Congenital Zika virus infection: a neuropathological review.

BACKGROUND: A relationship between Zika virus (ZikV) infection in pregnancy and the occurrence of microcephaly was established during the Zika outbreak in Brazil (2015-2016). Neuropathological findings in congenital Zika syndrome helped to understand its pathogenetic mechanisms. RESULTS: The most relevant postmortem findings in the central nervous system (CNS) of fetuses and neonates infected with ZikV early in gestation are microcephaly with ex-vacuo ventriculomegaly and large head circumference associated with obstructive hydrocephalus due to severe midbrain and aqueduct distortion. Babies with severe brain lesions are born with arthrogryposis. Histologically, there is extensive destruction of the hemispheric parenchyma, calcifications, various disturbances of neuronal migration, reactive gliosis, microglial hyperplasia and occasional perivascular cuffs of lymphocytes, also in the meninges. Hypoplastic lesions secondary to the lack of descending nerve fibers include small basis pontis, pyramids and spinal corticospinal tracts. Cerebellar hypoplasia is also common. Severe nerve motor nerve cell loss is observed in the anterior horn of the spinal cord. CONCLUSION: A spectrum of neuropathological changes, from severe microcephaly to obstructive hydrocephalus was observed. The severity of the lesions is directly related to the gestational age, the most severe occurring when the mother is infected in the first trimester. Infection of progenitor cells at the germinal matrix was demonstrated. The lack of spinal motor neurons is responsible for fetal acynesia and consequent arthrogryposis.

Low oxygen tension induces Krüppel-Like Factor 6 expression in trophoblast cells.

The transcription factor Krüppel-Like Factor 6 (KLF6) has important roles in cell differentiation, angiogenesis, apoptosis, and proliferation. Furthermore, there is evidence that KLF6 is required for proper placental development. While oxygen is a critical mediator of trophoblast differentiation and function, the involvement of oxygen in the regulation of KLF6 expression remains unexplored. In the present study we examined the expression of KLF6 in placental tissue from uncomplicated and preeclamptic pregnancies, the latter often characterized by an inadequately perfused placenta. We also determined the effect of hypoxia and the involvement of Hypoxia-Inducible Factor 1α (HIF-1α) on the expression of KLF6 in cultured trophoblast cells and placental tissues. Results revealed that villous, interstitial and endovascular extravillous cytotrophoblasts from placentas from normal and preeclamptic pregnancies express KLF6. In addition, KLF6 immunoreactivity was higher in the placental bed of preeclamptic pregnancies than in those of uncomplicated pregnancies. We demonstrated that hypoxia induced an early and transient increase in KLF6 protein levels in HTR8/SVneo extravillous cytotrophoblast cells and in placental explants. Reoxygenation returned KLF6 protein to basal levels. Moreover, hypoxia-induced up-regulation of KLF6 expression was dependent on HIF-1α as revealed by siRNA knockdown in HTR8/SVneo cells. These results indicate that KLF6 may mediate some of the effects of hypoxia in placental development. The regulation of KLF6 protein levels by oxygen has significant implications for understanding its putative role in diseases affected by tissue hypoxia.

Contractile cells and fibrillin-1 distribution is disturbed in terminal villi of placentae from patients with preeclampsia and systemic lupus erythematosus.

Placentae from patients with preeclampsia (PE) and systemic lupus erythematosus (SLE) present many alterations that may impair materno-fetal exchange. We investigated the distribution of contractile cells and fibrillin-1 in terminal villi of term placentae from patients with PE or SLE and compared to control placentae. Stroma in terminal villi exhibited intense labelling for fibrillin-1. The fibrillin-1 villi surface fraction was greater in PE and SLE placentae than in controls (13+/-0.4%, 14+/-0.5%, 10+/-0.4%; p=0.0001). Immunohistochemistry for alpha-smooth muscle (SM) actin showed few contractile cells in control terminal villi stroma, localized around fetal capillaries and showed rare processes in vasculo-syncytial membrane. PE and SLE placentae exhibited an increase in the number of capillaries presenting alpha-SM actin adventitial positive cells. The presence of alpha-SM actin processes interposed in the vasculo-syncytial membrane was greater in SLE villi than in PE and controls. Ultrastructural observations confirmed in SLE and PE terminal villi the presence of these processes in vasculo-syncytial membrane and also showed a thickened trophoblastic basement membrane. The present study demonstrates that an important myofibroelastic system is present in term terminal villi, and that this system is actively remodelled in PE and SLE placentae.