TLR-mediated preterm birth in response to pathogenic agents

Abstract

The incidence of preterm birth in developed countries has risen in the past decades. Underlying causes for this enigmatic pregnancy complication are numerous, yet infectious agents that induce dysregulation of immunity at the maternal-fetal interface pose one of the most probable causes of preterm birth. This paper highlights two factors regarding maternal infections that trigger unscheduled inflammatory sequences that are deleterious to the maternal-fetal balance necessary to maintain pregnancy. Firstly, we discuss the role of Toll-like receptors (TLRs) as sentinels of uterine immunity in the context of response to pathogens. We highlight the idea that particular TLR activations lead to differential immune cascades that induce preterm birth. Secondly, two alternative routes of pathogenic entry may prove to be critical for inducing preterm birth via a cytokine storm or a secondary and currently unknown cell-mediated mechanism of uterine inflammation. This paper summarizes pathways that underlie activation of adverse and diverse immune responses to foreign agents that may result in preterm birth.

Figure 1

Roads to Preterm. Birth pathogens may enter the placental blood supply via systemic circulation due to previous or current onset of infection. Murine models where intraperitoneal injections are employed are utilized to mimic maternal systemic infection in order to study the ability of a pathogen to activate decidual immunity. Data presented in this paper demonstrate that systemic infections correlate to TNF-α -dependent immune responses that ultimately induce preterm birth. In contrast, intrauterine ascending infections occur when a pathogen ascends the uterine cavity via the vaginal tract. Surgical procedures in mice, rats, and rabbits have mimicked uterine cavity infections through intrauterine infusion of pathogens directly into the amniotic sac or between two placental units. Importantly, data summarized here demonstrate that pathogens introduced through intrauterine ascension do not tend to activate a TNF-α -driven axis to induce preterm birth.