Hindawi Publishing Corporation Infectious Diseases in Obstetrics and Gynecology Volume 2010, Article ID 378472, 8 pages doi:10.1155/2010/378472 Review Article TLR-Mediated Preterm Birth in Response to Pathogenic Agents Jessica E. Thaxton, Tania A. Nevers, and Surendra Sharma Department of Pediatrics, Women and Infants’ Hospital of Rhode Island—Warren Alpert Medical School of Brown University, Providence, RI 02905, USA Correspondence should be addressed to Surendra Sharma, ssharma@wihri.org Received 7 May 2010; Revised 28 June 2010; Accepted 2 July 2010 Academic Editor: Bryan Larsen Copyright © 2010 Jessica E. Thaxton et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 dysregualtion 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. 1. Introduction Healthy pregnancy is the result of a tightly regulated system of crosstalk between maternal and fetal structures. Implan- tation and parturition are speciﬁcally characterized by states of inﬂammation [1, 2]. Proinﬂammatory cytokines, matrix degrading proteins, altered transcriptional factors, rapid hor- monal changes, and immune cell activity are paramount for uterine activation and the onset of labor [3]. In contrast, the gestation period, comprised of decidualization, placentation, and fetal development, requires uterine quiescence guided by high levels of progesterone and the production of anti- inﬂammatory cytokines from both maternal and fetal cells [4, 5]. Due to the immediacy with which the onset of labor takes place and the resultant necessary shift from anti- to proinﬂammatory signal cascades, it is not surprising that unscheduled parturition is the most high risk state of pregnancy for adverse outcomes. Preterm birth can result from a range of causes such as exposure to environmental triggers, maternal stress, fetal or maternal genetic abnormalities, or hormonal imbalance. However, infection is one of the most heralded causes of preterm birth due to the drastic link between underlying infectious agents and their ability to promote inﬂammatory responses [6–8]. It is well documented that the vast majority, upwards of 90% of preterm births that occur before gesta- tional week 28 can be correlated to the presence of infectious agents and severe inﬂammation [9]. Furthermore, a signif- icant number of placentas obtained from preterm deliveries show pathological signs of chorioamnionitis which can result from a number of diﬀerential pathogenic agents [10]. Thus, while the evidence for infection-mediated preterm birth is substantial, the underlying mechanisms that induce early birth in response to pathogenic presence remain vague. Investigation into the mechanisms that lead to preterm birth in response to pathogenic agents should take into account several key factors. Firstly, the route of entry that a given foreign agent takes determines where the agent will ultimately subsist and what pathways will be activated. Recent evidence demonstrates that the same pathogen, delivered through alternative routes, can lead to diﬀer- ential inﬂammatory responses ([11–13], our unpublished results). Therefore, the mechanisms that underlie initiation of preterm birth may be dependent on the organ or tissue where a pathogen enters. Secondly, diﬀerent pathogens may elicit disparate inﬂammatory responses. Data from humans