2 and animal models show that alternative sets of cytokines coupled with activation of maternal or fetal cells are triggered in response to diﬀerent pathogenic agents, yet all result in unscheduled inﬂammation [14, 15]. A strong explanation for initiation of distinct immune pathways is probably the activation of toll-like receptors (TLRs). TLRs are a diverse set of innate immune sentinel receptors highly conserved throughout evolution. Each TLR1–10 is speciﬁc for a dif- ferent pathogen associated molecular pattern (PAMP) [16]. Importantly, TLRs are highly expressed at the maternal-fetal interface on trophoblasts and uterine immune cells [17]. It is likely that diﬀerential uterine immune responses occur due to the diversity of pathogens that ensues activation of any one of the TLRs, ultimately leading to deleterious inﬂammation and preterm birth. This paper aims to summarize speciﬁc viral and bacterial pathogens that may program preterm birth outcomes. Fur- thermore, we expound upon possible routes of transmission and areas of replication that diﬀerent foreign organisms may home to. Finally, after a brief discussion of the necessary steps toward an inﬂammatory environment that programs term labor, we elaborate on pathogenic triggers of this process that may activate TLRs to induce preterm birth. 2. Keys to Parturition In order to delineate the aberrant induction of inﬂammation by infectious agents, the role of inﬂammation in healthy pregnancy outcomes must be understood. The act of birth is characterized by the onset of uterine contractions that lead to expulsion of the fetus from the uterine cavity. The act of giving birth is the ultimate step in a proinﬂammatory signaling cascade that is orchestrated by an intrauterine milieu coupled to hormonal cues. Temporal increase in inﬂammatory signals initiates labor. Inﬂammatory cytokines and chemokines such as TNF-α, IL-1β and IL-8 increase in the placental microenvironment, including amniotic ﬂuid and fetal membranes. This induces signals for innate immune cells to become activated [18, 19]. Upon initiation of a proinﬂammatory cascade including NF-κB activation, uterine immune cells produce inﬂamma- tory chemokines and cytokines. Increased uterine activation of transcription by NF-κB leads directly to high levels of COX-2, PGE2, the gap junction protein connexin 43, and upregulation of the oxytocin receptor [20]. The increase of the aforementioned proteins and receptors leads to active uterine stretching and thus to the induction of birth. The pregnant uterus is replete with specialized immune cells primed to play roles in implantation, placentation, and parturition. The major cell types studied thus far are uterine NK cells (uNK), dendritic cells, T regulatory cells (Treg), and macrophages. uNK cells are the most thoroughly studied uterine immune cells due to lack of their natural cytotoxicity, an alternative receptor repertoire to peripheral blood counterparts, and the ability to produce vascular growth factors, cytokines, and chemokines during early stages of pregnancy [21, 22]. In humans, uNK cells are reduced after the second trimester. This trend is also followed in mice. However, uNK cells can be ampliﬁed in Infectious Diseases in Obstetrics and Gynecology mice in response to inﬂammatory triggers at later stages of pregnancy. It is thus tempting to speculate that such a phenomenon may also occur in humans. Research has expanded to investigate the ability of uNK cells to create a balanced milieu at the maternal-fetal interface due to their ability to produce IL-10, IP10, and IL-8 during cross-talk with trophoblasts and dendritic cells [23–35]. uNK cells are found interwoven throughout decidual areas where spiral arteries are bountiful. This positioning is demonstrative of their role in growth and decidualization of the placental organ [22]. uNK cells peak in humans in ﬁrst trimester and their numbers start to decrease at the end of second trimester. Mouse models deﬁcient in uNK cells show that proper birth takes place in the absence of these cells; however, the placentation that occurs is shallow and less developed than models where uNK cells are available [26]. While uNK cells are not thought to play a direct role in term birth, several murine studies have shown that these cells can become cytotoxic in nature in the presence of certain pathogens and ultimately lead to preterm birth through production of TNF- α [13, 14]. Thus, it stands to reason that the disappearance of uNK cells in mid-third trimester is a fail-safe mechanism for the course of term birth that allows the uterus to minimize unscheduled inﬂammatory events. While uNK cells do not play a documented role in term birth, macrophages may hold the key to conduction of proper parturition. Uterine macrophages are found in proportions upwards of 20% of the total uterine lym- phocyte population. Over the course of pregnancy, uter- ine macrophages are present as innate immune sentinels due to their expression of TLRs. However, macrophages are immunomodulatory over the course of gestation as they simultaneously produce TNF-α, IL-10, and TGF-β throughout placentation [27]. Along similar lines, matrix metalloproteinases (MMPs) are secreted in early and late gestation for tissue degradation which in turn induces MIP- 1α and MCP-1 to signal the further invasion of macrophages for phagocytosis [28–30]. Reports show that late stage stim- ulation of uterine macrophages induces high levels of IL-8 production, a neutrophil and macrophage chemoattractant. In line with these ﬁndings, the act of parturition itself is associated with high levels of macrophage and neutrophil inﬁltration as these two cell types can quickly engulf, remove, and remodel tissue [31]. The function and phenotype of dendritic cells in the uterus is beginning to be expounded upon. Recent studies have highlighted their role in crosstalk with uNK cells and trophoblasts in order to orchestrate production of cytokines such as TNF-α, IL-12, and IL-10 [32]. While the role of DCs in parturition remains unknown, it is fair to assume that these cells add to the balanced cytokine and signaling milieu required throughout gestation. Furthermore, recent characterization in mice of a uterine-speciﬁc subset of DCs that is skewed toward production of IL-15 and CCL6 adds to evidence that their actions are dichotomous [33]. Thus, while these cells contribute to an immunosuppressive atmosphere over the course of gestation, they possess the capacity to contribute to proinﬂammatory responses upon pathogenic activation.