The unique immunological and microbial aspects of pregnancy

Nature Reviews Immunology

Volumn 17, Issue 8, 2017, Pages 469-482

  Mor, Gil ^a   Aldo, Paulomi ^a   Alvero, Ayesha B ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BLASTOCYST; CANCER IMMUNOLOGY; FEMALE; FETUS DEVELOPMENT; FETUS GROWTH; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOLOGY; IMPLANTATION; LABOR; MICROFLORA; PREGNANCY; PRIORITY JOURNAL; REPRODUCTION; REVIEW; TROPHOBLAST; VIRUS INFECTION; ANTIGEN PRESENTING CELL; DENDRITIC CELL; FETOMATERNAL TRANSFUSION; FETUS;

ANTIGEN-PRESENTING CELLS; DENDRITIC CELLS; FEMALE; FETUS; HUMANS; MATERNAL-FETAL EXCHANGE; PREGNANCY;

EID: 85026424840     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2017.64     Document Type: Review

References (182)

1. Bulmer, J. N., Pace, D. & Ritson, A. Immunoregulatory cells in human decidua: morphology, immunohistochemistry and function. Reprod. Nutr. Dev. 28, 1599-1613 (1988).
2. Abelius, M. S. et al. The placental immune milieu is characterized by a Th2- and anti-inflammatory transcription profile, regardless of maternal allergy, and associates with neonatal immunity. Am. J. Reprod. Immunol. 73, 445-459 (2015).
3. Gardner, M. & Luciw, P. Macaque models of human infectious disease. ILAR J. 49, 220-255 (2008).
4. Fettke, F., Schumacher, A., Costa, S. D. & Zenclussen, A. C. B cells: the old new players in reproductive immunology. Front. Immunol. 5, 285 (2014).
5. Muzzio, D. O. et al. B cell development undergoes profound modifications and adaptations during pregnancy in mice. Biol. Reprod. 91, 115 (2014).
6. Lessin, D. L., Hunt, J. S., King, C. R. & Wood, G. W. Antigen expression by cells near the maternal-fetal interface. Am. J. Reprod. Immunol. Microbiol. 16, 1-7 (1988).
7. Medawar, P. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7, 320-338 (1952).
8. Moffett-King, A. Natural killer cells and pregnancy. Nat. Rev. Immunol. 2, 656-663 (2002).
9. Laskarin, G. et al. Antigen-presenting cells and materno-fetal tolerance: an emerging role for dendritic cells. Am. J. Reprod. Immunol. 58, 255-267 (2007).
10. Abrahams, V. M., Straszewski-Chavez, S. L., Guller, S. & Mor, G. First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis. Mol. Hum. Reprod. 10, 55-63 (2004).
11. Balkundi, D. R., Hanna, N., Hileb, M., Dougherty, J. & Sharma, S. Labor-associated changes in Fas ligand expression and function in human placenta. Pediatr. Res. 47, 301-308 (2000).
12. Hanna, J. et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat. Med. 12, 1065-1074 (2006).
13. Birnberg, T. et al. Dendritic cells are crucial for decidual development during embryo implantation. Am. J. Reprod. Immunol. 57, 342 (2007).
14. Collins, M. K., Tay, C. S. & Erlebacher, A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J. Clin. Invest. 119, 2062-2073 (2009).
15. Holtan, S. G., Creedon, D. J., Haluska, P. & Markovic, S. N. Cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents. Mayo Clin. Proc. 84, 985-1000 (2009).
16. Beaman, K. D. et al. Pregnancy is a model for tumors, not transplantation. Am. J. Reprod. Immunol. 76, 3-7 (2016).
17. Lin, W. W. & Karin, M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 117, 1175-1183 (2007).
18. Chen, R., Alvero, A. B., Silasi, D. A. & Mor, G. Inflammation, cancer and chemoresistance: taking advantage of the Toll-like receptor signaling pathway. Am. J. Reprod. Immunol. 57, 93-107 (2007).
19. Allavena, P. et al. Anti-inflammatory properties of the novel antitumor agent Yondelis (Trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res. 65, 2964-2971 (2005).
20. Romero, R. et al. The role of inflammation and infection in preterm birth. Semin. Reprod. Med. 25, 21-39 (2007).
21. Wegmann, T. G. & Guilbert, L. J. Immune signaling at the maternal-fetal interface and trophoblast differentiation. Dev. Comp. Immunol. 16, 425-430 (1992).
22. Saito, S., Miyazaki, S. & Sasaki, Y. in Immunology of Pregnancy (ed. Mor, G.) 37-48 (Springer New York, 2006).
23. Chaouat, G. et al. Immune suppression and Th1/Th2 balance in pregnancy revisited: a (very) personal tribute to Tom Wegmann. Am. J. Reprod. Immunol. 37, 427-434 (1997).
24. Ng, S. C. et al. Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy. Am. J. Reprod. Immunol. 48, 77-86 (2002).
25. Mor, G. & Cardenas, I. The immune system in pregnancy: a unique complexity. Am. J. Reprod. Immunol. 63, 425-433 (2010).
26. Mor, G., Cardenas, I., Abrahams, V. & Guller, S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann. NY Acad. Sci. 1221, 80-87 (2011).
27. Norwitz, E. R. et al. Molecular regulation of parturition: the role of the decidual clock. Cold Spring Harb. Perspect. Med. 5, a023143 (2015).
28. Gnainsky, Y. et al. Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action. Reproduction 149, 75-85 (2015).
29. Zenclussen, A. C. & Hammerling, G. J. Cellular regulation of the uterine microenvironment that enables embryo implantation. Front. Immunol. 6, 321 (2015).
30. Plaks, V. et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J. Clin. Invest. 118, 3954-3965 (2008).
31. Morelli, A. E. & Thomson, A. W. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat. Rev. Immunol. 7, 610-621 (2007).
32. Saito, S., Nakashima, A., Shima, T. & Ito, M. Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol. 63, 601-610 (2010).
33. Elovitz, M. A. & Mrinalini, C. Animal models of preterm birth. Trends Endocrinol. Metab. 15, 479-487 (2004).
34. Faas, M. M. & de Vos, P. Uterine NK cells and macrophages in pregnancy. Placenta http://dx.doi.org/10.1016/j.placenta.2017.03.001 (2017).
35. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164, 6166-6173 (2000).
36. Abrahams, V. M., Kim, Y. M., Straszewski, S. L., Romero, R. & Mor, G. Macrophages and apoptotic cell clearance during pregnancy. Am. J. Reprod. Immunol. 51, 275-282 (2004).
37. Burke, S. D. et al. Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am. J. Reprod. Immunol. 63, 472-481 (2010).
38. Vacca, P. et al. Crosstalk between decidual NK and CD14+ myelomonocytic cells results in induction of Tregs and immunosuppression. Proc. Natl Acad. Sci. USA 107, 11918-11923 (2010).
39. Tilburgs, T. et al. Human HLA-G+ extravillous trophoblasts: immune-activating cells that interact with decidual leukocytes. Proc. Natl Acad. Sci. USA 112, 7219-7224 (2015).
40. Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nat. Rev. Immunol. 13, 23-33 (2013).
41. Rowe, J. H., Ertelt, J. M., Xin, L. & Way, S. S. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102-106 (2012).
42. Burt, T. D. Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease. Am. J. Reprod. Immunol. 69, 346-358 (2013).
43. Jasper, M. J., Tremellen, K. P. & Robertson, S. A. Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue. Mol. Hum. Reprod. 12, 301-308 (2006).
44. Zenclussen, A. C. et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am. J. Pathol. 166, 811-822 (2005).
45. Sasaki, Y. et al. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol. Hum. Reprod. 10, 347-353 (2004).
46. Lindstrom, T. M. & Bennett, P. R. The role of nuclear factor kappa B in human labour. Reproduction 130, 569-581 (2005).
47. Edey, L. F. et al. The local and systemic immune response to intrauterine LPS in the prepartum mouse. Biol. Reprod. 95, 125 (2016).
48. Condon, J. C., Jeyasuria, P., Faust, J. M. & Mendelson, C. R. Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition. Proc. Natl Acad. Sci. USA 101, 4978-4983 (2004).
49. Plazyo, O. et al. HMGB1 induces an inflammatory response in the chorioamniotic membranes that is partially mediated by the inflammasome. Biol. Reprod. 95, 130 (2016).
50. Behnia, F., Sheller, S. & Menon, R. Mechanistic differences leading to infectious and sterile inflammation. Am. J. Reprod. Immunol. 75, 505-518 (2016).
51. Jeyasuria, P., Subedi, K., Suresh, A. & Condon, J. C. Elevated levels of uterine anti-apoptotic signaling may activate NFKB and potentially confer resistance to caspase 3-mediated apoptotic cell death during pregnancy in mice. Biol. Reprod. 85, 417-424 (2011).
52. Gomez-Lopez, N. et al. Intra-amniotic administration of HMGB1 induces spontaneous preterm labor and birth. Am. J. Reprod. Immunol. 75, 3-7 (2016).
53. Obata, Y., Furusawa, Y. & Hase, K. Epigenetic modifications of the immune system in health and disease. Immunol. Cell Biol. 93, 226-232 (2015).
54. Bidarimath, M., Khalaj, K., Wessels, J. M. & Tayade, C. MicroRNAs, immune cells and pregnancy. Cell. Mol. Immunol. 11, 538-547 (2014).
55. Parham, P. & Moffett, A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat. Rev. Immunol. 13, 133-144 (2013).
56. Ramhorst, R. et al. Modulation and recruitment of inducible regulatory T cells by first trimester trophoblast cells. Am. J. Reprod. Immunol. 67, 17-27 (2012).
57. Romero, R. et al. The preterm parturition syndrome. BJOG 113 (Suppl. 3), 17-42 (2006).
58. Manaster, I. et al. Endometrial NK cells are special immature cells that await pregnancy. J. Immunol. 181, 1869-1876 (2008).
59. Zhang, J., Chen, Z., Smith, G. N. & Croy, B. A. Natural killer cell-triggered vascular transformation: maternal care before birth? Cell. Mol. Immunol. 8, 1-11 (2011).
60. Aldo, P. B. et al. Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am. J. Reprod. Immunol. 72, 270-284 (2014).
61. Svensson-Arvelund, J. et al. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J. Immunol. 194, 1534-1544 (2015).
62. Repnik, U. et al. Comparison of macrophage phenotype between decidua basalis and decidua parietalis by flow cytometry. Placenta 29, 405-412 (2008).
63. Houser, B. L., Tilburgs, T., Hill, J., Nicotra, M. L. & Strominger, J. L. Two unique human decidual macrophage populations. J. Immunol. 186, 2633-2642 (2011).
64. Oettel, A. et al. Human umbilical vein endothelial cells foster conversion of CD4+CD25-Foxp3- T cells into CD4+Foxp3+ regulatory T cells via transforming growth factor-β. Sci. Rep. 6, 23278 (2016).
65. Poloski, E. et al. JEG-3 trophoblast cells producing human chorionic gonadotropin promote conversion of human CD4+FOXP3- T cells into CD4+FOXP3+ regulatory T cells and foster T cell suppressive activity. Biol. Reprod. 94, 106 (2016).
66. Nancy, P. et al. Chemokine gene silencing in decidual stromal cells limits T cell access to the maternal-fetal interface. Science 336, 1317-1321 (2012).
67. Lockwood, C. J. et al. Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am. J. Pathol. 183, 841-856 (2013).
68. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197-216 (2002).
69. Medzhitov, R. & Janeway, C. Jr. Innate immunity. N. Engl. J. Med. 343, 338-344 (2000).
70. Abrahams, V. M. et al. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J. Immunol. 175, 8096-8104 (2005).
71. Abrahams, V. M., Romero, R. & Mor, G. TLR-3 and TLR-4 mediate differential chemokine production and immune cell recruitment by first trimester trophoblast cells. Am. J. Reprod. Immunol. 53, 279 (2005).
72. Abrahams, V. M. et al. Stimulation of first trimester trophoblast cells with poly(I:C) induces SLPI secretion. Am. J. Reprod. Immunol. 53, 280 (2005).
73. Mor, G., Romero, R., Aldo, P. B. & Abrahams, V. M. Is the trophoblast an immune regulator?: the role of Toll-like receptors during pregnancy. Crit. Rev. Immunol. 25, 375-388 (2005).
74. Costello, M. J., Joyce, S. K. & Abrahams, V. M. NOD protein expression and function in first trimester trophoblast cells. Am. J. Reprod. Immunol. 57, 67-80 (2007).
75. Romero, R., Chaiworapongsa, T. & Espinoza, J. Micronutrients and intrauterine infection, preterm birth and the fetal inflammatory response syndrome. J. Nutr. 133, 1668S-1673S (2003).
76. Espinoza, J., Erez, O. & Romero, R. Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery. Am. J. Obstet. Gynecol. 194, 630-637 (2006).
77. Goldenberg, R. L., Hauth, J. C. & Andrews, W. W. Intrauterine infection and preterm delivery. N. Engl. J. Med. 342, 1500-1507 (2000).
78. Lamont, R. F. The role of infection in preterm labour and birth. Hosp. Med. 64, 644-647 (2003).
79. Kiefer, D. G. et al. Is midtrimester short cervix a sign of intraamniotic inflammation? Am. J. Obstet. Gynecol. 200, 374.e1-374.e5 (2009).
80. Peltier, M. R. et al. Polybrominated diphenyl ethers enhance the production of proinflammatory cytokines by the placenta. Placenta 33, 745-749 (2012).
81. Wang, H. & Hirsch, E. Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of Toll-like receptor 4. Biol. Reprod. 69, 1957-1963 (2003).
82. Agrawal, V., Smart, K., Jilling, T. & Hirsch, E. Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2. PLoS ONE 8, e63990 (2013).
83. Bayraktar, M. et al. IL-10 modulates placental responses to TLR ligands. Am. J. Reprod. Immunol. 62, 390-399 (2009).
84. Kiefer, D. G. et al. Amniotic fluid inflammatory score is associated with pregnancy outcome in patients with mid trimester short cervix. Am. J. Obstet. Gynecol. 206, 68.e1-68.e6 (2012).
85. Straszewski-Chavez, S. L., Abrahams, V. M. & Mor, G. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr. Rev. 26, 877-897 (2005).
86. Mor, G. Pregnancy reconceived. Nat. Hist. 116, 36-41 (2007).
87. Abrahams, V. M. & Mor, G. Toll-like receptors and their role in the trophoblast. Placenta 26, 540-547 (2005).
88. Adams Waldorf, K. M., Rubens, C. E. & Gravett, M. G. Use of nonhuman primate models to investigate mechanisms of infection-associated preterm birth. BJOG 118, 136-144 (2011).
89. Koga, K. & Mor, G. Toll-like receptors at the maternal- fetal interface in normal pregnancy and pregnancy disorders. Am. J. Reprod. Immunol. 63, 587-600 (2010).
90. Elovitz, M. A., Mrinalini, C. & Sammel, M. D. Elucidating the early signal transduction pathways leading to fetal brain injury in preterm birth. Pediatr. Res. 59, 50-55 (2006).
91. Burd, I. et al. Inflammation-induced preterm birth alters neuronal morphology in the mouse fetal brain. J. Neurosci. Res. 88, 1872-1881 (2010).
92. Pirianov, G. et al. The cyclopentenone 15-deoxy-δ 12,14-prostaglandin J2 delays lipopolysaccharide-induced preterm delivery and reduces mortality in the newborn mouse. Endocrinology 150, 699-706 (2009).
93. Koga, K. et al. Activation of TLR3 in the trophoblast is associated with preterm delivery. Am. J. Reprod. Immunol. 61, 196-212 (2009).
94. Cardenas, I. et al. Nod1 activation by bacterial iE-DAP induces maternal-fetal inflammation and preterm labor. J. Immunol. 187, 980-986 (2011).
95. Pettker, C. M. et al. Value of placental microbial evaluation in diagnosing intra-amniotic infection. Obstet. Gynecol. 109, 739-749 (2007).
96. Goldenberg, R. L., Culhane, J. F., Iams, J. D. & Romero, R. Epidemiology and causes of preterm birth. Lancet 371, 75-84 (2008).
97. Digiulio, D. B. et al. Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods. J. Perinat. Med. 38, 503-513 (2010).
98. Cao, B. & Mysorekar, I. U. Intracellular bacteria in placental basal plate localize to extravillous trophoblasts. Placenta 35, 139-142 (2014).
99. Stout, M. J. et al. Identification of intracellular bacteria in the basal plate of the human placenta in term and preterm gestations. Am. J. Obstet. Gynecol. 208, 226.e1-226.e7 (2013).
100. Racicot, K. et al. Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J. Immunol. 191, 934-941 (2013).
101. Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl Med. 6, 237ra65 (2014).
102. Prince, A. L., Antony, K. M., Chu, D. M. & Aagaard, K. M. The microbiome, parturition, and timing of birth: more questions than answers. J. Reprod. Immunol. 104-105, 12-19 (2014).
103. Prince, A. L., Antony, K. M., Ma, J. & Aagaard, K. M. The microbiome and development: a mother's perspective. Semin. Reprod. Med. 32, 14-22 (2014).
104. Ramos Bde, A., Kanninen, T. T., Sisti, G. & Witkin, S. S. Microorganisms in the female genital tract during pregnancy: tolerance versus pathogenesis. Am. J. Reprod. Immunol. 73, 383-389 (2015).
105. Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109-1113 (2008).
106. Hu, Y. et al. Different immunological responses to early-life antibiotic exposure affecting autoimmune diabetes development in NOD mice. J. Autoimmun. 72, 47-56 (2016).
107. Gomez de Aguero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296-1302 (2016).
108. Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36-49 (2014).
109. Chard, T., Craig, P. H., Menabawey, M. & Lee, C. Alpha interferon in human pregnancy. Br. J. Obstet. Gynaecol. 93, 1145-1149 (1986).
110. Howatson, A. G., Farquharson, M., Meager, A., McNicol, A. M. & Foulis, A. K. Localization of α-interferon in the human feto-placental unit. J. Endocrinol. 119, 531-534 (1988).
111. Aboagye-Mathiesen, G., Toth, F. D., Zdravkovic, M. & Ebbesen, P. Functional characteristics of human trophoblast interferons. Am. J. Reprod. Immunol. 35, 309-317 (1996).
112. Aboagye-Mathiesen, G., Toth, F. D., Zdravkovic, M. & Ebbesen, P. Human trophoblast interferons: production and possible roles in early pregnancy. Early Pregnancy 1, 41-53 (1995).
113. Lee, B. N. et al. Production of interferons and β-chemokines by placental trophoblasts of HIV-1-infected women. Infect. Dis. Obstet. Gynecol. 9, 95-104 (2001).
114. Reuben, J. M. et al. Induction of inflammatory cytokines in placental monocytes of gravidae infected with the human immunodeficiency virus type 1. J. Interferon Cytokine Res. 16, 963-971 (1996).
115. Odorizzi, P. M. & Wherry, E. J. Immunology. An interferon paradox. Science 340, 155-156 (2013).
116. Sharif, M. N. et al. Twist mediates suppression of inflammation by type I IFNs and Axl. J. Exp. Med. 203, 1891-1901 (2006).
117. Racicot, K. et al. Type I interferon regulates the placental inflammatory response to bacteria and is targeted by virus: mechanism of polymicrobial infection-induced preterm birth. Am. J. Reprod. Immunol. 75, 451-460 (2016).
118. Boasso, A., Hardy, A. W., Anderson, S. A., Dolan, M. J. & Shearer, G. M. HIV-induced type I interferon and tryptophan catabolism drive T cell dysfunction despite phenotypic activation. PLoS ONE 3, e2961 (2008).
119. Wilson, E. B. & Brooks, D. G. Decoding the complexity of type I interferon to treat persistent viral infections. Trends Microbiol. 21, 634-640 (2013).
120. Wilson, E. B. et al. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340, 202-207 (2013).
121. Iwasaki, A. Antiviral immune responses in the genital tract: clues for vaccines. Nat. Rev. Immunol. 10, 699-711 (2010).
122. Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291-295 (2010).
123. Tian, M. et al. The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats. Sci. Rep. 6, 27683 (2016).
124. Silasi, M. et al. Viral infections during pregnancy. Am. J. Reprod. Immunol. 73, 199-213 (2015).
125. Giugliano, S. et al. Hepatitis C virus sensing by human trophoblasts induces innate immune responses and recruitment of maternal NK cells: potential implications for limiting vertical transmission. J. Immunol. 195, 3737-3747 (2015).
126. Coyne, C. B. & Lazear, H. M. Zika virus - reigniting the TORCH. Nat. Rev. Microbiol. 14, 707-715 (2016).
127. Olivadoti, M., Toth, L. A., Weinberg, J. & Opp, M. R. Murine gammaherpesvirus 68: a model for the study of Epstein-Barr virus infections and related diseases. Comp. Med. 57, 44-50 (2007).
128. Dutia, B. M., Allen, D. J., Dyson, H. & Nash, A. A. Type I interferons and IRF-1 play a critical role in the control of a gammaherpesvirus infection. Virology 261, 173-179 (1999).
129. Garcia-Sastre, A. & Biron, C. A. Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312, 879-882 (2006).
130. Cardenas, I. et al. Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J. Immunol. 185, 1248-1257 (2010).
131. Cappelletti, M. et al. Inflammation and preterm birth. J. Leukoc. Biol. 99, 67-78 (2016).
132. Romero, R. et al. CXCL10 and IL-6: markers of two different forms of intra-amniotic inflammation in preterm labor. Am. J. Reprod. Immunol. http://dx.doi. org/10.1111/aji.12685 (2017).
133. Cardenas, I. et al. Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis. Am. J. Reprod. Immunol. 65, 110-117 (2011).
134. Cappelletti, M. et al. Type I interferons regulate susceptibility to inflammation-induced preterm birth. JCI Insight 2, e91288 (2017).
135. Gervasi, M. T. et al. Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy. J. Matern. Fetal Neonatal Med. 25, 2002-2013 (2012).
136. Kourtis, A. P., Read, J. S. & Jamieson, D. J. Pregnancy and infection. N. Engl. J. Med. 370, 2211-2218 (2014).
137. Kwon, J. Y., Romero, R. & Mor, G. New insights into the relationship between viral infection and pregnancy complications. Am. J. Reprod. Immunol. 71, 387-390 (2014).
138. Price, M. E., Fisher-Hoch, S. P., Craven, R. B. & McCormick, J. B. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ 297, 584-587 (1988).
139. Jamieson, D. J., Uyeki, T. M., Callaghan, W. M., Meaney-Delman, D. & Rasmussen, S. A. What obstetrician-gynecologists should know about Ebola: a perspective from the Centers for Disease Control and Prevention. Obstet. Gynecol. 124, 1005-1010 (2014).
140. Berry, S. M. et al. Premature parturition is characterized by in utero activation of the fetal immune system. Am. J. Obstet. Gynecol. 173, 1315-1320 (1995).
141. Faucher, B. et al. Long-term ocular outcome in congenital toxoplasmosis: a prospective cohort of treated children. J. Infect. 64, 104-109 (2012).
142. Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643-660 (2014).
143. Cordeiro, C. N., Tsimis, M. & Burd, I. Infections and brain development. Obstet. Gynecol. Surv. 70, 644-655 (2015).
144. Estes, M. L. & McAllister, A. K. Maternal immune activation: implications for neuropsychiatric disorders. Science 353, 772-777 (2016).
145. Rose, D. R. et al. Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav. Immun. 63, 60-70 (2017).
146. Zuckerman, L., Rehavi, M., Nachman, R. & Weiner, I. Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology 28, 1778-1789 (2003).
147. Smith, S. E., Li, J., Garbett, K., Mirnics, K. & Patterson, P. H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. 27, 10695-10702 (2007).
148. Garbett, K. A., Hsiao, E. Y., Kalman, S., Patterson, P. H. & Mirnics, K. Effects of maternal immune activation on gene expression patterns in the fetal brain. Transl Psychiatry 2, e98 (2012).
149. Shi, L., Fatemi, S. H., Sidwell, R. W. & Patterson, P. H. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J. Neurosci. 23, 297-302 (2003).
150. Shi, L. et al. Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav. Immun. 23, 116-123 (2009).
151. Shi, L., Tu, N. & Patterson, P. H. Maternal influenza infection is likely to alter fetal brain development indirectly: the virus is not detected in the fetus. Int. J. Dev. Neurosci. 23, 299-305 (2005).
152. Korzeniewski, S. J. et al. A "multi-hit" model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events. J. Perinat. Med. 42, 731-743 (2014).
153. Mahic, M. et al. Maternal immunoreactivity to herpes simplex virus 2 and risk of autism spectrum disorder in male offspring. mSphere 2, e00016-17 (2017).
154. Price, M., Fisher-Hoch, S., Craven, R. & McCormick, J. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ 297, 584-587 (1988).
155. Bello, O. O., Akinajo, O. R., Odubamowo, K. H. & Oluwasola, T. A. Lassa fever in pregnancy: report of 2 cases seen at the University College Hospital, Ibadan. Case Rep. Obstet. Gynecol. 2016, 9673683 (2016).
156. Racicot, K. et al. Cutting edge: fetal/placental type I IFN can affect maternal survival and fetal viral load during viral infection. J. Immunol. 198, 3029-3032 (2017).
157. de Carvalho, N. S., de Carvalho, B. F., Fugaca, C. A., Doris, B. & Biscaia, E. S. Zika virus infection during pregnancy and microcephaly occurrence: a review of literature and Brazilian data. Braz. J. Infect. Dis. 20, 282-289 (2016).
158. Dyer, O. US agency says Zika virus causes microcephaly. BMJ 353, i2167 (2016).
159. Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816-818 (2016).
160. Mor, G. Placental inflammatory response to Zika virus may affect fetal brain development. Am. J. Reprod. Immunol. 75, 421-422 (2016).
161. Dekel, N., Gnainsky, Y., Granot, I. & Mor, G. Inflammation and implantation. Am. J. Reprod. Immunol. 63, 17-21 (2010).
162. Syggelou, A., Iacovidou, N., Kloudas, S., Christoni, Z. & Papaevangelou, V. Congenital cytomegalovirus infection. Ann. NY Acad. Sci. 1205, 144-147 (2010).
163. Picone, O. et al. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat. Diagn. 33, 751-758 (2013).
164. Chernyshov, V., Slukvin, I. & Bondarenko, G. Phenotypic characterization of CD7+, CD3+, and CD8+ lymphocytes from first trimester human decidua using two color flow cytometry. Am. J. Reprod. Immunol. 29, 5-16 (1993).
165. Enders, G., Miller, E., Cradock-Watson, J., Bolley, I. & Ridehalgh, M. Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases. Lancet 343, 1548-1551 (1994).
166. Pastuszak, A. L. et al. Outcome after maternal varicella infection in the first 20 weeks of pregnancy. N. Engl. J. Med. 330, 901-905 (1994).
167. Dontigny, L. et al. Rubella in pregnancy. J. Obstet. Gynaecol. Can. 30, 152-168 (2008).
168. Lee, J. Y. & Bowden, D. S. Rubella virus replication and links to teratogenicity. Clin. Microbiol. Rev. 13, 571-587 (2000).
169. Brown, Z. A. et al. The acquisition of herpes simplex virus during pregnancy. N. Engl. J. Med. 337, 509-515 (1997).
170. Xu, F., Markowitz, L. E., Gottlieb, S. L. & Berman, S. M. Seroprevalence of herpes simplex virus types 1 and 2 in pregnant women in the United States. Am. J. Obstet. Gynecol. 196, 43.e1-43.e6 (2007).
171. Ciaranello, A. L. et al. What will it take to eliminate pediatric HIV? Reaching WHO target rates of mother-to-child HIV transmission in Zimbabwe: a model-based analysis. PLoS Med. 9, e1001156 (2012).
172. Wang, B. et al. Loss to follow-up in a community clinic in South Africa - roles of gender, pregnancy and CD4 count. S. Afr. Med. J. 101, 253-257 (2011).
173. Leikin, E., Lysikiewicz, A., Garry, D. & Tejani, N. Intrauterine transmission of hepatitis A virus. Obstet. Gynecol. 88, 690-691 (1996).
174. Erkan, T., Kutlu, T., Cullu, F. & Tumay, G. T. A case of vertical transmission of hepatitis A virus infection. Acta Paediatr. 87, 1008-1009 (1998).
175. Guo, Z. et al. Risk factors of HBV intrauterine transmission among HBsAg-positive pregnant women. J. Viral Hepat. 20, 317-321 (2013).
176. Bai, X. et al. Potential roles of placental human β-defensin-3 and apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3G in prevention of intrauterine transmission of hepatitis B virus. J. Med. Virol. 87, 375-379 (2015).
177. Yeung, L. T., King, S. M. & Roberts, E. A. Mother-to-infant transmission of hepatitis C virus. Hepatology 34, 223-229 (2001).
178. Slowik, M. K. & Jhaveri, R. Hepatitis B and C viruses in infants and young children. Semin. Pediatr. Infect. Dis. 16, 296-305 (2005).
179. Patra, S., Kumar, A., Trivedi, S. S., Puri, M. & Sarin, S. K. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann. Intern. Med. 147, 28-33 (2007).
180. Neuzil, K. M., Reed, G. W., Mitchel, E. F., Simonsen, L. & Griffin, M. R. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am. J. Epidemiol. 148, 1094-1102 (1998).
181. Siston, A. M. et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 303, 1517-1525 (2010).
182. Schuler-Faccini, L. et al. Zika virus: a new human teratogen? Implications for women of reproductive age. Clin. Pharmacol. Ther. 100, 28-30 (2016).