The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

Chiu, Chi-Fen; Chu, Li-Wei; Liao, I‐Chen; Simanjuntak, Yogy; Lin, Yi-Ling; Juan, Chi Chang; Ping, Yueh Hsin

doi:10.3389/fmicb.2020.00214

Cited by 91 publications

(86 citation statements)

References 46 publications

(55 reference statements)

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“…Many authors have reported on the capacity of ZIKV to infect neurons and other neuronal cells that most likely detrimentally affect their function and contribute to congenital Zika syndrome (CZS), which has as its main characteristics microcephaly and ventriculomegaly ( 1 , 3 – 5 , 7 , 8 ). In this scenario, studies aiming to understand the mother-fetus interface of ZIKV vertical transmission have been strongly recommended ( 9 ). In the vertical transmission, one major barrier is the placenta, a highly specialized organ that ensures the fetus’ development, by allowing the exchange of nutrients, solutes and acting as physiological barrier against toxic molecules and pathogens, such as viruses ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…In this scenario, studies aiming to understand the mother-fetus interface of ZIKV vertical transmission have been strongly recommended ( 9 ). In the vertical transmission, one major barrier is the placenta, a highly specialized organ that ensures the fetus’ development, by allowing the exchange of nutrients, solutes and acting as physiological barrier against toxic molecules and pathogens, such as viruses ( 9 , 10 ). Estimates are that the viral genome can be detected in the placenta of 20–50% of pregnant women exposed to ZIKV ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Zika Induces Human Placental Damage and Inflammation

et al. 2020

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In Brazil, an epidemic of Zika virus (ZIKV) infections was declared in 2015 that coincided with alarming reports of microcephaly in newborns associated with mother infection. Although the virus has placental tropism, changes in the tissue morphology and immunity of infected patients have not yet been elucidated. Here, we investigated the histopathological and ultrastructural changes along with the immunological profile and the BDNF expression in rare placental material. Tissues were obtained in the 2015–2016 Brazilian epidemic, of ten ZIKV-infected patients during pregnancy, five resulting in cases of fetal microcephaly and five non-microcephaly, compared to five non-infected control placentae. Viral antigens were only detected in samples from the ZIKV infected patients. Infected placentae presented histopathological severe damage, while the ultrastructural evaluation showed abnormal organelles, such as clusters of virus-like particles consistent with the ZIKV dimensions. Increased infiltration of CD68 + and TCD8 + cells, expression of MMPs, cytokines (IFN-γ and TNF-α) and other immunological mediators (RANTES/CCL5 and VEGFR-2) confirmed excessive inflammation and vascular permeability dysfunction. An evaluation of BDNF showed a decrease that could modulate neuronal damage in the developing fetus. The placental changes caused by ZIKV are not pathognomonic, however, the data provide evidence that this infection leads to severe placental injury.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zika Induces Human Placental Damage and Inflammation

et al. 2020

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“…In vivo ( 3 – 8 ) and in vitro ( 9 – 11 ) studies have demonstrated that ZIKV replicates in the placenta, in the brain tissues of fetuses with microcephaly, or in placenta-derived primary cells. However, knowledge of the mechanism through which ZIKV infects and replicates in the placenta remains elusive ( 12 , 13 ). ZIKV, similarly to other flaviviruses, has a single-stranded positive-sense RNA genome of approximately 11 kb that is translated into a single large polyprotein, and this polyprotein is cleaved into individual proteins at the rough endoplasmic reticulum (ER) ( 14 – 16 ).…”

Section: Introductionmentioning

confidence: 99%

Placental Alkaline Phosphatase Promotes Zika Virus Replication by Stabilizing Viral Proteins through BIP

Chen

Liu

et al. 2020

mBio

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Zika virus (ZIKV) infection during pregnancy causes intrauterine growth defects and microcephaly, but knowledge of the mechanism through which ZIKV infects and replicates in the placenta remains elusive. Here, we found that ALPP, an alkaline phosphatase expressed primarily in placental tissue, promoted ZIKV infection in both human placental trophoblasts and astrocytoma cells. ALPP bound to ZIKV structural and nonstructural proteins and thereby prevented their proteasome-mediated degradation and enhanced viral RNA replication and virion biogenesis. In addition, the function of ALPP in ZIKV infection depends on its phosphatase activity. Furthermore, we demonstrated that ALPP was stabilized through interactions with BIP, which is the endoplasmic reticulum (ER)-resident heat shock protein 70 chaperone. The chaperone activity of BIP promoted ZIKV infection and mediated the interaction between ALPP and ZIKV proteins. Collectively, our findings reveal a previously unrecognized mechanism through which ALPP facilitates ZIKV replication by coordinating with the BIP protein. IMPORTANCE ZIKV is a recently emerged mosquito-borne flavivirus that can cause devastating congenital Zika syndrome in pregnant women and Guillain-Barré syndrome in adults, but how ZIKV specifically targets the placenta is not well understood. Here, we identified an alkaline phosphatase (ALPP) that is expressed primarily in placental tissue and promotes ZIKV infection by colocalizing with ZIKV proteins and preventing their proteasome-mediated degradation. The phosphatase activity of ALPP could be required for optimal ZIKV infection, and ALPP is stabilized by BIP via its chaperone activity. This report provides novel insights into host factors required for ZIKV infection, which potentially has implications for ZIKV infection of the placenta.

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“…In line with this, peripheral blood mononuclear cells were identified as important cellular targets of American ZIKV strain infection, and for promoting ZIKV spread 39 . It is important to note that astrocytes are functional elements in the BBB, thus these cells can contribute to propagation and progress of ZIKV infection, causing injury of neural cells through direct infection-induced and/or indirect immune-mediated mechanisms 40 – 42 .…”

Section: Discussionmentioning

confidence: 99%

Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats

Bobermin

Quincozes‐Santos

Santos

et al. 2020

Sci Rep

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Zika virus (ZIKV) infection during pregnancy was associated with microcephaly in neonates, but clinical and experimental evidence indicate that ZIKV also causes neurological complications in adults. However, the changes in neuron-glial communication, which is essential for brain homeostasis, are still unknown. Here, we report that hippocampal slices from adult rats exposed acutely to ZIKV showed significant cellular alterations regarding to redox homeostasis, inflammatory process, neurotrophic functions and molecular signalling pathways associated with neurons and glial cells. Our findings support the hypothesis that ZIKV is highly neurotropic and its infection readily induces an inflammatory response, characterized by an increased expression and/or release of pro-inflammatory cytokines. We also observed changes in neural parameters, such as adenosine receptor A2a expression, as well as in the release of brain-derived neurotrophic factor and neuron-specific enolase, indicating plasticity synaptic impairment/neuronal damage. In addition, ZIKV induced a glial commitment, with alterations in specific and functional parameters such as aquaporin 4 expression, S100B secretion and glutathione synthesis. ZIKV also induced p21 senescence-associated gene expression, indicating that ZIKV may induce early senescence. Taken together, our results indicate that ZIKV-induced neuroinflammation, involving nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NFκB) pathways, affects important aspects of neuron-glia communication. Therefore, although ZIKV infection is transient, long-term consequences might be associated with neurological and/or neurodegenerative diseases.

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The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

Cited by 91 publications

References 46 publications

Zika Induces Human Placental Damage and Inflammation

Zika Induces Human Placental Damage and Inflammation

Placental Alkaline Phosphatase Promotes Zika Virus Replication by Stabilizing Viral Proteins through BIP

Zika virus exposure affects neuron-glia communication in the hippocampal slices of adult rats

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