Trophoblast-microbiome interaction: a new paradigm on immune regulation
2015; Elsevier BV; Volume: 213; Issue: 4 Linguagem: Inglês
10.1016/j.ajog.2015.06.039
ISSN1097-6868
Autores Tópico(s)COVID-19 Impact on Reproduction
ResumoThe immunologic paradigm of pregnancy led to the conceptualization of pregnancy as an organ transplant that requires, for its success, suppression of the maternal immune system. Growing scientific evidence suggests that in many ways the placenta functions as a tumor rather than a transplant and the immune regulation of the maternal-fetal interface is the result of the coordinated interaction between all its cellular components, including bacteria. Examining the role of microbiota in reproduction is in its infancy, but there is growing literature that supports its relevance. We discuss a potential normal function of bacteria in the establishment of immune tolerance and compelling evidence that a viral infection might be the underlying cause of perturbation of homeostasis. There is compelling evidence that many infectious diseases of human beings are caused by >1 microorganism and are defined as polymicrobial infections. We propose that pregnancy complications, such as preterm birth, are the result of polymicrobial infections. We examine the potential cellular and molecular mechanisms by which a viral infection of the placenta might disrupt the normal interaction between the cellular component of the implantation site and bacteria. As we better understand the normal homeostasis among the maternal immune system, placenta, and commensal, we will be able to elucidate pathogenic conditions and design better approaches to treat pregnancy complications associated with infection. The immunologic paradigm of pregnancy led to the conceptualization of pregnancy as an organ transplant that requires, for its success, suppression of the maternal immune system. Growing scientific evidence suggests that in many ways the placenta functions as a tumor rather than a transplant and the immune regulation of the maternal-fetal interface is the result of the coordinated interaction between all its cellular components, including bacteria. Examining the role of microbiota in reproduction is in its infancy, but there is growing literature that supports its relevance. We discuss a potential normal function of bacteria in the establishment of immune tolerance and compelling evidence that a viral infection might be the underlying cause of perturbation of homeostasis. There is compelling evidence that many infectious diseases of human beings are caused by >1 microorganism and are defined as polymicrobial infections. We propose that pregnancy complications, such as preterm birth, are the result of polymicrobial infections. We examine the potential cellular and molecular mechanisms by which a viral infection of the placenta might disrupt the normal interaction between the cellular component of the implantation site and bacteria. As we better understand the normal homeostasis among the maternal immune system, placenta, and commensal, we will be able to elucidate pathogenic conditions and design better approaches to treat pregnancy complications associated with infection. The immunologic paradigm of pregnancy was described for the first time by a transplant immunologist, Sir Peter Medawar,1Medawar P. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates.Symp Soc Exp Biol. 1952; 7: 320-338Google Scholar, 2Medawar P.B. Immunity to homologous grafted skin, III: the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye.Br J Exp Pathol. 1948; 29: 58-69PubMed Google Scholar who observed the antigenic mixture of the fetus containing paternal antigens that are not rejected by the maternal immune system. This unique observation led to the conceptualization of pregnancy as a "semiallograft" and it was proposed that pregnancy represents a natural model of transplantation that could help explain the immunologic bases for transplant rejection and acceptance.2Medawar P.B. Immunity to homologous grafted skin, III: the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye.Br J Exp Pathol. 1948; 29: 58-69PubMed Google Scholar Consequently, the study of the immunology of pregnancy followed the immunological models associated with organ transplant. Over the years several mechanisms have been proposed to explain the immune privileged state of the fetus, all of them with the basic understanding that the maternal immune system is antagonistic to the fetus/placental unit.3Mor G. Inflammation and pregnancy: the role of toll-like receptors in trophoblast-immune interaction.Ann N Y Acad Sci. 2008; 1127: 121-128Crossref PubMed Scopus (143) Google Scholar Since the success of an organ transplant is obtained by inducing immune suppression of the host, it was postulated that pregnancy may have a natural mechanism to induce systemic suppression of the maternal immune system. This concept has been studied by numerous investigators and over many years has become the conventional wisdom.4PrabhuDas M. Bonney E. Caron K. et al.Immune mechanisms at the maternal-fetal interface: perspectives and challenges.Nat Immunol. 2015; 16: 328-334Crossref PubMed Scopus (347) Google Scholar Indeed, a wide array of factors in human serum have been found to possess profound in vitro immunosuppressive activities.5Formby B. Immunologic response in pregnancy: its role in endocrine disorders of pregnancy and influence on the course of maternal autoimmune diseases.Endocrinol Metab Clin North Am. 1995; 24: 187-205PubMed Google Scholar However, if we carefully analyze this hypothesis it is difficult to imagine how, from an evolutionary point of view, pregnancy involves a stage of profound immune suppression. Early human beings were not able to wash their hands or clean their food and, with the absence of antiseptics, were continually exposed to bacteria, parasites, and other microorganisms. If pregnant women were systemically immunologically suppressed, they would not have survived and the human species would have become extinct. Even today, in many parts of the world, pregnant women are continually exposed to harsh, unsanitary conditions and a suppressed immune system would make it impossible for the mother and fetus to survive. Furthermore, in countries such as Africa where HIV is pandemic, HIV-positive women do not develop AIDS during pregnancy.6Wira C.R. Veronese F. Mucosal immunity in the male and female reproductive tract and prevention of HIV transmission.Am J Reprod Immunol. 2011; 65: 182-185Crossref PubMed Scopus (9) Google Scholar In fact, there are recent studies clearly demonstrating that the maternal antiviral immunity is not affected by pregnancy.7Romero R. Espinoza J. Goncalves L.F. Kusanovic J.P. Friel L.A. Nien J.K. Inflammation in preterm and term labor and delivery.Semin Fetal Neonatal Med. 2006; 11: 317-326Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar, 8Read J.S. Cahn P. Losso M. et al.Management of human immunodeficiency virus-infected pregnant women at Latin American and Caribbean sites.Obstet Gynecol. 2007; 109: 1358-1367Crossref PubMed Scopus (33) Google Scholar Together, these observations argue against the existence of such nonspecific immune suppression. Medawar's original observation was based on the assumption that the placenta was akin to a "piece of skin" with paternal antigens, which, under normal immunological conditions, should be rejected.1Medawar P. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates.Symp Soc Exp Biol. 1952; 7: 320-338Google Scholar, 2Medawar P.B. Immunity to homologous grafted skin, III: the fate of skin homografts transplanted to the brain, to subcutaneous tissue, and to the anterior chamber of the eye.Br J Exp Pathol. 1948; 29: 58-69PubMed Google Scholar However, the placenta is more than just a transplanted organ. Our knowledge of placental biology has significantly increased over the last 50 years. We now know that the placenta is a complex organ, which has evolved from the original "egg cover." Pregnancy and implantation, contrary to graft implants, has been taking place for >1 million years. Therefore, from an evolutionary point of view it is difficult to conceive that the placenta and the maternal immune system still maintain an antagonistic status. Thus, while there should be an active mechanism preventing the potential recognition of paternal antigens by the maternal immune system, the trophoblast and the maternal immune system have evolved and established a cooperative status, helping each other against common enemies: infectious microorganisms.9Erlebacher A. Mechanisms of T cell tolerance towards the allogeneic fetus.Nat Rev Immunol. 2013; 13: 23-33Crossref PubMed Scopus (201) Google Scholar, 10Mor G. Cardenas I. The immune system in pregnancy: a unique complexity.Am J Reprod Immunol. 2010; 63: 425-433Crossref PubMed Scopus (813) Google Scholar, 11Moffett A. Loke C. Immunology of placentation in eutherian mammals.Nat Rev Immunol. 2006; 6: 584-594Crossref PubMed Scopus (641) Google Scholar Therefore, it is important to evaluate the immunologic aspects associated with pregnancy to further understand the potential biological reasons associated with the risk of pregnancy complications potentially triggered by infection. One wonders why the model of transplantation may not represent the correct immunological situation of pregnancy: during organ transplantation there is a major influx of foreign antigens as a result of the introduction of a fully foreign organ. Under this circumstance the host immune system acutely reacts to the foreign antigens and mounts an immunologic response to reject the source of foreign antigens. During pregnancy the process is different. Pregnancy is a slow and gradual process where paternal/fetal antigens are released in a gradual and increasing manner as the blastocyst grows into an embryo and then into a fetus. The exposure of small amounts of foreign antigens during this process may actually induce tolerance rather than rejection.12Sabatos-Peyton C.A. Verhagen J. Wraith D.C. Antigen-specific immunotherapy of autoimmune and allergic diseases.Curr Opin Immunol. 2010; 22: 609-615Crossref PubMed Scopus (102) Google Scholar Consequently, pregnancy, contrary to transplantation, does not require systemic immune suppression. A second aspect that has been poorly evaluated for many years is the active role of the placenta in the modulation of the maternal immune system. Pregnant women represent an immunologically unique population because their immune system is influenced by signals originating from the placenta.13Kwon J.Y. Romero R. Mor G. New insights into the relationship between viral infection and pregnancy complications.Am J Reprod Immunol. 2014; 71: 387-390Crossref PubMed Scopus (49) Google Scholar, 14Cardenas I. Mor G. Aldo P. et al.Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis.Am J Reprod Immunol. 2011; 65: 110-117Crossref PubMed Scopus (107) Google Scholar The presence of the fetus and placenta alters maternal immunity and physiology to sustain and protect the pregnancy. We and others have shown that the placenta may function as an immune-modulatory organ that regulates the immune responses of cells present both at the implantation site as well as systemically.10Mor G. Cardenas I. The immune system in pregnancy: a unique complexity.Am J Reprod Immunol. 2010; 63: 425-433Crossref PubMed Scopus (813) Google Scholar, 15Naccasha N. Gervasi M.T. Chaiworapongsa T. et al.Phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and maternal infection.Am J Obstet Gynecol. 2001; 185: 1118-1123Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 16Abrahams V.M. Straszewski-Chavez S.L. Guller S. Mor G. First trimester trophoblast cells secrete Fas ligand which induces immune cell apoptosis.Mol Human Reprod. 2004; 10: 55-63Crossref PubMed Scopus (202) Google Scholar, 17Cardenas I. Means R.E. Aldo P. et al.Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor.J Immunol. 2010; 185: 1248-1257Crossref PubMed Scopus (179) Google Scholar However, this modulation is not suppressive, but protective. The placenta together with the decidua are responsible for establishing a unique microenvironment at the implantation site that: (1) prevents a proinflammatory cytokine storm; (2) inhibits the recruitment of T cells with cytolytic function; (3) educates the local immune system to facilitate the fetal development; (4) controls bacterial growth; and (5) protects the fetus from viral infections. In many ways, the placenta functions as a tumor rather than a transplant. Tumors secrete an array of factors that establish a local immunosuppressive microenvironment in which dysfunction and even death of tumor-specific T cells can occur. This immune-regulatory effect occurs at 2 sites: (1) locally at the tumor-host interface where cancer cells condition the tumor stroma, and (2) systemically where cells and/or factors mediate suppression of antitumoral T-cells in the blood and lymphoid organs. The placenta has also 2 regulatory sites that are: (1) locally, at the decidua where immune cells are differentiated toward a pregnancy supporting function, and (2) systemically, affecting the maternal immune system and preventing the expansion of T-cell clones that recognize paternal antigens. Bacterial infections are thought to pose a significant threat to a pregnancy and to the well-being of the fetus, by gaining access to gestational tissues, such as the decidua, the placenta, and the fetal membranes, through 1 of 3 major routes: by ascending into the uterus from the lower tract; by descending into the uterus from the peritoneal cavity; or via the maternal circulation.18Mitchell C.M. Haick A. Nkwopara E. et al.Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women.Am J Obstet Gynecol. 2015; 212: 611.e1-611.e9Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 19Wang 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. 2003; 69: 1957-1963Crossref PubMed Scopus (139) Google Scholar, 20Agrawal V. Smart K. Jilling T. Hirsch E. Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2.PLoS One. 2013; 8: e63990Crossref PubMed Scopus (47) Google Scholar, 21Bayraktar M. Peltier M. Vetrano A. et al.IL-10 modulates placental responses to TLR ligands.Am J Reprod Immunol. 2009; 62: 390-399Crossref PubMed Scopus (23) Google Scholar, 22Kiefer D.G. Keeler S.M. Rust O. et al.Amniotic fluid inflammatory score is associated with pregnancy outcome in patients with mid trimester short cervix.Am J Obstet Gynecol. 2012; 206: 68.e1-68.e6Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 23Espinoza J. Erez O. Romero R. Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery.Am J Obstet Gynecol. 2006; 194: 630-637Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar There are strong clinical links between bacterial infection and preterm birth.23Espinoza J. Erez O. Romero R. Preconceptional antibiotic treatment to prevent preterm birth in women with a previous preterm delivery.Am J Obstet Gynecol. 2006; 194: 630-637Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 24Romero R. Chaiworapongsa T. Espinoza J. Micronutrients and intrauterine infection, preterm birth and the fetal inflammatory response syndrome.J Nutr. 2003; 133: 1668-1673SPubMed Google Scholar, 25Andrews W.W. Copper R. Hauth J.C. Goldenberg R.L. Neely C. Dubard M. Second-trimester cervical ultrasound: associations with increased risk for recurrent early spontaneous delivery.Obstet Gynecol. 2000; 95: 222-226Crossref PubMed Scopus (125) Google Scholar, 26Goldenberg R.L. Hauth J.C. Andrews W.W. Intrauterine infection and preterm delivery.N Engl J Med. 2000; 342: 1500-1507Crossref PubMed Scopus (1984) Google Scholar, 27Lamont R.F. The role of infection in preterm labor and birth.Hosp Med. 2003; 64: 644-647Crossref PubMed Scopus (36) Google Scholar Indeed, infections have been reported as responsible for up to 40% of preterm birth cases.28Kiefer D.G. Keeler S.M. Rust O.A. Wayock C.P. Vintzileos A.M. Hanna N. Is midtrimester short cervix a sign of intraamniotic inflammation?.Am J Obstet Gynecol. 2009; 200: 374.e1-374.e5Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 29Peltier M.R. Klimova N.G. Arita Y. et al.Polybrominated diphenyl ethers enhance the production of proinflammatory cytokines by the placenta.Placenta. 2012; 33: 745-749Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Furthermore, 80% of preterm deliveries occurring at <30 weeks of gestation have evidence of infection.26Goldenberg R.L. Hauth J.C. Andrews W.W. Intrauterine infection and preterm delivery.N Engl J Med. 2000; 342: 1500-1507Crossref PubMed Scopus (1984) Google Scholar, 27Lamont R.F. The role of infection in preterm labor and birth.Hosp Med. 2003; 64: 644-647Crossref PubMed Scopus (36) Google Scholar While many of the pathways involved are still largely undefined, growing literature suggests that the way in which a microorganism can induce a pregnancy complication, such as preterm birth, involves innate immune responses toward the pathogen, leading to excessive inflammation and/or apoptosis at the maternal-fetal interface.30Romero R. Espinoza J. Goncalves L.F. Kusanovic J.P. Friel L. Hassan S. The role of inflammation and infection in preterm birth.Semin Reprod Med. 2007; 25: 21-39Crossref PubMed Scopus (651) Google Scholar, 31Straszewski-Chavez S.L. Abrahams V.M. Aldo P.B. Mor G. Isolation and characterization of a novel telomerase-immortalized human first trimester trophoblast cell line.Placenta. 2005; 26: A62Google Scholar, 32Straszewski-Chavez SL, Abrahams VM, Mor G. The role of apoptosis in the regulation of trophoblast survival and differentiation during pregnancy. Endocr Rev 005;26:877-97.Google Scholar Indeed, experimental in vivo models have demonstrated that delivery of infectious components (bacteria and bacterial products) to a variety of animals triggers preterm delivery.33Gonzalez J.M. Xu H. Ofori E. Elovitz M.A. Toll-like receptors in the uterus, cervix, and placenta: is pregnancy an immunosuppressed state?.Am J Obstet Gynecol. 2007; 197: 296.e1-296.e6Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 34Srinivas S.K. Ma Y. Sammel M.D. et al.Placental inflammation and viral infection are implicated in second trimester pregnancy loss.Am J Obstet Gynecol. 2006; 195: 797-802Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 35Taglauer E.S. Adams Waldorf K.M. Petroff M.G. The hidden maternal-fetal interface: events involving the lymphoid organs in maternal-fetal tolerance.Int J Dev Biol. 2010; 54: 421-430Crossref PubMed Scopus (40) Google Scholar, 36Koga K. Mor G. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders.Am J Reprod Immunol. 2010; 63: 587-600Crossref PubMed Scopus (203) Google Scholar Clinical studies have correlated placental infection/inflammation with prematurity37Romero R. Novel aspects of neutrophil biology in human pregnancy.Am J Reprod Immunol. 2005; 53: 275Google Scholar, 38Romero R. Kadar N. Vaisbuch E. Hassan S.S. Maternal death following cardiopulmonary collapse after delivery: amniotic fluid embolism or septic shock due to intrauterine infection?.Am J Reprod Immunol. 2010; 64: 113-125PubMed Google Scholar, 39Romero A.I. Lagging M. Westin J. et al.Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection.J Infect Dis. 2006; 194: 895-903Crossref PubMed Scopus (198) Google Scholar and this is supported by experimental studies.14Cardenas I. Mor G. Aldo P. et al.Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis.Am J Reprod Immunol. 2011; 65: 110-117Crossref PubMed Scopus (107) Google Scholar, 34Srinivas S.K. Ma Y. Sammel M.D. et al.Placental inflammation and viral infection are implicated in second trimester pregnancy loss.Am J Obstet Gynecol. 2006; 195: 797-802Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar, 40Golos T.G. Bondarenko G.I. Dambaeva S.V. Breburda E.E. Durning M. On the role of placental major histocompatibility complex and decidual leukocytes in implantation and pregnancy success using non-human primate models.Int J Dev Biol. 2010; 54: 431-443Crossref PubMed Scopus (26) Google Scholar, 41Koga K. Cardenas I. Aldo P. et al.Activation of TLR3 in the trophoblast is associated with preterm delivery.Am J Reprod Immunol. 2009; 61: 196-212Crossref PubMed Scopus (138) Google Scholar In spite of the strong literature linking bacterial infection and pregnancy complications, targeting bacterial infections have failed to prevent pregnancy complications.42Goldenberg R.L. Culhane J.F. Iams J.D. Romero R. Epidemiology and causes of preterm birth.Lancet. 2008; 371: 75-84Abstract Full Text Full Text PDF PubMed Scopus (4868) Google Scholar, 43Digiulio D.B. Gervasi M. Romero R. et al.Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods.J Perinat Med. 2010; 38: 503-513PubMed Google Scholar Furthermore, growing evidence suggests bacteria are a normal component of the pregnant and nonpregnant uterus.44Romero R. Espinoza J. Mazor M. Can endometrial infection/inflammation explain implantation failure, spontaneous abortion, and preterm birth after in vitro fertilization?.Fertil Steril. 2004; 82: 799-804Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 45Reid G. Brigidi P. Burton J.P. et al.Microbes central to human reproduction.Am J Reprod Immunol. 2015; 73: 1-11Crossref PubMed Scopus (31) Google Scholar, 46Cao B. Mysorekar I.U. Intracellular bacteria in placental basal plate localize to extravillous trophoblasts.Placenta. 2014; 35: 139-142Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 47Stout M.J. Conlon B. Landeau M. et al.Identification of intracellular bacteria in the basal plate of the human placenta in term and preterm gestations.Am J Obstet Gynecol. 2013; 208: 226.e1-226.e7Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 48Racicot K. Cardenas I. Wunsche V. et al.Viral infection of the pregnant cervix predisposes to ascending bacterial infection.J Immunol. 2013; 191: 934-941Crossref PubMed Scopus (126) Google Scholar These observations suggest that in most cases bacteria alone may not be sufficient to induce an inflammatory event leading to parturition and that the immune response to commensal bacterial product at the maternal-fetal unit is tightly controlled by regulatory mechanisms.17Cardenas I. Means R.E. Aldo P. et al.Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor.J Immunol. 2010; 185: 1248-1257Crossref PubMed Scopus (179) Google Scholar, 48Racicot K. Cardenas I. Wunsche V. et al.Viral infection of the pregnant cervix predisposes to ascending bacterial infection.J Immunol. 2013; 191: 934-941Crossref PubMed Scopus (126) Google Scholar When and why bacteria become detrimental for pregnancy has not been defined. The placenta is in direct contact with maternal component, thus it is imperative that a high level of immune protection is present at the maternal-fetal interface to protect the fetus against any infectious agent that reaches the placenta.49Madsen-Bouterse S.A. Romero R. Tarca A.L. et al.The transcriptome of the fetal inflammatory response syndrome.Am J Reprod Immunol. 2010; 63: 73-92Crossref PubMed Scopus (99) Google Scholar It is well known that classic immune cells, such as macrophages and natural killer cells, are present at the interface to facilitate innate immune responses. In addition to these immune cells, previous studies demonstrated that trophoblasts, the major constituents of the placenta, are also able to sense and respond to pathogen-associated molecular patterns such as lipopolysaccharide (LPS) or peptidoglycan.41Koga K. Cardenas I. Aldo P. et al.Activation of TLR3 in the trophoblast is associated with preterm delivery.Am J Reprod Immunol. 2009; 61: 196-212Crossref PubMed Scopus (138) Google Scholar We have confirmed the expression by the placenta of Toll-like receptors (TLRs), membranous receptors known to recognize microbial products and have demonstrated that via TLR4 trophoblasts elicit an immune response.50Abrahams V.M. Visintin I. Aldo P.B. Guller S. Romero R. Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells.J Immunol. 2005; 175: 8096-8104Crossref PubMed Google Scholar, 51Aldo 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. 2010; 64: 27-37PubMed Google Scholar, 52Abrahams V.M. Bole-Aldo P. Kim Y.M. et al.Divergent trophoblast responses to bacterial products mediated by TLRs.J Immunol. 2004; 173: 4286-4296Crossref PubMed Scopus (237) Google Scholar, 53Abrahams V.M. Schaefer T.M. Fahey J.V. et al.Expression and secretion of antiviral factors by trophoblast cells following stimulation by the TLR-3 agonist, Poly(I : C).Hum Reprod. 2006; 21: 2432-2439Crossref PubMed Scopus (90) Google Scholar Similar to other innate immune cells, ligation of TLR4 in trophoblast with LPS are able to activate both the classic myeloid differentiation factor 88–dependent and –independent signaling pathways leading to the production of cytokines and chemokines.52Abrahams V.M. Bole-Aldo P. Kim Y.M. et al.Divergent trophoblast responses to bacterial products mediated by TLRs.J Immunol. 2004; 173: 4286-4296Crossref PubMed Scopus (237) Google Scholar This finding strongly supports that trophoblast can indeed recognize pathogens and initiate an immune response. The immune interaction between the trophoblast and bacteria will be further discussed in the later part of the review. Human body harbors multiple microorganisms termed "microbiota" and they are known to interact with the host and play various important roles to benefit the host. Bacterial colonization in the placenta from the patients who delivered preterm due to intrauterine inflammation or chorioamnionitis has been well reported in numerous studies.30Romero R. Espinoza J. Goncalves L.F. Kusanovic J.P. Friel L. Hassan S. The role of inflammation and infection in preterm birth.Semin Reprod Med. 2007; 25: 21-39Crossref PubMed Scopus (651) Google Scholar, 54Vaisbuch E. Romero R. Erez O. et al.Activation of the alternative pathway of complement is a feature of pre-term parturition but not of spontaneous labor at term.Am J Reprod Immunol. 2010; 63: 318-330Crossref PubMed Scopus (31) Google Scholar, 55Romero R. Espinoza J. Chaiworapongsa T. Kalache K. Infection and prematurity and the role of preventive strategies.Semin Neonatol. 2002; 7: 259-274Abstract Full Text PDF PubMed Scopus (160) Google Scholar Based on these findings, a general belief among obstetricians was that the placenta should remain a sterile organ to maintain pregnancy through term. Recent study by Aagaard et al56Aagaard K. Ma J. Antony K.M. Ganu R. Petrosino J. Versalovic J. The placenta harbors a unique microbiome.Sci Transl Med. 2014; 6: 237ra65Crossref PubMed Scopus (1642) Google Scholar on placental microbiome provided a turning point for this dogma. By application of culture-independent whole genome shotgun metagenomic technology, they were able to sequence various bacterial species in the placenta obtained following normal term pregnancy, the dominant bacteria identified being Escherichia coli and the genus Escherichia species. Furthermore, Prevotella tannerae, Bacteroides species, Fusobacterium species, Streptomyces avermitilis, Neisseria polysaccharea, Neisseria lactamica, and Fusobacterium species, though low in abundance, were also sequenced. In line with this, presence of bacteria in the placenta has been reported by others substantiating the concept that placenta is inhabited by commensal bacteria.43Digiulio D.B. Gervasi M. Romero R. et al.Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods.J Perinat Med. 2010; 38: 503-513PubMed Google Scholar, 57Lee S.E. Romero R. Lee S.M. Yoon B.H. Amniotic fluid volume in intra-amniotic inflammation with and without culture-proven amniotic fluid infection in preterm premature rupture of membranes.J Perinat Med. 2010; 38: 39-44PubMed Google Scholar, 58Romero R. Hassan S.S. Gajer P. et al.The vaginal microbiota of pregnant women who subsequently have spontaneous preterm labor and delivery and those with a normal delivery at term.Microbiome. 2014; 2: 18Crossref PubMed Scopus (259) Google Scholar Of particular interest is the finding that microbiota composition of placenta shared a great similarity, not with vagina or gut in the proximity, but with that of the oral cavity. Although still controversial, there is growing evidences suggesting that the implantation site might not represent a sterile environment and the commensal bacterial might play a significant role during fetal development. Nonetheless, where and how the commensal bacteria migrate from and colonize in the placenta still remains a mystery. What is the role of microbiota in the context of immune modulation? Among various functions, such as metabolizing nutrients and enforcing mucosal barrier, microbiota have been found to take part i
Referência(s)