scholarly journals Life-long persistence of infectious Zika virus: inflammation and behavioral sequela

2020 ◽  
Author(s):  
Derek D.C. Ireland ◽  
Mohanraj Manangeeswaran ◽  
Aaron Lewkowicz ◽  
Kaliroi Engel ◽  
Sarah M. Clark ◽  
...  
Keyword(s):  
Zika Virus ◽  
Post Infection ◽  
Late Pregnancy ◽  
Congenital Defects ◽  
Low Grade ◽  
Mrna Levels ◽  
Neurodevelopmental Disease ◽  
Behavioral Monitoring ◽  
In Pregnancy

AbstractThe recent spread of Zika virus (ZIKV) and its association with congenital defects and neurological disorders has created an urgent need to understand the pathogenesis of ZIKV and identify therapeutic strategies that will prevent or eliminate them. The neurodevelopmental defects associated with ZikV infections early in pregnancy are well documented, however the potential defects associated with infections in late pregnancy and perinatal period are less well characterized. Further, the long-term sequelae of these infections are not fully understood. Immunocompetent C57BL/6 mice infected at one day old (P1), which neurodevelopmentally model late pregnancy in humans, develop a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10-15 days post-infection (dpi) but symptoms subside after a week, and most animals survive. Despite apparent recovery, MRI of convalescent mice shows reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80, Il-1α, and Ifn-γ together with Cd3, Cd8 and perforin (PrfA), suggested the persistence of a low-grade inflammatory process. Further, the brain parenchyma of convalescent mice harbor multiple small foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and replication of virus derived from these convalescent mice by blinded passage in Vero cells confirmed that low levels of live ZikV persist in CNS of convalescent mice life-long. Our studies establish that Zika can establish reservoirs in CNS and suggest that anti-viral treatment that clears virus from the CNS as well as long-term neurological and behavioral monitoring may be needed for patients known to be exposed to ZikV at an early age.Author’s summaryThe congenital brain malformations associated with ZikV infections early in pregnancy are well documented, however whether apparently asymptomatic perinatal exposure could lead to long term sequelae is not fully understood. Using a non-lethal neonatal mouse model, we examine host-pathogen interactions, anatomical changes and behavioral patterns by following survivors of the acute infection for over 1 year. We discover that infectious Zika virus has the potential to remain in the CNS for life, lodged within small foci surrounded by gliosis and infiltrating immune cells that may act to limit the viral spread, but also interfere with healing and contribute to life-long neuropathic and behavioral sequelae. These results suggest that anti-viral treatment and long-term neurological and behavioral monitoring may be indicated for patients known to have been exposed to Zika virus, regardless of neurodevelopmental disease severity.

scholarly journals Long-term persistence of infectious Zika virus: Inflammation and behavioral sequela in mice

2020 ◽  
Vol 16 (12) ◽  
pp. e1008689
Author(s):  
Derek D. C. Ireland ◽  
Mohanraj Manangeeswaran ◽  
Aaron P. Lewkowicz ◽  
Kaliroi Engel ◽  
Sarah M. Clark ◽  
...  
Keyword(s):  
Post Infection ◽  
Late Pregnancy ◽  
Vero Cells ◽  
Perinatal Period ◽  
Low Grade ◽  
Mrna Levels ◽  
Long Term Effects ◽  
Asymptomatic Children ◽  
Sense Strand

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10–15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80, Il-1α, and Ifn-γ together with Cd3, Cd8 and perforin (PrfA), suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.

scholarly journals Zika Virus Infects Human Placental Mast Cells and the HMC-1 Cell Line, and Triggers Degranulation, Cytokine Release and Ultrastructural Changes

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 975 ◽  
Author(s):  
Kíssila Rabelo ◽  
Antônio José da Silva Gonçalves ◽  
Luiz José de Souza ◽  
Anna Paula Sales ◽  
Sheila Maria Barbosa de Lima ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Line ◽  
Zika Virus ◽  
Post Infection ◽  
Immune Cell ◽  
Cell Types ◽  
Ultrastructural Changes ◽  
Congenital Defects ◽  
Zikv Infection ◽  
Intracellular Changes

Zika virus (ZIKV) is an emergent arthropod-borne virus whose outbreak in Brazil has brought major public health problems. Infected individuals have different symptoms, including rash and pruritus, which can be relieved by the administration of antiallergics. In the case of pregnant women, ZIKV can cross the placenta and infect the fetus leading to congenital defects. We have identified that mast cells in the placentae of patients who had Zika during pregnancy can be infected. This led to our investigation on the possible role of mast cells during a ZIKV infection, using the HMC-1 cell line. We analyzed their permissiveness to infection, release of mediators and ultrastructural changes. Flow cytometry detection of ZIKV-NS1 expression 24 h post infection in 45.3% of cells showed that HMC-1 cells are permissive to ZIKV infection. Following infection, β-hexosaminidase was measured in the supernatant of the cells with a notable release at 30 min. In addition, an increase in TNF-α, IL-6, IL-10 and VEGF levels were measured at 6 h and 24 h post infection. Lastly, different intracellular changes were observed in an ultrastructural analysis of infected cells. Our findings suggest that mast cells may represent an important source of mediators that can activate other immune cell types during a ZIKV infection, which has the potential to be a major contributor in the spread of the virus in cases of vertical transmission.

scholarly journals Cognition in pregnancy and motherhood: prospective cohort study

2010 ◽  
Vol 196 (2) ◽  
pp. 126-132 ◽  
Author(s):  
Helen Christensen ◽  
Liana S. Leach ◽  
Andrew Mackinnon
Keyword(s):  
Cohort Study ◽  
Prospective Cohort ◽  
Late Pregnancy ◽  
Cognitive Change ◽  
Biased Sampling ◽  
Cognitive Deterioration ◽  
Negative Findings ◽  
In Pregnancy

BackgroundResearch has reported that pregnant women and mothers become forgetful. However, in these studies, women are not recruited prior to pregnancy, samples are not representative and studies are underpowered.AimsThe current study sought to determine whether pregnancy and motherhood are associated with brief or long-term cognitive deterioration using a representative sample and measuring cognition during and before the onset of pregnancy and motherhood.MethodWomen aged 20–24 years were recruited prospectively and assessed in 1999, 2003 and 2007. Seventy-six women were pregnant at follow-up assessments, 188 became mothers between study waves and 542 remained nulliparous.ResultsNo significant differences in cognitive change were found as a function of pregnancy or motherhood, although late pregnancy was associated with deterioration on one of four tests of memory and cognition.ConclusionsThe hypothesis that pregnancy and motherhood are associated with persistent cognitive deterioration was not supported. Previous negative findings may be a result of biased sampling.

Convulsion in a Pregnant Woman

2017 ◽  
Author(s):  
Eudocia Q. Lee
Keyword(s):  
Brain Tumors ◽  
Multidisciplinary Approach ◽  
Medical Oncology ◽  
Low Grade ◽  
Chemotherapeutic Drugs ◽  
Maternal Fetal Medicine ◽  
Ethical Implications ◽  
Patient Gender ◽  
In Pregnancy

The management and treatment of brain tumors is the same regardless of patient gender, except when considering fertility and pregnancy. Fortunately, brain tumors are rare during pregnancy. Because the lives of the mother and the fetus may be at risk, the care of pregnant women with brain tumors has ethical implications and requires a multidisciplinary approach involving obstetrics, maternal-fetal medicine, neurosurgery, anesthesiology, neurology, medical oncology, and radiation oncology. Chemotherapy and radiation are generally considered incompatible with normal fetal development. Only a few chemotherapeutic drugs have been tested in pregnancy, and therefore most are considered contraindicated during pregnancy. Radiation can have long-term implications for the fetus, including increased risks of cancer and mental retardation. This chapter will review the management of low-grade gliomas in pregnancy.

scholarly journals The Small-Conductance Ca2+-Activated Potassium Channel, Subtype SK3, in the Human Myometrium Is Downregulated in Early Stages of Pregnancy

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
M. Rahbek ◽  
S. T. Rosenbaum ◽  
M. J. Dahl ◽  
D. A. Klaerke ◽  
L. Ødum ◽  
...  
Keyword(s):  
Immunohistochemical Staining ◽  
Late Pregnancy ◽  
Human Myometrium ◽  
Mrna Levels ◽  
Sk Channels ◽  
Uterine Smooth Muscle ◽  
Qrt Pcr ◽  
Endometrial Epithelium ◽  
Small Conductance ◽  
In Pregnancy

The human myometrium is mainly relaxed during pregnancy, but, up to term, contractions become more coordinated and forceful in order to initiate delivery. Small conductance Ca2+-activated K+ channels (SK channels) in human myometrium have been shown to be downregulated in late pregnancy. The aim was to investigate the presence of SK2 and SK3 in the human myometrium from nonpregnant women, pregnant women at term, and pregnancies delivered preterm and, in addition, to characterize the time of downregulation of these channels. Using qRT-PCR, we observed significantly lower levels of mRNA for SK2 than for SK3 in the nonpregnant tissue. The mRNA levels of SK3 were significantly reduced in tissue from pregnancies at term and pregnancies resulting in preterm deliveries, whereas no downregulation for SK2 was observed. Western blotting confirmed the qRT-PCR results. Using immunohistochemical staining, both SK2 and SK3 were detected in endometrial glandular epithelium. We conclude that SK3 mRNA is downregulated early in pregnancy—at least among those that result in preterm deliveries. Furthermore, we find that SK channels are expressed not only in the uterine smooth muscle but also in the endometrial epithelium.

scholarly journals Zika Virus

2020 ◽  
Author(s):  
Marciano Paes ◽  
Kíssila Rabelo
Keyword(s):  
Mast Cells ◽  
Zika Virus ◽  
Post Infection ◽  
Immune Cell ◽  
Cell Types ◽  
Ultrastructural Changes ◽  
Congenital Defects ◽  
Zikv Infection ◽  
Flow Cytometry Detection ◽  
Intracellular Changes

Zika virus (ZIKV) is an emergent arthropod-borne virus whose outbreak in Brazil has brought major public health problems. Infected individuals have different symptoms, including rash and pruritus, which can be relieved by the administration of antiallergics. In the case of pregnant women, ZIKV can cross the placenta and infect the fetus leading to congenital defects. We have identified that mast cells in the placentae of patients who had Zika during pregnancy can be infected. This led to our investigation on the possible role of mast cells during a ZIKV infection, using the HMC-1 cell line. We analyzed their permissiveness to infection, release of mediators and ultrastructural changes. Flow cytometry detection of ZIKV-NS1 expression 24h post infection in 45.3% of cells showed that HMC-1 cells are permissive to ZIKV infection. Following infection, β-hexosaminidase was measured in the supernatant of the cells with a notable release at 30 min. In addition, an increase in TNF-α, IL-6, IL-10 and VEGF levels were measured at 6h and 24h post infection. Lastly, different intracellular changes were observed in an ultrastructural analysis of infected cells. Our findings suggest that mast cells may represent an important source of mediators that can activate other immune cell types during a ZIKV infection, which has the potential to being a major contributor in the spread of the virus in cases of vertical transmission.

scholarly journals SSRIs and SNRIs (SRI) in Pregnancy: Effects on the Course of Pregnancy and the Offspring: How Far Are We from Having All the Answers?

2019 ◽  
Vol 20 (10) ◽  
pp. 2370 ◽  
Author(s):  
Asher Ornoy ◽  
Gideon Koren
Keyword(s):  
Maternal Depression ◽  
Language Impairment ◽  
Late Pregnancy ◽  
Autism Spectrum ◽  
Motor Delay ◽  
Adverse Neonatal Outcomes ◽  
Neonatal Adaptation ◽  
And Function ◽  
In Pregnancy

Serotonin has important roles in the development of the brain and other organs. Manipulations of synaptic serotonin by drugs such as serotonin reuptake inhibitors (SRI) or serotonin norepinephrine reuptake inhibitors (SNRI) might alter their development and function. Of interest, most studies on the outcome of prenatal exposure to SRI in human have not found significant embryonic or fetal damage, except for a possible, slight increase in cardiac malformations. In up to a third of newborns exposed to SRI, exposure may induce transient neonatal behavioral changes (poor neonatal adaptation) and increased rate of persistent pulmonary hypertension. Prenatal SRI may also cause slight motor delay and language impairment but these are transient. The data on the possible association of prenatal SRIs with autism spectrum disorder (ASD) are inconsistent, and seem to be related to pre-pregnancy treatment or to maternal depression. Prenatal SRIs also appear to affect the hypothalamic hypophyseal adrenal (HPA) axis inducing epigenetic changes, but the long-term consequences of these effects on humans are as yet unknown. SRIs are metabolized in the liver by several cytochrome P450 (CYP) enzymes. Faster metabolism of most SRIs in late pregnancy leads to lower maternal concentrations, and thus potentially to decreased efficacy which is more prominent in women that are rapid metabolizers. Studies suggest that the serotonin transporter SLC6A4 promoter is associated with adverse neonatal outcomes after SRI exposure. Since maternal depression may adversely affect the child’s development, one has to consider the risk of SRI discontinuation on the fetus and the child. As with any drug treatment in pregnancy, the benefits to the mother should be considered versus the possible hazards to the developing embryo/fetus.

Efficient Co-Harvesting of Solar Energy and Low-Grade Heat by Molecular Photoswitches for High Energy Density, Long-Term Stable Solar Thermal Battery

2019 ◽  
Author(s):  
Zhao-Yang Zhang ◽  
Tao LI
Keyword(s):  
Energy Density ◽  
Solar Energy ◽  
High Performance ◽  
High Energy ◽  
Solar Thermal ◽  
High Energy Density ◽  
Low Grade ◽  
Thermal Battery ◽  
Low Grade Heat

Solar energy and ambient heat are two inexhaustible energy sources for addressing the global challenge of energy and sustainability. Solar thermal battery based on molecular switches that can store solar energy and release it as heat has recently attracted great interest, but its development is severely limited by both low energy density and short storage stability. On the other hand, the efficient recovery and upgrading of low-grade heat, especially that of the ambient heat, has been a great challenge. Here we report that solar energy and ambient heat can be simultaneously harvested and stored, which is enabled by room-temperature photochemical crystal-to-liquid transitions of small-molecule photoswitches. The two forms of energy are released together to produce high-temperature heat during the reverse photochemical phase change. This strategy, combined with molecular design, provides high energy density of 320-370 J/g and long-term storage stability (half-life of about 3 months). On this basis, we fabricate high-performance, flexible film devices of solar thermal battery, which can be readily recharged at room temperature with good cycling ability, show fast rate of heat release, and produce high-temperature heat that is >20<sup> o</sup>C higher than the ambient temperature. Our work opens up a new avenue to harvest ambient heat, and demonstrate a feasible strategy to develop high-performance solar thermal battery.

Efficient Co-Harvesting of Solar Energy and Low-Grade Heat by Molecular Photoswitches for High Energy Density, Long-Term Stable Solar Thermal Battery

2019 ◽  
Author(s):  
Zhao-Yang Zhang ◽  
Tao LI
Keyword(s):  
Energy Density ◽  
Solar Energy ◽  
High Performance ◽  
High Energy ◽  
Solar Thermal ◽  
High Energy Density ◽  
Low Grade ◽  
Thermal Battery ◽  
Low Grade Heat

Solar energy and ambient heat are two inexhaustible energy sources for addressing the global challenge of energy and sustainability. Solar thermal battery based on molecular switches that can store solar energy and release it as heat has recently attracted great interest, but its development is severely limited by both low energy density and short storage stability. On the other hand, the efficient recovery and upgrading of low-grade heat, especially that of the ambient heat, has been a great challenge. Here we report that solar energy and ambient heat can be simultaneously harvested and stored, which is enabled by room-temperature photochemical crystal-to-liquid transitions of small-molecule photoswitches. The two forms of energy are released together to produce high-temperature heat during the reverse photochemical phase change. This strategy, combined with molecular design, provides high energy density of 320-370 J/g and long-term storage stability (half-life of about 3 months). On this basis, we fabricate high-performance, flexible film devices of solar thermal battery, which can be readily recharged at room temperature with good cycling ability, show fast rate of heat release, and produce high-temperature heat that is >20<sup> o</sup>C higher than the ambient temperature. Our work opens up a new avenue to harvest ambient heat, and demonstrate a feasible strategy to develop high-performance solar thermal battery.

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