inflammation and PTB rate with higher doses of Ureaplasma spp. infections ( Glaser et al, 2017 , 2018 ; Motomura et al, 2020 ; Tantengco et al, 2021 ).…”

“…However, this conclusion may depend on their load, location and polymicrobial presence. Our own in vitro studies have shown that poor immunogenicity by these microbes in human fetal membranes as well as in the cervix ( Noda-Nicolau et al, 2016 ; Tantengco et al, 2021 , 2022 ). These results suggest that the association between the genital mycoplasmas and adverse pregnancy outcomes might not be strong enough to warrant universal antimicrobial intervention.…”

Modeling ascending Ureaplasma parvum infection through the female reproductive tract using vagina‐cervix‐decidua‐organ‐on‐a‐chip and feto‐maternal interface‐organ‐on‐a‐chip

“…58 Most of our knowledge regarding the pathologic effects of bacterial infection in the cervix during pregnancy is based on in vivo animal and in vitro cell culture studies. 3,32,36,46 However, some findings from animal models may not apply to humans due to the inherent anatomical and physiological differences between humans and animal models, as well as the multifetal pregnancies in many of the routinely used models (e.g., mice and rats). Conversely, in vitro 2D cell culture studies also have limitations due to For all groups, n ≥ 3 pregnant mice.…”

“…Studies on the mechanistic and pathophysiologic effects of bacterial infections in the cervix during pregnancy are limited due to the difficulty of obtaining cervical samples 30 . The majority of the studies on the cellular damage caused by cervical infections were conducted using in vitro monocultures and animal models, including CD‐1 mice 31–36 . Previous studies have used CD‐1 mice in studying preterm cervical ripening and the role of LPS‐induced inflammation and Escherichia coli infection in PTB 37–39 .…”

Exosomes from Ureaplasma parvum-infected ectocervical epithelial cells promote feto-maternal interface inflammation but are insufficient to cause preterm delivery

“…The cells were then centrifuged at 1,000 rpm for 5 min. THP-1 monocytes were seeded in a 48-well plate (50,000 cells per well), and they were differentiated to THP-1 macrophages by incubating them in a culture medium containing 100 mM phorbol 12-myristate 13-acetate for three days at 37°C and 5% CO 2 environment, and grown to 80% confluency as described previously ( Tantengco et al, 2021a ).…”