Devaraju, M. et al. Beyond TORCH: a narrative review of the impact of antenatal and perinatal infections on the risk of disability. Neurosci. Biobehav. Rev. 153, 105390 (2023).
Ander, S. E., Diamond, M. S. & Coyne, C. B. Immune responses at the maternal–fetal interface. Sci. Immunol. 4, eaat6114 (2019).
Espino, A., El Costa, H., Tabiasco, J., Al-Daccak, R. & Jabrane-Ferrat, N. Innate immune response to viral infections at the maternal–fetal interface in human pregnancy. Front. Med. 8, 674645 (2021).
Hoo, R., Nakimuli, A. & Vento-Tormo, R. Innate immune mechanisms to protect against infection at the human decidual–placental interface. Front. Immunol. 11, 2070 (2020).
Semmes, E. C. & Coyne, C. B. Innate immune defenses at the maternal–fetal interface. Curr. Opin. Immunol. 74, 60–67 (2022).
Arutyunyan, A. et al. Spatial multiomics map of trophoblast development in early pregnancy. Nature 616, 143–151 (2023).
Greenbaum, S. et al. A spatially resolved timeline of the human maternal–fetal interface. Nature 619, 595–605 (2023).
Moore, A. R. et al. Gestationally dependent immune organization at the maternal–fetal interface. Cell Rep. 41, 111651 (2022). This paper describes the immuno-phenotyping of circulating, endovascular and tissue-resident cells at the maternal–fetal interface throughout gestation, and distinguishes maternal and fetal contributions.
Gauster, M., Moser, G., Wernitznig, S., Kupper, N. & Huppertz, B. Early human trophoblast development: from morphology to function. Cell Mol. Life Sci. 79, 345 (2022).
Arranz-Solis, D., Mukhopadhyay, D. & Saeij, J. J. P. Toxoplasma effectors that affect pregnancy outcome. Trends Parasitol. 37, 283–295 (2021).
Schatten, H. & Constantinescu, G. M. Comparative Reproductive Biology 1st edn (Blackwell, 2007).
Wooding, F. B. P. & Burton, G. Comparative Placentation: Structures, Functions and Evolution (Springer, 2008).
Kingdom, J., Huppertz, B., Seaward, G. & Kaufmann, P. Development of the placental villous tree and its consequences for fetal growth. Eur. J. Obstet. Gynecol. Reprod. Biol. 92, 35–43 (2000).
Reyes, L. & Golos, T. G. Hofbauer cells: their role in healthy and complicated pregnancy. Front. Immunol. 9, 2628 (2018).
Loegl, J. et al. Hofbauer cells of M2a, M2b and M2c polarization may regulate feto-placental angiogenesis. Reproduction 152, 447–455 (2016).
Thomas, J. R., Naidu, P., Appios, A. & McGovern, N. The ontogeny and function of placental macrophages. Front. Immunol. 12, 771054 (2021).
Guttman, J. A. & Finlay, B. B. Tight junctions as targets of infectious agents. Biochim. Biophys. Acta 1788, 832–841 (2009).
Ander, S. E. et al. Human placental syncytiotrophoblasts restrict Toxoplasma gondii attachment and replication and respond to infection by producing immunomodulatory chemokines. mBio 9, e01678-17 (2018).
Robbins, J. R., Zeldovich, V. B., Poukchanski, A., Boothroyd, J. C. & Bakardjiev, A. I. Tissue barriers of the human placenta to infection with Toxoplasma gondii. Infect. Immun. 80, 418–428 (2012).
Robbins, J. R., Skrzypczynska, K. M., Zeldovich, V. B., Kapidzic, M. & Bakardjiev, A. I. Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes. PLoS Pathog. 6, e1000732 (2010).
Zeldovich, V. B. et al. Placental syncytium forms a biophysical barrier against pathogen invasion. PLoS Pathog. 9, e1003821 (2013).
Bayer, A. et al. Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection. Cell Host Microbe 19, 705–712 (2016).
Corry, J., Arora, N., Good, C. A., Sadovsky, Y. & Coyne, C. B. Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal–fetal interface. Proc. Natl Acad. Sci. USA 114, 9433–9438 (2017).
Wickramage, I. et al. SINE RNA of the imprinted miRNA clusters mediates constitutive type III interferon expression and antiviral protection in hemochorial placentas. Cell Host Microbe 31, 1185–1199.e10 (2023). This paper reveals that dsRNA produced by imprinted placental microRNA clusters in primates and rodents triggers constitutive type III interferon production, conferring innate antiviral protection in these haemochorial placentas.
Yang, L. et al. Innate immune signaling in trophoblast and decidua organoids defines differential antiviral defenses at the maternal–fetal interface. eLife 11, e79794 (2022). This study defines the innate immunological properties of trophoblast and decidua organoids derived from term placental tissue, revealing distinct responses to viral infection and differential susceptibility to CMV.
Burton, G. J., Watson, A. L., Hempstock, J., Skepper, J. N. & Jauniaux, E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J. Clin. Endocrinol. Metab. 87, 2954–2959 (2002).
Pollheimer, J., Vondra, S., Baltayeva, J., Beristain, A. G. & Knofler, M. Regulation of placental extravillous trophoblasts by the maternal uterine environment. Front. Immunol. 9, 2597 (2018).
Apps, R., Gardner, L., Sharkey, A. M., Holmes, N. & Moffett, A. A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur. J. Immunol. 37, 1924–1937 (2007).
Chen, L. J., Han, Z. Q., Zhou, H., Zou, L. & Zou, P. Inhibition of HLA-G expression via RNAi abolishes resistance of extravillous trophoblast cell line TEV-1 to NK lysis. Placenta 31, 519–527 (2010).
Chumbley, G., King, A., Robertson, K., Holmes, N. & Loke, Y. W. Resistance of HLA-G and HLA-A2 transfectants to lysis by decidual NK cells. Cell Immunol. 155, 312–322 (1994).
Yang, Y. et al. Advances in the study of HLA class Ib in maternal–fetal immune tolerance. Front. Immunol. 13, 976289 (2022).
Mori, M., Bogdan, A., Balassa, T., Csabai, T. & Szekeres-Bartho, J. The decidua—the maternal bed embracing the embryo-maintains the pregnancy. Semin. Immunopathol. 38, 635–649 (2016).
Vento-Tormo, R. et al. Single-cell reconstruction of the early maternal–fetal interface in humans. Nature 563, 347–353 (2018). This publication profiles the first-trimester human maternal–fetal interface using single-cell RNA sequencing, revealing complex interactions between maternal and fetal cell populations, including identifying the distinct immunological properties of dNK cell subsets.
Carlino, C. et al. Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy. Blood 111, 3108–3115 (2008).
Huang, Y., Zhu, X. Y., Du, M. R. & Li, D. J. Human trophoblasts recruited T lymphocytes and monocytes into decidua by secretion of chemokine CXCL16 and interaction with CXCR6 in the first-trimester pregnancy. J. Immunol. 180, 2367–2375 (2008).
Manaster, I. & Mandelboim, O. The unique properties of uterine NK cells. Am. J. Reprod. Immunol. 63, 434–444 (2010).
Thomas, J. R. et al. Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells. J. Exp. Med. 218, e20200891 (2020). This study provides a detailed characterization of first-trimester HBCs, demonstrating their transcriptional similarity to yolk sac macrophages, capacity to secrete factors involved in placental angiogenesis and remodelling, and microbicidal defence mechanisms.
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).
Aluvihare, V. R., Kallikourdis, M. & Betz, A. G. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5, 266–271 (2004).
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).
Sket, T., Ramuta, T. Z., Starcic Erjavec, M. & Kreft, M. E. The role of innate immune system in the human amniotic membrane and human amniotic fluid in protection against intra-amniotic infections and inflammation. Front. Immunol. 12, 735324 (2021).
Marsh, B., Zhou, Y., Kapidzic, M., Fisher, S. & Blelloch, R. Regionally distinct trophoblast regulate barrier function and invasion in the human placenta. eLife 11, e78829 (2022).
Carter, A. M. & Pijnenborg, R. Evolution of invasive placentation with special reference to non-human primates. Best. Pract. Res. Clin. Obstet. Gynaecol. 25, 249–257 (2011).
Yong, H. E. J. et al. Significance of the placental barrier in antenatal viral infections. Biochim. Biophys. Acta – Mol. Basis Dis. 1867, 166244 (2021).
Kumar, M., Saadaoui, M. & Al Khodor, S. Infections and pregnancy: effects on maternal and child health. Front. Cell. Infect. Microbiol. 12, 873253 (2022).
Yates, E. F. & Mulkey, S. B. Viral infections in pregnancy and impact on offspring neurodevelopment: mechanisms and lessons learned. Pediatr. Res. 96, 64–72 (2024).
Enders, G., Daiminger, A., Bader, U., Exler, S. & Enders, M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. J. Clin. Virol. 52, 244–246 (2011).
Noronha, L. D. et al. Zika virus infection at different pregnancy stages: anatomopathological findings, target cells and viral persistence in placental tissues. Front. Microbiol. 9, 2266 (2018).
Creisher Patrick, S. & Klein Sabra, L. Pathogenesis of viral infections during pregnancy. Clin. Microbiol. Rev. 37, e0007323 (2024).
Megli, C. J. & Coyne, C. B. Infections at the maternal–fetal interface: an overview of pathogenesis and defence. Nat. Rev. Microbiol. 20, 67–82 (2022).
Cruz-Holguín, V. J. et al. Collateral damage in the placenta during viral infection in pregnancy: a possible mechanism for vertical transmission and an adverse pregnancy outcome. Diseases 12, 59 (2024).
Neu, N., Duchon, J. & Zachariah, P. TORCH infections. Clin. Perinatol. 42, 77–103 (2015).
Pereira, L., Maidji, E., McDonagh, S., Genbacev, O. & Fisher, S. Human cytomegalovirus transmission from the uterus to the placenta correlates with the presence of pathogenic bacteria and maternal immunity. J. Virol. 77, 13301–13314 (2003).
Aronoff, D. M., Correa, H., Rogers, L. M., Arav-Boger, R. & Alcendor, D. J. Placental pericytes and cytomegalovirus infectivity: implications for HCMV placental pathology and congenital disease. Am. J. Reprod. Immunol. 78, e12728 (2017).
Njue, A. et al. The role of congenital cytomegalovirus infection in adverse birth outcomes: a review of the potential mechanisms. Viruses 13, 20 (2021).
Uenaka, M. et al. Histopathological analysis of placentas with congenital cytomegalovirus infection. Placenta 75, 62–67 (2019).
Miner, J. J. & Diamond, M. S. Zika virus pathogenesis and tissue tropism. Cell Host Microbe 21, 134–142 (2017).
Sheridan, M. A. et al. Vulnerability of primitive human placental trophoblast to Zika virus. Proc. Natl Acad. Sci. USA 114, E1587–E1596 (2017).
Tabata, T. et al. Zika virus replicates in proliferating cells in explants from first-trimester human placentas, potential sites for dissemination of infection. J. Infect. Dis. 217, 1202–1213 (2017).
Weisblum, Y. et al. Zika virus infects early- and midgestation human maternal decidual tissues, inducing distinct innate tissue responses in the maternal–fetal interface. J. Virol. 91, 01905-16 (2017).
Venceslau, E. M., Guida, J. P., Amaral, E., Modena, J. L. P. & Costa, M. L. Characterization of placental infection by Zika virus in humans: a review of the literature. Rev. Bras. Ginecol. Obstet. 42, 577–585 (2020).
Yockey, L. J. et al. Vaginal exposure to Zika virus during pregnancy leads to fetal brain infection. Cell 166, 1247–1256.e4 (2016).
Sankaran, D., Partridge, E. & Lakshminrusimha, S. Congenital syphilis—an illustrative review. Children 10, 1310 (2023).
Vazquez-Boland, J. A., Krypotou, E. & Scortti, M. Listeria placental infection. mBio 8, e13186 (2017).
Parkash, V. et al. Immunohistochemical detection of Listeria antigens in the placenta in perinatal listeriosis. Int. J. Gynecol. Pathol. 17, 343–350 (1998).
Sheffield, J. S. et al. Placental histopathology of congenital syphilis. Obstet. Gynecol. 100, 126–133 (2002).
Eallonardo, S. J. & Freitag, N. E. Crossing the barrier: a comparative study of Listeria monocytogenes and Treponema pallidum in placental invasion. Cells 13, 88 (2023).
Bakardjiev, A. I., Stacy, B. A. & Portnoy, D. A. Growth of Listeria monocytogenes in the guinea pig placenta and role of cell-to-cell spread in fetal infection. J. Infect. Dis. 191, 1889–1897 (2005).
Critchfield, A. S. et al. Cervical mucus properties stratify risk for preterm birth. PLoS One 8, e69528 (2013).
Smith-Dupont, K. B. et al. Probing the potential of mucus permeability to signify preterm birth risk. Sci. Rep. 7, 10302 (2017).
Hoang, T. et al. The cervicovaginal mucus barrier to HIV-1 is diminished in bacterial vaginosis. PLoS Pathog. 16, e1008236 (2020).
Brokaw, A., Furuta, A., Dacanay, M., Rajagopal, L. & Adams Waldorf, K. M. Bacterial and host determinants of group B streptococcal vaginal colonization and ascending infection in pregnancy. Front. Cell Infect. Microbiol. 11, 720789 (2021).
Ruma, M. et al. Maternal periodontal disease, systemic inflammation, and risk for preeclampsia. Am. J. Obstet. Gynecol. 198, 389.e1–e5 (2008).
Bollani, L. et al. Congenital toxoplasmosis: the state of the art. Front. Pediatr. 10, 894573 (2022).
Kemmerling, U., Osuna, A., Schijman, A. G. & Truyens, C. Congenital transmission of Trypanosoma cruzi: a review about the interactions between the parasite, the placenta, the maternal and the fetal/neonatal immune responses. Front. Microbiol. 10, 1854 (2019).
Torrico, F. et al. Maternal Trypanosoma cruzi infection, pregnancy outcome, morbidity, and mortality of congenitally infected and non-infected newborns in Bolivia. Am. J. Trop. Med. Hyg. 70, 201–209 (2004).
Altemani, A. M., Bittencourt, A. L. & Lana, A. M. Immunohistochemical characterization of the inflammatory infiltrate in placental Chagas’ disease: a qualitative and quantitative analysis. Am. J. Trop. Med. Hyg. 62, 319–324 (2000).
Hasby Saad, M., El-Anwar, N., Lotfy, S., Fouda, M. & Hasby, E. Human placental PPAR-γ and SOX-2 expression in serologically proved toxoplasmosis. Parasite Immunol. 40, e12529 (2018).
Mjihdi, A. et al. Acute Trypanosoma cruzi infection in mouse induces infertility or placental parasite invasion and ischemic necrosis associated with massive fetal loss. Am. J. Pathol. 161, 673–680 (2002).
Duaso, J. et al. Trypanosoma cruzi induces tissue disorganization and destruction of chorionic villi in an ex vivo infection model of human placenta. Placenta 31, 705–711 (2010).
Duaso, J. et al. Trypanosoma cruzi induces apoptosis in ex vivo infected human chorionic villi. Placenta 32, 356–361 (2011).
Bauserman, M. et al. An overview of malaria in pregnancy. Semin. Perinatol. 43, 282–290 (2019).
Koga, K. & Mor, G. Review article: Toll-like receptors at the maternal–fetal interface in normal pregnancy and pregnancy disorders. Am. J. Reprod. Immunol. 63, 587–600 (2010).
Motomura, K., Hara, M., Ito, I., Morita, H. & Matsumoto, K. Roles of human trophoblasts’ pattern recognition receptors in host defense and pregnancy complications. J. Reprod. Immunol. 156, 103811 (2023).
Mysorekar, I. U. & Diamond, M. S. Modeling Zika virus infection in pregnancy. N. Engl. J. Med. 375, 481–484 (2016).
Kliman, H. J., Nestler, J. E., Sermasi, E., Sanger, J. M. & Strauss, J. F. 3rd Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology 118, 1567–1582 (1986).
Okae, H. et al. Derivation of human trophoblast stem cells. Cell Stem Cell 22, 50–63.e6 (2018). This paper describes the derivation of human TSCs from early placental CTBs and blastocysts, yielding a self-renewing model that can be stimulated to differentiate into the three major trophoblast lineages.
Sheridan, M. A. et al. Characterization of primary models of human trophoblast. Development 148, dev199749 (2021).
Hori, T. et al. Trophoblast stem cell-based organoid models of the human placental barrier. Nat. Commun. 15, 962 (2024).
Turco, M. Y. et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat. Cell Biol. 19, 568–577 (2017).
Turco, M. Y. et al. Trophoblast organoids as a model for maternal–fetal interactions during human placentation. Nature 564, 263–267 (2018). This study demonstrates that trophoblast organoids isolated from first-trimester placental tissue recapitulate the transcriptomic and methylation profiles of early-gestation trophoblasts and spontaneously differentiate into CTBs, EVTs and STBs.
Rollman, T. B. et al. Human trophoblast stem cells restrict human cytomegalovirus replication. J. Virol. 98, e0193523 (2024).
Wu, H. et al. Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids. Nat. Commun. 14, 5541 (2023).
da Silva, R. J. et al. The trophoblast surface becomes refractory to adhesion by congenitally transmitted Toxoplasma gondii and Listeria monocytogenes during cytotrophoblast to syncytiotrophoblast development. mSphere 9, e00748-23 (2024).
Karvas, R. M. et al. Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens. Cell Stem Cell 29, 810–825.e8 (2022).
Morrison, T. E. & Diamond, M. S. Animal models of Zika virus infection, pathogenesis, and immunity. J. Virol. 91, e00009-17 (2017).
Narasimhan, H., Chudnovets, A., Burd, I., Pekosz, A. & Klein, S. L. Animal models of congenital Zika syndrome provide mechanistic insight into viral pathogenesis during pregnancy. PLoS Negl. Trop. Dis. 14, e0008707 (2020).
Koenig, M. R. et al. Vertical transmission of African-lineage Zika virus through the fetal membranes in a rhesus macaque (Macaca mulatta) model. PLoS Pathog. 19, e1011274 (2023).
Itell, H. L., Kaur, A., Deere, J. D., Barry, P. A. & Permar, S. R. Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections. Curr. Opin. Virol. 25, 126–133 (2017).
Moström, M. J. et al. Protective effect of pre-existing natural immunity in a nonhuman primate reinfection model of congenital cytomegalovirus infection. PLoS Pathog. 19, e1011646 (2023).
Bialas, K. M. et al. Maternal CD4+ T cells protect against severe congenital cytomegalovirus disease in a novel nonhuman primate model of placental cytomegalovirus transmission. Proc. Natl Acad. Sci. USA 112, 13645–13650 (2015).
Schleiss, M. R. & McVoy, M. A. Guinea pig cytomegalovirus: a model for the prevention and treatment of maternal–fetal cytomegalovirus transmission. Future Virol. 5, 207–217 (2010).
Griffith, B. P. et al. The placenta as a site of cytomegalovirus infection in guinea pigs. J. Virol. 55, 402–409 (1985).
Mess, A. The guinea pig placenta: model of placental growth dynamics. Placenta 28, 812–815 (2007).
Berkebile, Z. W. et al. The placental response to guinea pig cytomegalovirus depends upon the timing of maternal infection. Front. Immunol. 12, 686415 (2021).
Rollman, T. B. et al. CD4+ but not CD8+ T cells are required for protection against severe guinea pig cytomegalovirus infections. PLOS Pathog. 20, e1012515 (2024).
Koga, K. et al. Original article: activation of TLR3 in the trophoblast is associated with preterm delivery. Am. J. Reprod. Immunol. 61, 196–212 (2009). This study shows that activation of TLR3 in trophoblasts is associated with an increased risk of preterm delivery in mice, potentially through induction of inflammatory responses at the maternal–fetal interface.
Robertson, S. A. et al. Targeting Toll-like receptor-4 to tackle preterm birth and fetal inflammatory injury. Clin. Transl. Immunol. 9, e1121 (2020).
Arce, R. M., Caron, K. M., Barros, S. P. & Offenbacher, S. Toll-like receptor 4 mediates intrauterine growth restriction after systemic Campylobacter rectus infection in mice. Mol. Oral. Microbiol. 27, 373–381 (2012).
Liu, H., Redline, R. W. & Han, Y. W. Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response1. J. Immunol. 179, 2501–2508 (2007).
Barboza, R. et al. TLR4-mediated placental pathology and pregnancy outcome in experimental malaria. Sci. Rep. 7, 8623 (2017).
Rodrigues-Duarte, L., Pandya, Y., Neres, R. & Penha-Gonçalves, C. Fetal and maternal innate immunity receptors have opposing effects on the severity of experimental malaria in pregnancy: beneficial roles for fetus-derived Toll-like receptor 4 and type I interferon receptor 1. Infect. Immun. 86, e00708-17 (2018).
Ikeda, R., Ushio, N., Abdou, A. M., Furuoka, H. & Nishikawa, Y. Toll-like receptor 2 is involved in abnormal pregnancy in mice infected with Toxoplasma gondii during late pregnancy. Front. Microbiol. 12, 741104 (2021).
Gorman, M. J. et al. An immunocompetent mouse model of Zika virus infection. Cell Host Microbe 23, 672–685.e6 (2018).
Grant, A. et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882–890 (2016).
Szaba, F. M. et al. Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection. PLoS Pathog. 14, e1006994 (2018).
Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature 534, 267–271 (2016).
Lazear, H. M. et al. A mouse model of Zika virus pathogenesis. Cell Host Microbe 19, 720–730 (2016).
Miner, J. J. et al. Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell 165, 1081–1091 (2016).
Alippe, Y. et al. Fetal MAVS and type I IFN signaling pathways control ZIKV infection in the placenta and maternal decidua. J. Exp. Med. 221, e20240694 (2024).
Casazza, R. L., Philip, D. T. & Lazear, H. M. Interferon λ signals in maternal tissues to exert protective and pathogenic effects in a gestational stage-dependent manner. mBio 13, e0385721 (2022). This paper demonstrates that in mice, IFNλ signalling in maternal tissues can exert both protective and pathogenic effects on congenital ZIKV infection depending on the gestational stage.
Jagger, B. W. et al. Gestational stage and IFN-λ signaling regulate ZIKV infection in utero. Cell Host Microbe 22, 366–376.e3 (2017).
Motomura, K. et al. Fetal and maternal NLRP3 signaling is required for preterm labor and birth. JCI Insight 7, e158238 (2022).
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).
Medzhitov, R. The spectrum of inflammatory responses. Science 374, 1070–1075 (2021).
Thaxton, J. E., Romero, R. & Sharma, S. TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes1. J. Immunol. 183, 1144–1154 (2009).
Riley, J. K., Heeley, J. M., Wyman, A. H., Schlichting, E. L. & Moley, K. H. TRAIL and KILLER are expressed and induce apoptosis in the murine preimplantation embryo1. Biol. Reprod. 71, 871–877 (2004).
Yockey, L. J. et al. Type I interferons instigate fetal demise after Zika virus infection. Sci. Immunol. 3, eaao1680 (2018).
Aldo, P. B., Mulla, M. J., Romero, R., Mor, G. & Abrahams, V. M. Viral ssRNA induces first trimester trophoblast apoptosis through an inflammatory mechanism. Am. J. Reprod. Immunol. 64, 27–37 (2010).
Choi, G. B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016).
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).
Chaturvedi, V. et al. CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage. J. Clin. Invest. 125, 1713–1725 (2015). This publication shows that CXCR3 blockade can protect against fetal wastage and prevent the accumulation of maternal T cells with fetal specificity in the decidua following L. monocytogenes infection.
Ma, J. et al. Zika virus non-structural protein 4 A blocks the RLR–MAVS signaling. Front. Microbiol. 9, 1350 (2018).
Zhao, Z. et al. Zika virus causes placental pyroptosis and associated adverse fetal outcomes by activating GSDME. eLife 11, e73792 (2022).
You, Y. et al. Twist1–IRF9 interaction is necessary for IFN-stimulated gene anti-Zika viral infection. J. Immunol. 210, 1899–1912 (2023).
Coldbeck-Shackley, R. C. et al. Constitutive expression and distinct properties of IFN-ε protect the female reproductive tract from Zika virus infection. PLOS Pathog. 19, e1010843 (2023).
Abrahams, V. M. et al. Expression and secretion of antiviral factors by trophoblast cells following stimulation by the TLR-3 agonist, poly(I:C). Hum. Reprod. 21, 2432–2439 (2006).
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).
Gargano, L. M., Moser, J. M. & Speck, S. H. Role for MyD88 signaling in murine gammaherpesvirus 68 latency. J. Virol. 82, 3853–3863 (2008).
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).
Barboza, R. et al. MyD88 signaling is directly involved in the development of murine placental malaria. Infect. Immun. 82, 830–838 (2014).
Senegas, A. et al. Toxoplasma gondii-induced foetal resorption in mice involves interferon-γ-induced apoptosis and spiral artery dilation at the maternofoetal interface. Int. J. Parasitol. 39, 481–487 (2009).
Duriez, M. et al. Human decidual macrophages and NK cells differentially express Toll-like receptors and display distinct cytokine profiles upon TLR stimulation. Front. Microbiol. https://doi.org/10.3389/fmicb.2014.00316 (2014).
Anders, A. P., Gaddy, J. A., Doster, R. S. & Aronoff, D. M. Current concepts in maternal–fetal immunology: recognition and response to microbial pathogens by decidual stromal cells. Am. J. Reprod. Immunol. 77, e12623 (2017).
Matias, M. L. et al. Endogenous and uric acid-induced activation of NLRP3 inflammasome in pregnant women with preeclampsia. PLoS One 10, e0129095 (2015).
Gomez-Lopez, N. et al. A role for the inflammasome in spontaneous labor at term with acute histologic chorioamnionitis. Reprod. Sci. 24, 934–953 (2017).
Megli, C., Morosky, S., Rajasundaram, D. & Coyne, C. B. Inflammasome signaling in human placental trophoblasts regulates immune defense against Listeria monocytogenes infection. J. Exp. Med. 218, e20200649 (2020).
Murphy, S. P., Fast, L. D., Hanna, N. N. & Sharma, S. Uterine NK cells mediate inflammation-induced fetal demise in IL-10-null mice. J. Immunol. 175, 4084–4090 (2005).
Cheng, S. B. & Sharma, S. Interleukin-10: a pleiotropic regulator in pregnancy. Am. J. Reprod. Immunol. 73, 487–500 (2015).
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).
Robertson, S. A., Skinner, R. J. & Care, A. S. Essential role for IL-10 in resistance to lipopolysaccharide-induced preterm labor in mice. J. Immunol. 177, 4888–4896 (2006).
Robertson, S. A., Care, A. S. & Skinner, R. J. Interleukin 10 regulates inflammatory cytokine synthesis to protect against lipopolysaccharide-induced abortion and fetal growth restriction in mice. Biol. Reprod. 76, 738–748 (2007).
Crespo, Â. C. et al. Decidual NK cells transfer granulysin to selectively kill bacteria in trophoblasts. Cell 182, 1125–1139.e18 (2020). This study demonstrates that dNK cells in the placenta transfer granulysin to trophoblasts, selectively killing bacteria without harming the trophoblast cells themselves.
Buchrieser, J. et al. IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise. Science 365, 176–180 (2019).
Zani, A. et al. Interferon-induced transmembrane proteins inhibit cell fusion mediated by trophoblast syncytins. J. Biol. Chem. 294, 19844–19851 (2019).
Vota, D. et al. Zika virus infection of first trimester trophoblast cells affects cell migration, metabolism and immune homeostasis control. J. Cell. Physiol. 236, 4913–4925 (2021).
Yockey, L. J. & Iwasaki, A. Interferons and proinflammatory cytokines in pregnancy and fetal development. Immunity 49, 397–412 (2018).
Moldenhauer, L. M., Hull, M. L., Foyle, K. L., McCormack, C. D. & Robertson, S. A. Immune–metabolic interactions and T cell tolerance in pregnancy. J. Immunol. 209, 1426–1436 (2022).
Marshall, E. E. & Geballe, A. P. Multifaceted evasion of the interferon response by cytomegalovirus. J. Interferon Cytokine Res. 29, 609–619 (2009).
Fatemi, S. H. et al. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol. Neurobiol. 22, 25–33 (2002).
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).
Ashary, N. et al. Single-cell RNA-seq identifies cell subsets in human placenta that highly expresses factors driving pathogenesis of SARS-CoV-2. Front. Cell Dev. Biol. 8, 783 (2020).
Barrozo, E. R. et al. SARS-CoV-2 niches in human placenta revealed by spatial transcriptomics. Med 4, 612–634.e4 (2023).
Wang, Y. et al. Cell-type specific distribution and activation of type I IFN pathway molecules at the placental maternal–fetal interface in response to COVID-19 infection. Front. Endocrinol. 13, 951388 (2023).
Schwartz, D. A., Dashraath, P. & Baud, D. Oropouche virus (OROV) in pregnancy: an emerging cause of placental and fetal infection associated with stillbirth and microcephaly following vertical transmission. Viruses 16, 1435 (2024).
Castro, M. C. & Lima Neto, A. S. Unprecedented spread and genetic evolution of the Oropouche virus. Nat. Med. https://doi.org/10.1038/s41591-024-03336-5 (2024).
Gaytant, M. A., Steegers, E. A., Semmekrot, B. A., Merkus, H. M. & Galama, J. M. Congenital cytomegalovirus infection: review of the epidemiology and outcome. Obstet. Gynecol. Surv. 57, 245–256 (2002).
Mahant, S. et al. Neonatal herpes simplex virus infection among medicaid-enrolled children: 2009–2015. Pediatrics 143, e20183233 (2019).
Shi, T. L. et al. The risk of herpes simplex virus and human cytomegalovirus infection during pregnancy upon adverse pregnancy outcomes: a meta-analysis. J. Clin. Virol. 104, 48–55 (2018).
Felker, A. M., Nguyen, P. & Kaushic, C. Primary HSV-2 infection in early pregnancy results in transplacental viral transmission and dose-dependent adverse pregnancy outcomes in a novel mouse model. Viruses 13, 1929 (2021).
Lamont, R. F. et al. Varicella-zoster virus (chickenpox) infection in pregnancy. BJOG 118, 1155–1162 (2011).
Robertson, N. J. & McKeever, P. A. Fetal and placental pathology in two cases of maternal varicella infection. Pediatr. Pathol. 12, 545–550 (1992).
Winter, A. K. & Moss, W. J. Rubella. Lancet 399, 1336–1346 (2022).
Lazar, M. et al. Immunolocalization and distribution of rubella antigen in fatal congenital rubella syndrome. EBioMedicine 3, 86–92 (2016).
Mulkey, S. B. et al. Neurodevelopmental abnormalities in children with in utero zika virus exposure without congenital zika syndrome. JAMA Pediatr. 174, 269–276 (2020).
Brasil, P. et al. Zika virus infection in pregnant women in Rio de Janeiro. N. Engl. J. Med. 375, 2321–2334 (2016).
Wedi, C. O. et al. Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis. Lancet HIV 3, e33–e48 (2016).
Amin, O., Powers, J., Bricker, K. M. & Chahroudi, A. Understanding viral and immune interplay during vertical transmission of HIV: implications for cure. Front. Immunol. 12, 757400 (2021).
Bruce-Brand, C., Wright, C. A. & Schubert, P. T. HIV, placental pathology, and birth outcomes—a brief overview. J. Infect. Dis. 224, S683–S690 (2021).
Di Martino, V. et al. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology 40, 1426–1433 (2004).
Vousden, N., Bunch, K. & Knight, M. Incidence, risk factors and impact of seasonal influenza in pregnancy: a national cohort study. PLoS One 16, e0244986 (2021).
He, J. et al. A systematic review and meta-analysis of influenza A virus infection during pregnancy associated with an increased risk for stillbirth and low birth weight. Kidney Blood Press. Res. 42, 232–243 (2017).
Badr, D. A. et al. Severe acute respiratory syndrome coronavirus 2 and pregnancy outcomes according to gestational age at time of infection. Emerg. Infect. Dis. 27, 2535–2543 (2021).
Wei, S. Q., Bilodeau-Bertrand, M., Liu, S. & Auger, N. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. CMAJ 193, E540–E548 (2021).
Stenton, S. et al. SARS-COV2 placentitis and pregnancy outcome: a multicentre experience during the Alpha and early Delta waves of coronavirus pandemic in England. EClinicalMedicine 47, 101389 (2022).