6 Importantly, since herpes viruses are latent or chronic, if the virus is inactive during the term of pregnancy there are no signiﬁcant ﬁndings that viral carriers have adverse pregnancy outcomes [65]. While cytomegalovirus belongs to the herpes virus family, it has been associated with activation of TLR2 in humans, while murine CMV is speciﬁc for TLR9. Mouse models demonstrate that CpG motifs speciﬁc for TLR9 activation do lead to adverse pregnancy outcomes in IL-10/ mice [15]. In wild type mice, the adverse eﬀects were on nonlive born pups that experienced cranial-facial and distal limb malformation [66]. Interestingly, infants born to CMV-infected mothers have shown similar malformations [67]. 7. Conclusion Taken together, the aforementioned studies and resultant data demonstrate that pathogenic route of entry as well as the speciﬁc TLR activated may be two important deter- minants of the immune responses that induce preterm birth. Murine studies have begun to delve into the role of NF-κB and its direct role in TNF-α production. Impor- tantly, an amassment of current literature seems to suggest that systemic inﬂammatory responses may induce TNF-α through the NF-κB pathway to activate events leading to preterm birth. In contrast, in the intrauterine setting the mode of action is most likely TNF-α-independent. Therefore, more research needs to occur to better understand the underlying inﬂammatory or hormonal imbalances that are induced by intrauterine infection that lead to preterm birth outcomes. In regards to activation of speciﬁc TLRs, systemic injection of diﬀerent PAMPs demonstrates that alternative immune cell subsets respond based on the pathogen at play. Bacterial pathogens signaling through TLR2 or TLR4 show strong staining within human chorion and amnion membranes. Murine studies emphasize the role of uNK cell ampliﬁcation and TNF-α production in response to TLR4 activation. TLR3 activation data from our lab demonstrates, in WT mice, that uNK cells amplify and produce TNF- α in response to poly(I:C), a viral mimic. Importantly, other reports show that systemic injection of poly(I:C) induces trophoblast apoptosis after a vigorous cytokine storm lending to a preterm birth outcome. Taken together, these two reports are not disparate. Finally, in the context of TLR9 activation it has been shown that macrophages and neutrophils inﬁltrate the placental zone and lead to preterm birth or intrauterine fetal death outcomes. As a whole, the reports discussed in this paper lend strong evidence to the postulate that the pathway to induction of preterm birth is dependent on the TLR activated—a product of the type of pathogenic infection. Secondly, the route of entry, intrauterine ascension versus systemic infection, plays a role in determining the cytokine proﬁle activated and the ensuing mechanism of fetal rejection. From a clinical standpoint, it may be paramount to account for not only the type of infectious agent at play within the maternal-fetal system, but also the route through which the pregnancy was compromised. Infectious Diseases in Obstetrics and Gynecology References [1] M. S. M. van Mourik, N. S. Macklon, and C. J. Heijnen, “Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment,” Journal of Leukocyte Biology, vol. 85, no. 1, pp. 4–19, 2009. [2] J. E. Norman, S. Bollapragada, M. Yuan, and S. M. Nelson, “Inﬂammatory pathways in the mechanism of parturition,” BMC Pregnancy and Childbirth, vol. 7, no. 1, article S7, 2007. [3] C. R. Mendelson, “Minireview: fetal-maternal hormonal signaling in pregnancy and labor,” Molecular Endocrinology, vol. 23, no. 7, pp. 947–954, 2009. [4] R. W. Kelly, A. E. King, and H. O. D. Crithley, “Cytokine control in human endometrium,” Reproduction, vol. 121, no. 1, pp. 3–19, 2001. [5] J. R. Challis, C. J. Lockwood, L. Myatt, J. E. Norman, J. F. Strauss III, and F. Petraglia, “Inﬂammation and pregnancy,” Reproductive Sciences, vol. 16, no. 2, pp. 206–215, 2009. [6] D. H. Watts, M. A. Krohn, S. L. Hillier, and D. A. Eschenbach, “The association of occult amniotic ﬂuid infection with gestational age and neonatal outcome among women in preterm labor,” Obstetrics and Gynecology, vol. 79, no. 3, pp. 351–357, 1992. [7] R. Romero, M. Sirtori, E. Oyarzun et al., “Infection and labor. V. Prevalence, microbiology, and clinical signiﬁcance of intraamniotic infection in women with preterm labor and intact membranes,” American Journal of Obstetrics and Gynecology, vol. 161, no. 3, pp. 817–824, 1989. [8] R. L. Goldenberg, J. C. Hauth, and W. W. Andrews, “Intrauter- ine infection and preterm delivery,” The New England Journal of Medicine, vol. 342, no. 20, pp. 1500–1507, 2000. [9] R. L. Goldenberg, J. F. Culhane, J. D. Iams, and R. Romero, “Epidemiology and causes of preterm birth,” The Lancet, vol. 371, no. 9606, pp. 75–84, 2008. [10] O. M. Faye-Petersen, “The placenta in preterm birth,” Journal of Clinical Pathology, vol. 61, no. 12, pp. 1261–1275, 2008. [11] V. Ilievski, S.-J. Lu, and E. Hirsch, “Activation of Toll- like receptors 2 or 3 and preterm delivery in the mouse,” Reproductive Sciences, vol. 14, no. 4, pp. 315–320, 2007. [12] V. M. Abrahams, P. B. Aldo, S. P. Murphy et al., “TLR6 modu- lates ﬁrst trimester trophoblast responses to peptidoglycan,” The Journal of Immunology, vol. 180, no. 9, pp. 6035–6043, 2008. [13] S. P. Murphy, N. N. Hanna, L. D. Fast et al., “Evidence for participation of uterine natural killer cells in the mechanisms responsible for spontaneous preterm labor and delivery,” American Journal of Obstetrics and Gynecology, vol. 3, no. 308, pp. 1–9, 2009. [14] S. P. Murphy, L. D. Fast, N. N. Hanna, and S. Sharma, “Uterine NK cells mediate inﬂammation-induced fetal demise in IL- 10-null mice,” The Journal of Immunology, vol. 175, no. 6, pp. 4084–4090, 2005. [15] J. E. Thaxton, R. Romero, and S. Sharma, “TLR9 activation coupled to IL-10 deﬁciency induces adverse pregnancy out- comes,” The Journal of Immunology, vol. 183, no. 2, pp. 1144– 1154, 2009. [16] S. Bauer, T. M u¨ller, and S. Hamm, “Pattern recognition by Toll-like receptors,” Advances in Experimental Medicine and Biology, vol. 653, pp. 15–34, 2009. [17] S. Patni, P. Flynn, L. P. Wynen et al., “An introduction to Toll-like receptors and their possible role in the initiation of labour,” BJOG, vol. 114, no. 11, pp. 1326–1334, 2007. [18] R. Romero, D. T. Brody, E. Oyarzun et al., “Infection and labor. III. Interleukin-1: a signal for the onset of parturition,”