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Interpretation attempt of Trypanosoma cruzi— placenta interactions

Based on the observations mentioned above, we can depict four scenarios of interactions between the parasite and the placenta, considering the importance of placental lesions and the occurrence of transmission (Fig. 23.1).

  • 1. The huge parasite load in the intervillous space overflows the placental defenses, leading to infection and rupture of the trophoblastic barrier. This results in the transmission of large quantities of free trypomastigotes as well as of amastigote-infected cells, and to severe and mortal congenital Chagas disease. In such a situation, the placental inflammation (placentitis) is strongly marked and has pathological instead of protective effects, with the substantial release of TNF-a contributing to the trophoblast rupture, as well as to fetal and neonatal mortality.52 The high local production of other inflammatory mediators, such as reactive oxygen species, NO and peroxynitrite, has deleterious effects on placental vascularization.53 This is probably what occurs in acute or reactivated infection during pregnancy displaying the highest parasitemias (see section: Parasitic load during pregnancy and transmission of congenital infection).
  • 2. In the presence of moderate parasite amounts in the intervillous space, the placental innate defenses are only slightly activated. Indeed, T. cruzi, being partially deficient in strong PAMPs,54 can hardly stimulate the TLRs expressed on the trophoblast.40 This does not induce the rupture of the trophoblastic barrier and transmission can occur by the marginal zone deprived of trophoblast (see section: Histopathologic studies of placentas from infected or uninfected neonates41). Parasites invade cells of this zone, and those surviving the mesenchymal defense (second placental line of defense) can easily spread by successive infections of fibroblasts, myofibroblasts, and macrophages (Hofbauer cells) within the chorion. They finally infect myocytes and endothelial cells lining fetal vessels embedded in chorionic plate or umbilical cord, and gain access to the fetal circulation.122 This situation likely corresponds to the common mild congenital T. cruzi infections observed in roughly 5% of live newborns of chronically infected women (see section: Situation in Latin American endemic countries). Additionally, the infection spreads in membranes surrounding the fetus, inducing their embrittlement. This leads to their premature rupture and contribute to the premature birth, frequently observed in these cases.55
  • 3. Parasite transmission (of trypomastigotes as well as amastigote-infected cells) occurs at delivery, when placental breaches/tears appear naturally with labor contractions. This route, which can be avoided by cesarean delivery (see section: Timing of maternal—fetal transmission of Trypanosoma cruzi) is used for transmission of HIV-infected leukocytes.56 It is independent of the activation of placental innate defenses.
  • 4. There is neither parasite transmission, nor disruption of the trophoblastic barrier, nor inflammation; placental innate defenses are not activated by the too low blood parasite amount; this might concern the 95% of chronically infected pregnant women displaying weak parasitemias (see section: Parasitic load during pregnancy and transmission of congenital infection) and delivering uninfected newborns.

A placental microbiome has been recently discovered.57 Its role in the transmission of congenital infection deserves further investigations.

Mutations in the placental genes for the disintegrin and metalloproteinases ADAM12 and MMP2 are associated to the susceptibility to congenital infection with T. cruzi.58 Whether such mutations in placental genes are sufficiently frequent to contribute to transmission remains to be determined.

 
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