Abstract
Trypanosoma cruzi, during vertical transmission, crosses the placental barrier. The trophoblast, a continuous renewing epithelium, is the first tissue of this anatomical barrier to have contact with the parasite. The epithelial turnover, including the trophoblast, is part of the innate immune response due to the fact that pathogens attach to the surface of cells prior invasion. Cellular processes such as proliferation, differentiation, and apoptotic cell death are part of the trophoblast turnover. Interestingly, T. cruzi induces all of them. In addition, the placenta expresses TLRs, whose activation leads to the secretion of pro-inflammatory and immunomodulating cytokines. T. cruzi is recognized by TLR-2, TLR-4, TLR-7, and TLR-9. In the present review, we analyze the current evidence about the trophoblast epithelial turnover, the induction of a specific cytokine profile as a local placental innate immune response, as well as other possible defense mechanisms against the parasite.
Keywords
- Trypanosoma cruzi
- placenta
- epithelial turnover
- TLRs
- cytokine profile
1. Introduction
Congenital Chagas disease, caused by
Mother and developing fetus are protected against environmental challenges by the immune system; the placenta is able to modulate fetal as well as maternal immune responses. Maternal immune system presents an enhanced capacity of cellular and molecular recognition and communication between each other. Therefore, during normal pregnancy, the maternal immune defenses assure the health of the mother and developing child. Moreover, the fetus during its development also acquires immune defenses that are able to modulate the maternal immune system. Considering this facts, the immune system responses are unique and particularly effective [6].
The maternal and the fetal developing innate and adaptative immune systems determine the probability of fetal/neonatal infection. Fetal infection is related to diverse pregnancy disorders such as abortion, preterm labor, intrauterine growth retardation, and preeclampsia [7]. Particularly, congenital
The innate immune system presents a main role in protecting the developing child against
Importantly, congenital transmission rates for
2. Antiparasitic mechanisms of the placenta
Importantly, during congenital transmission, the parasites must cross the placental barrier [8, 16].
2.1. Placenta
The placenta is a temporary organ that provides nutrition and gas exchange for the developing fetus, ensuring normal embryo-fetal growth and development and supporting pregnancy-related changes in maternal physiological systems [17]. The human placenta is classified as discoidal, villous, and hemochorial and consists of a fetal portion, which originates from the
The placenta may contain as much as 500 mL of maternal blood, in the IVS, exposing the trophoblast to pathogens that might be present in it [5]. Therefore, the trophoblast is a key factor against congenital infection since it is the first fetal tissue that comes into contact with pathogens circulating in the maternal blood [11]. On the other hand, the placenta, as an immune regulatory organ, acts as a modulator of fetal as well as maternal immune responses [6]. The placenta, in particular the trophoblast, is also part of a local innate immune response. Three types of defense mechanisms in innate immunity have been described: (i) anatomical barriers, such as the placental barrier (Figure 1), (ii) cellular innate immune responses, and (iii) humoral innate immune responses. During tissue invasion, pathogen breaks the anatomical barriers, and innate immune cells are activated and secrete cytokines and chemokines to control pathogen replication [18, 19].
2.2. The trophoblast
The trophoblast is a bistratified epithelium composed of the superficial syncytiotrophoblast (ST) and the basal cytotrophoblast (CT). There is strong evidence that the ST layer is resistant to numerous pathogens, including
2.3. The trophoblast epithelial turnover
The basal CT cells are the only ones of the trophoblast with proliferative capacity. The superficial multinucleated ST layer is highly differentiated and is unable to proliferate. Importantly, the ST contacts directly with the maternal blood [23, 24, 25], where in case of
2.3.1. Cell proliferation
We have previously shown that the parasite induces, in the trophoblast, cellular proliferation. These experiments were performed in HPCVE and in the trophoblastic cell line BeWo; both models are commonly used in trophoblast studies [27]. In HPCVE
2.3.2. Cell differentiation
As described above, CT cells differentiate continuously and fuse with the ST [24, 25].
2.3.3. Apoptotic cell death
2.4. The trophoblast and the innate immune cellular response against T. cruzi
The innate immune response against pathogens is initiated by pathogen pattern recognition receptors (PRRs), which include
2.5. Other placental defense mechanisms against T. cruzi
The placenta, and particularly the trophoblast, expresses many noncoding RNAs including microRNAs (miRNAs) that regulate placental development function. Moreover, different miRNAs exhibit specialized functions during normal and pathological pregnancies. Placental miRNAs, packaged within exosomes and other vesicles or bound in protein complexes, are capable of communicating distinctive signals to maternal and fetal tissues [5]. Placenta-specific and trophoblast-derived miRNAs, encoded in the chromosome 19 miRNA cluster (C19MC), are released within exosomes and confer resistance to viral infection in other mammalian cells [42]. Preliminary results from our laboratory show that
In summary, the studies about the placental defense mechanism that determines the probability of infection, together with parasite, maternal, and fetal/newborn factors, are of outstanding interest since they are potential diagnostic, prognostic, and therapeutic tools.
References
- 1.
Altemani AM, Bittencourt AL, Lana AM. Immunohistochemical characterization of the inflammatory infiltrate in placental Chagas’ disease: A qualitative and quantitative analysis. The American Journal of Tropical Medicine and Hygiene. 2000; 62 (2):319-324 - 2.
Shippey 3rd SH, Zahn CM, Cisar MM, Wu TJ, Satin AJ. Use of the placental perfusion model to evaluate transplacental passage of Trypanosoma cruzi . American Journal of Obstetrics and Gynecology. 2005;192 (2):586-591 - 3.
Liempi A, Castillo C, Duaso J, Droguett D, Sandoval A, Barahona K, et al. Trypanosoma cruzi induces trophoblast differentiation: A potential local antiparasitic mechanism of the human placenta? Placenta. 2014 Dec;35 (12):1035-1042 - 4.
Liempi A, Castillo C, Carrillo I, Munoz L, Droguett D, Galanti N, et al. A local innate immune response against Trypanosoma cruzi in the human placenta: The epithelial turnover of the trophoblast. Microb Pathog. 2016 Oct;99 :123-129 - 5.
Arora N, Sadovsky Y, Dermody TS, Coyne CB. Microbial vertical transmission during human pregnancy. Cell Host & Microbe. 2017; 21 (5):561-567 - 6.
Mor G, Cardenas I. The immune system in pregnancy: A unique complexity. American Journal of Reproductive Immunology. 2010; 63 (6):425-433 - 7.
Koga K, Aldo PB, Mor G. Toll-like receptors and pregnancy: Trophoblast as modulators of the immune response. The Journal of Obstetrics and Gynaecology Research. 2009; 35 (2):191-202 - 8.
Kemmerling U, Bosco C, Infection GN. Invasion mechanisms of Trypanosoma cruzi in the congenital transmission of Chagas' disease: A proposal. Biological Research. 2010;43 (3):307-316 - 9.
Carlier Y, Truyens C. Congenital Chagas disease as an ecological model of interactions between Trypanosoma cruzi parasites, pregnant women, placenta and fetuses. Acta Tropica. 2015;151 :103-115 - 10.
Hermann E, Berthe A, Truyens C, Alonso-Vega C, Parrado R, Torrico F, et al. Killer cell immunoglobulin-like receptor expression induction on neonatal CD8(+) T cells in vitro and following congenital infection with Trypanosoma cruzi . Immunology. 2010;129 (3):418-426 - 11.
Liempi A, Castillo C, Carrillo I, Munoz L, Droguett D, Galanti N, et al. A local innate immune response against Trypanosoma cruzi in the human placenta: The epithelial turnover of the trophoblast. Microbial Pathogenesis. 2016;99 :123-129 - 12.
Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2018 Jan 6; 391 (10115):82-94 - 13.
Duaso J, Yanez E, Castillo C, Galanti N, Cabrera G, Corral G, et al. Reorganization of extracellular matrix in placentas from women with asymptomatic chagas disease: Mechanism of parasite invasion or local placental defense? J Trop Med. 2012; 2012 :758357 - 14.
Duaso J, Rojo G, Cabrera G, Galanti N, Bosco C, Maya J, et al. Trypanosoma cruzi induces tissue disorganization and destruction of chorionic villi in anex vivo infection model of human placenta. Placenta. 2010;31 (8):705-711 - 15.
Lujan CD, Triquell MF, Sembaj A, Guerrero CE, Fretes RE. Trypanosoma cruzi : Productive infection is not allowed by chorionic villous explant from normal human placentain vitro . Experimental Parasitology. 2004;108 (3-4):176-181 - 16.
Castillo C, Munoz L, Carrillo I, Liempi A, Gallardo C, Galanti N, et al. Ex vivo infection of human placental chorionic villi explants withTrypanosoma cruzi andToxoplasma gondii induces different Toll-like receptor expression and cytokine/chemokine profiles. American Journal of Reproductive Immunology. 2017 Jul;78 (1-8) - 17.
Furukawa S, Kuroda Y, Sugiyama A. A comparison of the histological structure of the placenta in experimental animals. Journal of Toxicologic Pathology. 2014; 27 (1):11-18 - 18.
Janeway Jr CA, Medzhitov R. Innate immune recognition. Annual Review of Immunology. 2002; 20 :197-216 - 19.
Hazlett L, Wu M. Defensins in innate immunity. Cell and Tissue Research. 2011; 343 (1):175-188 - 20.
Diaz-Lujan C, Triquell MF, Castillo C, Hardisson D, Kemmerling U, Fretes RE. Role of placental barrier integrity in infection by Trypanosoma cruzi . Acta Tropica. 2016;164 :360-368 - 21.
Diaz-Lujan C, Triquell MF, Schijman A, Paglini P, Fretes RE. Differential susceptibility of isolated human trophoblasts to infection by Trypanosoma cruzi . Placenta. 2012;33 (4):264-270 - 22.
Robbins JR, Zeldovich VB, Poukchanski A, Boothroyd JC, Bakardjiev AI. Tissue barriers of the human placenta to infection with Toxoplasma gondii . Infection and Immunity. 2012;80 (1):418-428 - 23.
Huppertz B, Borges M. Placenta trophoblast fusion. Methods in Molecular Biology. 2008; 475 :135-147 - 24.
Mayhew TM. Turnover of human villous trophoblast in normal pregnancy: What do we know and what do we need to know? Placenta. 2014; 35 (4):229-240 - 25.
Huppertz B, Gauster M. Trophoblast fusion. Advances in Experimental Medicine and Biology. 2011; 713 :81-95 - 26.
Carlier Y, Sosa-Estani S, Luquetti AO, Buekens P. Congenital Chagas disease: An update. Memórias do Instituto Oswaldo Cruz. 2015; 110 (3):363-368 - 27.
Drewlo S, Baczyk D, Dunk C, Kingdom J. Fusion assays and models for the trophoblast. Methods in Molecular Biology. 2008; 475 :363-382 - 28.
Droguett D, Carrillo I, Castillo C, Gomez F, Negrete M, Liempi A, et al. Trypanosoma cruzi induces cellular proliferation in the trophoblastic cell line BeWo. Experimental Parasitology. 2017;173 :9-17 - 29.
Wang SC. PCNA: A silent housekeeper or a potential therapeutic target? Trends in Pharmacological Sciences. 2014; 35 (4):178-186 - 30.
Duaso J, Rojo G, Jana F, Galanti N, Cabrera G, Bosco C, et al. Trypanosoma cruzi induces apoptosis in ex vivo infected human chorionic villi. Placenta. 2011;32 (5):356-361 - 31.
Baergen KBPKR. Pathology of the Human Placenta. 5th ed. Springer Science-Business Media, Inc.; 2006. p. 1065 - 32.
Castillo C, Villarroel A, Duaso J, Galanti N, Cabrera G, Maya JD, et al. Phospholipase C gamma and ERK1/2 mitogen activated kinase pathways are differentially modulated by Trypanosoma cruzi during tissue invasion in human placenta. Experimental Parasitology. 2013;133 (1):12-17 - 33.
Forbes K, Westwood M. Maternal growth factor regulation of human placental development and fetal growth. The Journal of endocrinology. 2010; 207 (1):1-16 - 34.
Gauster M, Siwetz M, Huppertz B. Fusion of villous trophoblast can be visualized by localizing active caspase 8. Placenta. 2009; 30 (6):547-550 - 35.
Gauster M, Moser G, Orendi K, Huppertz B. Factors involved in regulating trophoblast fusion: Potential role in the development of preeclampsia. Placenta. 2009; 30 (Suppl A):S49-S54 - 36.
Pidoux G, Gerbaud P, Cocquebert M, Segond N, Badet J, Fournier T, et al. Review: Human trophoblast fusion and differentiation: Lessons from trisomy 21 placenta. Placenta. 2012; 33 (Suppl):S81-S86 - 37.
Carrillo I, Droguett D, Castillo C, Liempi A, Munoz L, Maya JD, et al. Caspase-8 activity is part of the BeWo trophoblast cell defense mechanisms against Trypanosoma cruzi infection. Experimental Parasitology. 2016;168 :9-15 - 38.
Tarleton RL. Immune system recognition of Trypanosoma cruzi . Current Opinion in Immunology. 2007;19 (4):430-434 - 39.
Gravina HD, Antonelli L, Gazzinelli RT, Ropert C. Differential use of TLR2 and TLR9 in the regulation of immune responses during the infection with Trypanosoma cruzi . PLoS One. 2013;8 (5):e63100 - 40.
Haider S, Knofler M. Human tumour necrosis factor: Physiological and pathological roles in placenta and endometrium. Placenta. 2009; 30 (2):111-123 - 41.
Hamilton ST, Scott G, Naing Z, Iwasenko J, Hall B, Graf N, et al. Human cytomegalovirus-induces cytokine changes in the placenta with implications for adverse pregnancy outcomes. PLoS One. 2012; 7 (12):e52899 - 42.
Bayer A, Delorme-Axford E, Sleigher C, Frey TK, Trobaugh DW, Klimstra WB, et al. Human trophoblasts confer resistance to viruses implicated in perinatal infection. American Journal of Obstetrics and Gynecology. 2015; 212 (1):71e1-71e8 - 43.
Zhou A, Li S, Wu J, Khan FA, Zhang S. Interplay between microRNAs and host pathogen recognition receptors (PRRs) signaling pathways in response to viral infection. Virus Research. 2014; 184 :1-6 - 44.
Zheng Y, Cai X, Bradley JE. MicroRNAs in parasites and parasite infection. RNA Biology. 2013; 10 (3):371-379 - 45.
Donker RB, Mouillet JF, Chu T, Hubel CA, Stolz DB, Morelli AE, et al. The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes. Molecular Human Reproduction. 2012; 18 (8):417-424 - 46.
Sadovsky Y, Mouillet JF, Ouyang Y, Bayer A, Coyne CB. The function of TrophomiRs and other microRNAs in the human placenta. Cold Spring Harbor Perspectives in Medicine. 2015; 5 (8):a023036