Abstract
Ureaplasma species are the most frequently isolated microorganisms inside the amniotic cavity and have been associated with spontaneous abortion, chorioamnionitis, premature rupture of the membranes (PROM), preterm labour (PL) pneumonia in neonates and bronchopulmonary dysplasia in neonates. The mechanisms by which Ureaplasmas cause such diseases remain unclear, but it is believed that inappropriate induction of inflammatory responses is involved, triggered by the innate immune system. As part of its mechanism of activation, the innate immune system employs germ-lined encoded receptors, called pattern recognition receptors (PRRs) in order to “sense” pathogens. One such family of PRRs are the Toll like receptor family (TLR). In the current study we aimed to elucidate the role of TLRs in Ureaplasma-induced inflammation in human amniotic epithelial cells. Using silencing, as well as human embryonic kidney (HEK) transfected cell lines, we demonstrate that TLR2, TLR6 and TLR9 are involved in the inflammatory responses against Ureaplasma parvum and urealyticum serovars. Ureaplasma lipoproteins, such as Multiple Banded antigen (MBA), trigger responses via TLR2/TLR6, whereas the whole bacterium is required for TLR9 activation. No major differences were observed between the different serovars. Cell activation by Ureaplasma parvum and urealyticum seem to require lipid raft function and formation of heterotypic receptor complexes comprising of TLR2 and TLR6 on the cell surface and TLR9 intracellularly.
Highlights
Intrauterine infection is a major cause of spontaneous preterm birth (PTB)
Human amniotic epithelial cells were incubated with Ureaplasma SV2, serovar 3 (SV3), and SV14 for different time points and the supernatants were assayed for inflammatory cytokines
Since we demonstrated that Ureaplasma-induced cellular activation is mediated mainly through TLR2 on the cell surface, we proceeded to determine whether TLR2 was recruited within lipid rafts upon stimulation by different Ureaplasma serovars or Multiple Banded antigen (MBA)
Summary
Intrauterine infection is a major cause of spontaneous preterm birth (PTB). There is accumulating epidemiologic and experimental evidence that intrauterine or postnatal infection with Ureaplasma species is a significant risk factor for adverse pregnancy outcomes and complications of extreme preterm birth such as bronchopulmonary dysplasia and intraventricular hemorrhage [1]. Ureaplasma infection is a major risk factor for spontaneous premature rupture of membranes (PROM), clinical chorioamnionitis and preterm delivery [2;3]. It is believed that the innate immune response to these bacteria can lead to the activation of pattern recognition receptors (PRRs), production and release of pro-inflammatory mediators leading to the complications associated with preterm and term infants. Increased levels of pro-inflammatory mediators such as interleukin-6 (IL-6), tumour-necrosis-factor (TNF-a), IL-1band IL-8 have been shown in amniotic fluid infected with Ureaplasma, supporting this hypothesis [8]
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