Plasmodium falciparum alters the trophoblastic barrier and stroma villi organization of human placental villi explants.

BACKGROUND: The sequestration of Plasmodium falciparum infected erythrocytes in the placenta, and the resulting inflammatory response affects maternal and child health. Despite existing information, little is known about the direct impact of P. falciparum on the placental barrier formed by trophoblast and villous stroma. This study aimed to assess placental tissue damage caused by P. falciparum in human placental explants (HPEs). METHODS: HPEs from chorionic villi obtained of human term placentas (n = 9) from normal pregnancies were exposed to P. falciparum-infected erythrocytes (IE) for 24 h. HPEs were embedded in paraffin blocks and used to study tissue damage through histopathological and histochemical analysis and apoptosis using TUNEL staining. Culture supernatants were collected to measure cytokine and angiogenic factors and to determine LDH activity as a marker of cytotoxicity. A subset of archived human term placenta paraffin-embedded blocks from pregnant women with malaria were used to confirm ex vivo findings. RESULTS: Plasmodium falciparum-IE significantly damages the trophoblast layer and the villous stroma of the chorionic villi. The increased LDH activity and pathological findings such as syncytial knots, fibrin deposits, infarction, trophoblast detachment, and collagen disorganization supported these findings. The specific damage to the trophoblast and the thickening of the subjacent basal lamina were more pronounced in the ex vivo infection. In contrast, apoptosis was higher in the in vivo infection. This disparity could be attributed to the duration of exposure to the infection, which significantly varied between individuals naturally exposed over time and the 24-h exposure in the ex vivo HPE model. CONCLUSION: Exposure to P. falciparum-IE induces a detachment of the syncytiotrophoblast, disorganization of the stroma villi, and an increase in apoptosis, alterations that may be associated with adverse results such as intrauterine growth restriction and low birth weight.

Chagas disease affects the human placental barrier's turnover dynamics during pregnancy.

BACKGROUND: Trypanosoma cruzi crosses the placental barrier and produces the congenital transmission of Chagas disease (CD). Structural alterations of the chorionic villi by this parasite have been described in vitro, but little is known about trophoblast turnover in placentas from women with CD. OBJECTIVE: To analyze the proliferation and fusion processes in placentas from women with CD. METHODS: Archived human term placenta paraffin-embedded blocks were used, from women with CD (CDP), and no pathology (NP). Immunohistochemistry tests were performed for Ki67 to calculate the proliferation index (PI) of cytotrophoblast (CTB) and Syncytin-1, a fusion marker of syncytiotrophoblast (STB). Hematoxylin/Eosin stained sections were employed to analyze STB percentages, STB detachment areas and syncytial knots quantity. Non parametric Student's t-tests were performed (p < 0.05). RESULTS: Syncytial knots and STB detachment significantly increased in placental villi from the CDP group. STB percentage was significantly lower in the CDP group as well as the PI and Syncytin-1 expression significantly decreased in these placentas, compared with control (NP). CONCLUSION: Dynamic of trophoblast turnover is altered in placentas from women with CD. These changes may lead into a gap in the placental barrier possibly allowing the parasite entry into the chorionic villi.

Azithromycin is able to control Toxoplasma gondii infection in human villous explants.

BACKGROUND: Although Toxoplasma gondii infection is normally asymptomatic, severe cases of toxoplasmosis may occur in immunosuppressed patients or congenitally infected newborns. When a fetal infection is established, the recommended treatment is a combination of pyrimethamine, sulfadiazine and folinic acid (PSA). The aim of the present study was to evaluate the efficacy of azithromycin to control T. gondii infection in human villous explants. METHODS: Cultures of third trimester human villous explants were infected with T. gondii and simultaneously treated with either PSA or azithromycin. Proliferation of T. gondii, as well as production of cytokines and hormones by chorionic villous explants, was analyzed. RESULTS: Treatment with either azithromycin or PSA was able to control T. gondii infection in villous explants. After azithromycin or PSA treatment, TNF-α, IL-17A or TGF-ß1 levels secreted by infected villous explants did not present significant differences. However, PSA-treated villous explants had decreased levels of IL-10 and increased IL-12 levels, while treatment with azithromycin increased production of IL-6. Additionally, T. gondii-infected villous explants increased secretion of estradiol, progesterone and HCG+ß, while treatments with azithromycin or PSA reduced secretion of these hormones concurrently with decrease of parasite load. CONCLUSIONS: In conclusion, these results suggest that azithromycin may be defined as an effective alternative drug to control T. gondii infection at the fetal-maternal interface.

Histopathologies, immunolocalization, and a glycan binding screen provide insights into Plasmodium falciparum interactions with the human placenta.

During pregnancy, Plasmodium falciparum-infected erythrocytes cytoadhere to the placenta. Infection is likely initiated at two sites where placental trophoblasts contact maternal blood: 1) via syncytiotrophoblast (STB), a multicellular transporting and biosynthetic layer that forms the surface of chorionic villi and lines the intervillous space, and 2) through invasive cytotrophoblasts, which line uterine vessels that divert blood to the placenta. Here, we investigated mechanisms of infected erythrocyte sequestration in relationship to the microanatomy of the maternal-fetal interface. Histological analyses revealed STB denudation in placental malaria, which brought the stromal cores of villi in direct contact with maternal blood. STB denudation was associated with hemozoin deposition (P = 0.01) and leukocyte infiltration (P = 0.001) and appeared to be a feature of chronic placental malaria. Immunolocalization of infected red blood cell receptors (CD36, ICAM1/CD54, and chondroitin sulfate A) in placentas from uncomplicated pregnancies showed that STB did not stain, while the underlying villous stroma was immunopositive. Invasive cytotrophoblasts expressed ICAM1. In malaria, STB denudation exposed CD36 and chondroitin sulfate A in the villous cores to maternal blood, and STB expressed ICAM1. Finally, we investigated infected erythrocyte adherence to novel receptors by screening an array of 377 glycans. Infected erythrocytes bound Lewis antigens that immunolocalized to STB. Our results suggest that P. falciparum interactions with STB-associated Lewis antigens could initiate placental malaria. Subsequent pathologies, which expose CD36, ICAM1, and chondroitin sulfate A, might propagate the infection.

Phospholipase C gamma and ERK1/2 mitogen activated kinase pathways are differentially modulated by Trypanosoma cruzi during tissue invasion in human placenta.

Chagas' disease is caused by the haemophlagelated protozoan Trypanosoma cruzi (T. cruzi). During congenital transmission the parasite breaks down the placental barrier, however studies about the physiopathology of this process are scarce. Different signal transduction pathways are involved during cell invasion of the parasite. However, the possible role of those processes during tissue infection has not been studied. In the present study we analyzed the modulation of two signal transduction pathways, PLC-γ and ERK1/2 MAPK, during ex vivo infection of human placental chorionic villi explants. Chorionic villi from healthy woman placentas were incubated in the presence or absence of 10(5) or 10(6)T. cruzi trypomastigotes (DM28c strain) with or without specific inhibitors for each pathway. Effective infection was tested determining parasite DNA by PCR. The activation of PLC-γ and ERK1/2 MAPK signaling pathways was determined by western blotting and immunofluorescence. The low concentration of T. cruzi trypomastigotes activates both signaling pathways; however, the high concentration of parasite induces a modest activation of the PLC-γ pathway and impairs the ERK1/2 MAPK pathway activation. Interestingly, inhibition of any of those signaling pathways did not prevent parasite infection, as it was previously shown in cell cultures. We conclude that both signal transduction pathways are modulated during ex vivo T. cruzi infection of human placental chorionic villi explants.

Cyclooxygenase (COX)-2 modulates Toxoplasma gondii infection, immune response and lipid droplets formation in human trophoblast cells and villous explants.

Congenital toxoplasmosis is represented by the transplacental passage of Toxoplasma gondii from the mother to the fetus. Our studies demonstrated that T. gondii developed mechanisms to evade of the host immune response, such as cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) induction, and these mediators can be produced/stored in lipid droplets (LDs). The aim of this study was to evaluate the role of COX-2 and LDs during T. gondii infection in human trophoblast cells and villous explants. Our data demonstrated that COX-2 inhibitors decreased T. gondii replication in trophoblast cells and villous. In BeWo cells, the COX-2 inhibitors induced an increase of pro-inflammatory cytokines (IL-6 and MIF), and a decrease in anti-inflammatory cytokines (IL-4 and IL-10). In HTR-8/SVneo cells, the COX-2 inhibitors induced an increase of IL-6 and nitrite and decreased IL-4 and TGF-ß1. In villous explants, the COX-2 inhibitors increased MIF and decreased TNF-α and IL-10. Furthermore, T. gondii induced an increase in LDs in BeWo and HTR-8/SVneo, but COX-2 inhibitors reduced LDs in both cells type. We highlighted that COX-2 is a key factor to T. gondii proliferation in human trophoblast cells, since its inhibition induced a pro-inflammatory response capable of controlling parasitism and leading to a decrease in the availability of LDs, which are essentials for parasite growth.

Ex vivo infection of human placental chorionic villi explants with Trypanosoma cruzi and Toxoplasma gondii induces different Toll-like receptor expression and cytokine/chemokine profiles.

PROBLEM: Trypanosoma cruzi and Toxoplasma gondii present, respectively, low and high congenital transmission rates. The placenta as an immune regulatory organ expresses TLRs, leading to the secretion of cytokines. Both parasites are recognized by TLR-2, TLR-4, and TLR-9. Here, we studied if the parasites induce differences in TLR protein expression, cytokine profiles, and whether receptor inhibition is related to parasite infection. METHOD OF STUDY: Placental tissue explants were infected ex vivo with each parasite, TLRs protein expression, cytokine profile and parasite infection were determined by Western blotting, ELISA and qPCR. RESULTS: Trypanosoma cruzi and Toxoplasma gondii infection is related to TLR-2 and TLR-4/TLR-9, respectively. Trypanosoma cruzi elicits an increase in TNF-α, IL-1ß, IL-6, IL-8 and IL-10 cytokine secretion whereas T. gondii only increases the secretion of IL-8. CONCLUSION: The susceptibility of the placenta to each parasite is mediated partially by the innate immune response.

Granulomatous villitis formed by inflammatory cells with maternal origin: a rare manifestation type of placental toxoplasmosis.

We present a case of placental toxoplasmosis with granulomatous villitis. The patient was a 26-year-old gravida 1 female with the findings of intrauterine death at 16th week of gestation. The pregnancy was terminated. Pathological examination revealed an autolysed fetus and a placenta with necrotizing granulomas within the villous stroma. Encysted Toxoplasma gondii was rarely observed within the granulomas and serologic examination of the mother confirmed acute toxoplasmosis. A fluorocein in situ hybridization examination, using sex chromosome probes, revealed that the villous granulomas were formed by inflammatory cells, originated from the maternal immune system. In conclusion, T. gondii should be taken into consideration as a rare cause of placental granulomatous inflammation. To the best of our knowledge, this is the first case of granulomatous villitis due to toxoplasmosis, in which formation by maternal inflammatory cells has been demonstrated.

Role of placental barrier integrity in infection by Trypanosoma cruzi.

American trypanosomiasis has long been a neglected disease endemic in LatinAmerica, but congenital transmission has now spread Chagas disease to cause a global health problem. As the early stages of the infection of placental tissue and the vertical transmission by Trypanosoma cruzi are still not well understood, it is important to investigate the relevance of the first structure of the placental barrier in chorionic villi infection by T. cruzi during the initial stage of the infection. Explants of human chorionic villi from healthy pregnant women at term were denuded of their syncytiotrophoblast and co-cultured for 3h, 24h and 96h with 800,000 trypomastigotes (simulating acute infection). T. cruzi infected cells were identified by immunohistochemistry for cytokeratin-7 (+cytotrophoblast) and CD68 (+macrophages), and the infection was quantified. In placental tissue, the parasite load was analyzed by qPCR and microscopy, and the motile trypomastigotes were quantified in culture supernatant. In denuded chorionic villous, the total area occupied by the parasite (451.23µm2, 1.33%) and parasite load (RQ: 87) was significantly higher (p<0.05) than in the entire villous (control) (5.98µm2, 0.016%) (RQ:1) and with smaller concentration of nitric oxide. Stromal non-macrophage cells were infected as well as cytotrophoblasts and some macrophages, but with significant differences being observed. The parasite quantity in the culture supernatant was significantly higher (p<0.05) in denuded culture explants from 96h of culture. Although the human complete chorionic villi limited the infection, the detachment of the first structure of the placenta barrier (syncytiotrophoblast) increased both the infection of the villous stroma and the living trypomastigotes in the culture supernatant. Therefore structural and functional alterations to chorionic villi placental barrier reduce placental defenses and may contribute to the vertical transmission of Chagas.

Placental alkaline phosphatase (PLAP) study in diabetic human placental villi infected with Trypanosoma cruzi.

Previous work has demonstrated that PLAP activity decreases in serum and placental villi from term chagasic and diabetic pregnant women. In vitro, T. cruzi induces changes in human syncytiotrophoblast's PLAP. Our aim was to determine if infection with T. cruzi induces changes in PLAP activity in diabetic and chagasic women's placenta, in order to elucidate if PLAP plays a role in the mechanisms of interaction between placenta and T. cruzi, and whether hyperglycemic conditions could worsen the placental infection. Using zymogrammes, Western blot, biochemical and immunohistological techniques, PLAP activity was determined in placental villi from diabetic and chagasic women, and in normal placentas cultured under hyperglycemic conditions with or without trypomastigotes. A significant reduction of PLAP expression was immunologically detected in infected diabetic and normal placental villi cultured under hyperglycemic conditions of 71 and 81%, respectively, compared with controls. A significant decrease of PLAP specific activity was registered in homogenates and in the culture media from both infected diabetic and normal placentas under hyperglycemic conditions (of about 50-70%), and in chagasic ones (of about 87%), when compared with controls. Thus, PLAP might be involved in parasite invasion and diabetic and hyperglycemic placentas could be more susceptible to T. cruzi infection.

[Cellular components and placental alkaline phosphatase in Trypanosoma cruzi infection ]. / Componentes celulares y fosfatasa alcalina placentaria en la infección por T. cruzi.

Trypanosoma cruzi induces changes in the protein pattern of human placenta syncytiotrophoblast. Placental alkaline phosphatase (PLAP) is a glycoenzyme anchored to the membrane by a glycosyl-phosphatidylinositol molecule. PLAP activity and its presence was altered by the parasite in cultures of human placental villi and HEp2 cells with T.cruzi. The cells treated before the cultures with agents which affect PILAP or glycosyl-phosphatidylinositol (antibodies, PL-C, genistein, lithium) presented less parasitic invasion than the control ones. It was also observed a modification in the pattern of actine filaments of the host cells infected. We concluded that PLAP would participate in the process of T. cruzi invasion into placental syncitiotrophoblast cells, by a mechanism that involves hydrolysis of the glycosyl-phosphatidylinositol molecules, the activation of tyrosine kinase proteins, the increase of cytosolic calcium and the rearrangement of actine filaments of the host cells.

Massive chronic intervillositis of the placenta associated with malaria infection.

Massive chronic intervillositis (MCI) is an infrequently recognized placental lesion thought to be of immunologic origin that has been associated with poor fetal outcome. It is characterized by a prominent inflammatory infiltrate in the intervillous space, composed mainly of monocytes and macrophages that can simulate a maternal malignant disorder involving the placenta. The villi are characteristically spared. We report 74 cases of placental malarial infection with morphologic features of MCI. In all cases, the massive inflammatory infiltrate was limited to the intervillous space, which appeared largely obliterated. Increased fibrin deposition and prominent syncytial knots were frequent associated findings. Inflammatory cells were CD45 and CD68 positive, consistent with a monocyte-macrophage population. Some polymorphonuclear leukocytes and scattered T and B lymphocytes were also present. Villi were not inflamed. Malarial pigment was present in all cases, and parasitized maternal erythrocytes were evident in 73 of 74 patients. The histologic pattern of MCI was observed in 17.6% of placentas with malarial parasites. Malarial MCI affected predominantly primigravida women (77%) and was associated with a reduced birth weight, which in 39 (53%) of the infants was less than 2500 g, and a low gestational age. None of the infants with placentas with MCI died in the early neonatal period. Morphologic changes of MCI are seen in a significant percentage of placentas with malarial infection, especially in primigravida women, and are associated with a low birth weight. Malarial infection should therefore be considered in the differential diagnosis of massive intervillous infiltrates.

Syncytiotrophoblast degradation and the pathophysiology of the malaria-infected placenta.

Malaria is associated with excessive parasitic infection of the placenta and a reduction in neonatal birthweight. This study has investigated placental cell death in women with active and past malarial infection. Term placentae, with and without malarial pathology, were obtained from women in The Gambia. Active and past malaria infections were identified in placental sections and histological examination was used to determine the number of villi, the incidence of apoptosis, syncytial degradation, fibrinoid deposition and the frequency of syncytial knots. Placentae with active malaria infection showed erythrocyte adhesion of infected cells to syncytiotrophoblast, syncytial degradation, increased syncytial knotting and, in rare cases, localized destruction of the villi. Past malarial infection was characterized by syncytiotrophoblast disruption and fibrin-type fibrinoid (FTF) deposition. Perivillous FTF deposition was consistent with increased syncytial lesions and both increased lesions and syncytial knots were associated with birthweight reductions. Active malaria infection produced no alteration in placental apoptosis. The numbers of chorionic villi remained unchanged and infiltration of inflammatory cells, although not measured directly, appeared to be non-pervasive within the infected tissue. These observations establish a direct link between malaria parasitic infection and syncytiotrophoblast damage. The placental rejection of parasite-affected syncytia may invoke structural changes to compensate for inadequate placental exchange. Syncytial destruction could have serious implications; impairing fetal growth and in some rare cases, providing a previously unrecognized pathway to congenital infection.

Epidermal growth factor (EGF) in the human placental infection with Trypanosoma cruzi.

Maternal infection of Trypanosoma cruzi is associated with premature births, abortions and placentitis. A decrease in EGF levels has been suggested to occur in animals infected by T. cruzi, but there is no research about the levels of EGF in human patients with Chagas' disease. We evaluated serum EGF levels in pregnant women with and without the disease, and with immunological methods detected EGF receptors and EGF in both groups of placentae and in cultures of normal placental villi with and without parasites. PLAP in placentae from those women was also immunologically detected, since EGF can induce the release of PLAP from the trophoblast surface and PLAP is suggested to be a receptor allowing parasite invasion of the placenta. Plasma from women with Chagas' disease contained lower level of EGF when compared to plasma of healthy women. Placentae from women with Chagas' disease showed lower PLAP expression but same level of detectable EGF receptors and EGF when compared with placentae from women without the disease. Culture with parasites did not reduce EGFr level. Results suggest a lower availability of EGF in women with Chagas' disease, which could explain several malfunctions of the placenta associated with maternal Chagas' disease.

Trypanosoma cruzi infection induces microfilament depletion in human placenta syncytiotrophoblast.

Congenital Chagas disease, endemic in Latin America, is associated with premature labour, miscarriage, and placentitis. Metacyclic trypomastigotes adhere to specific receptors on the outer membrane of host cells as a prelude to intracellular invasion, causing calcium ion mobilization, rearrangement of host cell microfilaments, recruitment of lysosomes and parasite internalization. The actin cytoskeleton plays an important role in many cellular processes including the parasite invasion into mammalian cells. In order to observe if placental cytoskeleton is altered in the process of parasite invasion into placental villi, actin microfilaments were studied. Using immunohistochemical techniques, it was observed that the presence of actin in the syncytiotrophoblast was intense throughout the brush border in control placentae belonging to non-chagasic women. But after culture with the trypomastigote, this labelling disappeared, indicating that the parasite induced disassembly of the cortical actin cytoskeleton when the placenta was infected. As a control, placentae from chagasic women were studied, and no actin was found. The same results were obtained by the electron microscope. We confirmed that cortical actin rearrangements may be an early step in the Trypanosoma cruzi invasion mechanism into placental cells, in order to allow lysosomes access to the plasma membrane, and formation of the parasitophorous vacuole. The recruitment of lysosomes occurs directly beneath the invasion site, and this process is required for parasite internalization.

Immunohistochemical characterization of the inflammatory infiltrate in placental Chagas' disease: a qualitative and quantitative analysis.

Chagas' disease, a systemic illness endemic to some regions of South America, is caused by the protozoan Trypanosoma cruzi. Transplacental infection may occur during any phase and cause fetal death. This study is the first to characterize the inflammatory cells in chagasic villitis by immunohistochemistry. Paraffin sections of 8 placentas with villitis by T. cruzi (4 live births and 4 stillbirths), as well as 8 control placentas without inflammation, were stained with hematoxylin and eosin, monoclonal antibodies for CD45RO, CD20, CD45RO/OPD4, CD8, HNKI, CD15, MAC387, and CD68 proteins, and a polyclonal antibody for S-100 protein. Quantification of positive cells was performed in 3 different high-power fields. In all cases of chagasic villitis, the inflammatory infiltrate was composed mainly of CD68+ macrophages, T lymphocytes, and a few natural killer cells. Among T cells, CD8+ cells outnumbered CD4+ cells in all placentas (CD4+:CD8+ ratios ranged from 0.04 to 0.38). B cells were absent or rare. In stillbirths, villitis was diffuse and severe with numerous T. cruzi, while in live births it was focal with few parasites. Other features that characterized villitis in stillbirths were 1) frequent trophoblastic necrosis, 2) presence of MAC387+ macrophages and CD15+ granulocytes attached to the sites of trophoblastic necrosis, 3) low CD4+: CD8+ ratios in most cases, 4) increased numbers of S-100 positive cells in the villous stroma. In conclusion, CD68+ macrophages and CD8+ T lymphocytes were the major cell population in villitis caused by T. cruzi. However, the pattern of inflammatory reaction differed between stillbirths and live births and was probably related to the number of parasites in the placental villi.

[Increase of Hofbauer cells in human placentas cocultured in vitro with Trypanosoma cruzi]. / Aumento de células de Hofbauer en placentas humanas cocultivadas in vitro con Trypanosoma cruzi.

To analyze the interaction between normal human placentas with Trypanosoma cruzi, optical and electron microscopy of chorionic villi stroma cocultured in vitro with 1.5 x 106 Tulahuen strain Trypomastigotes of the T. cruzi for 1 h, 3 hs and 12 hs in Eagle minimal essential medium were done. An agglutination of chorionic villi in experimental cultures (with T. cruzi) from 1 h cultures was observed that was not present in control ones. this phenomenon resisted soft mechanical agitation to separate the isolated villi. Microscopical observations of stromal villi showed edema, separated structures and increment of Hofbauer cells as found by qualitative analysis. The chorionic villi agglutination could be caused by glycoproteins' modifications of the trophoblast, which in turn could be caused by secreted products of T. cruzi, as other authors have postulated in various cells' types. The increment of Hofbauer cells could represent a regulator mechanism of the placenta to equilibrate the intracellular water of the villi stroma.

Toxic and therapeutic effects of Nifurtimox and Benznidazol on Trypanosoma cruzi ex vivo infection of human placental chorionic villi explants.

Nifurtimox (Nfx) and Benznidazole (Bnz) are the only available drugs in use for the treatment of Chagas disease. These drugs are recommended but not fully validated in evidence-based medicine and reports about the differential toxicity of both drugs are controversial. Here, we evaluated the toxic and therapeutic effects of Nfx and Bnz on human placental chorionic villi explants (HPCVE) during ex vivo infection of Trypanosoma cruzi, performing histopathological, histochemical, immunohistochemical as well as immunofluorescence analysis of the tissue. Additionally, we determined the effect of both drugs on parasite load by real time PCR. Bnz prevents the parasite induced tissue damage in ex vivo infected HPCVE compared to Nfx, which is toxic per se. The presence of T. cruzi antigens and DNA in infected explants suggests that these drugs do not impair parasite invasion into the HPCVE. Additionally, our results confirm reports suggesting that Bnz is less toxic than Nfx and support the need for the development of more effective and better-tolerated drugs.

Role of matrix metalloproteinases 2 and 9 in ex vivo Trypanosoma cruzi infection of human placental chorionic villi.

BACKGROUND: Chagas' disease is caused by the haemophlagelated protozoan Trypanosoma cruzi (T. cruzi). During congenital transmission the parasite breaks down the placental barrier. In the present study we analyzed the participation of matrix metalloproteases (MMPs) in the extracellular matrix (ECM) remodeling during T. cruzi ex vivo infection of human placental chorionic villi explants. METHODS: Chorionic villi from healthy woman placentas were incubated in the presence or absence of 105 or 106 T. cruzi trypomastigotes (Y strain) with or without the MMPs inhibitor doxycycline. Effective infection was tested measuring parasite DNA by real time PCR (qPCR). MMP-2 and MMP-9 expression were determined by western blotting and immunohistochemistry and their activities were measured by zymography. The effect of MMPs on ECM structure was analyzed histochemically. RESULTS: T. cruzi induces the expression and activity of MMP-2 and MMP-9 in chorionic villi. Inhibition of the MMPs prevents the tissue damage induced by T. cruzi and partially decreases the ex vivo infection of the chorionic villi. CONCLUSION: MMPs are partially responsible for the ECM changes observed in human chorionic villi during T. cruzi infection and participate in tissue invasion. On the other hand, MMPs may be part of a local placental antiparasitic mechanism.