Potential neuroprotective and anti-inflammatory effects provided by omega-3 (DHA) against Zika virus infection in human SH-SY5Y cells

AbstractZika virus (ZIKV) has a strong tropism for the nervous system and has been related to post-infection neurological syndromes. Once neuronal cells are infected, the virus is capable of modulating cell metabolism, leading to neurotoxicity and cellular death. The negative effect of ZIKV in neuron cells has been characterized. However, the description of molecules capable of reversing these cytotoxic effects is still under investigation. In this context, it has been largely demonstrated that docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, is highly neuroprotective. Here, we hypothesized that DHA’s neuroprotective proprieties could have an influence on ZIKV-induced neurotoxicity in SH-SY5Y cells. Our data showed that pre-treatment of SH-SY5Y cells with DHA increased the cell viability and proliferation in ZIKV-infected cells. Moreover, DHA triggered an anti-inflammatory response in those infected cells. Besides, DHA was capable of restoring mitochondria function and number in ZIKV-infected SH-SY5Y cells. In addition, cells pre-treated with DHA prior to ZIKV infection presented a lower viral load at different times of infection. Taking together, these results demonstrated that DHA has a potential anti-inflammatory and neuroprotective effect against ZIKV infection in these neuron-like cells and could be a useful tool in the treatment against this virus.

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Chloroquine inhibits Zika Virus infection in different cellular models

10.1101/051268 ◽

2016 ◽

Cited By ~ 10

Author(s):

Rodrigo Delvecchio ◽

Luiza M Higa ◽

Paula Pezzuto ◽

Ana Luiza Valadão ◽

Patrícia P Garcez ◽

...

Keyword(s):

Antiviral Activity ◽

Zika Virus ◽

Antiviral Agents ◽

Virus Production ◽

Congenital Defects ◽

Zikv Infection ◽

Cytotoxic Effects ◽

Cellular Models ◽

Infected Cells

SummaryZika virus (ZIKV) infectionin uteromight lead to microcephaly and other congenital defects. In adults, cases of Guillain-Barré syndrome and meningoencephalitis associated with ZIKV infection have been reported, and no specific therapy is available so far. There is urgency for the discovery of antiviral agents capable of inhibiting viral replication and its deleterious effects. Chloroquine is widely administered as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in VERO, human brain microvascular endothelial, and neural stem cells. We demonstratedin vitrothat chloroquine reduces the number of ZIKV-infected cells, virus production and cell death promoted by ZIKV infection without cytotoxic effects. Our results suggest that chloroquine is a promising candidate for ZIKV clinical trials, since it is already approved for clinical use and can be safely administered to pregnant woman.

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Palmitoleate Protects against Zika Virus-Induced Placental Trophoblast Apoptosis

Biomedicines ◽

10.3390/biomedicines9060643 ◽

2021 ◽

Vol 9 (6) ◽

pp. 643

Author(s):

Philma Glora Muthuraj ◽

Aryamav Pattnaik ◽

Prakash K. Sahoo ◽

Md Torikul Islam ◽

Asit K. Pattnaik ◽

...

Keyword(s):

Fatty Acid ◽

Er Stress ◽

Zika Virus ◽

Intrauterine Growth Restriction ◽

Maternal Circulation ◽

Zikv Infection ◽

Human Trophoblast ◽

Homologous Protein ◽

Stress Markers ◽

Infected Cells

Zika virus (ZIKV) infection in pregnancy is associated with the development of microcephaly, intrauterine growth restriction, and ocular damage in the fetus. ZIKV infection of the placenta plays a crucial role in the vertical transmission from the maternal circulation to the fetus. Our previous study suggested that ZIKV induces endoplasmic reticulum (ER) stress and apoptosis of placental trophoblasts. Here, we showed that palmitoleate, an omega-7 monounsaturated fatty acid, prevents ZIKV-induced ER stress and apoptosis in placental trophoblasts. Human trophoblast cell lines (JEG-3 and JAR) and normal immortalized trophoblasts (HTR-8) were used. We observed that ZIKV infection of the trophoblasts resulted in apoptosis and treatment of palmitoleate to ZIKV-infected cells significantly prevented apoptosis. However, palmitate (saturated fatty acid) did not offer protection from ZIKV-induced ER stress and apoptosis. We also observed that the Zika viral RNA copies were decreased, and the cell viability improved in ZIKV-infected cells treated with palmitoleate as compared to the infected cells without palmitoleate treatment. Further, palmitoleate was shown to protect against ZIKV-induced upregulation of ER stress markers, C/EBP homologous protein and X-box binding protein-1 splicing in placental trophoblasts. In conclusion, our studies suggest that palmitoleate protects placental trophoblasts against ZIKV-induced ER stress and apoptosis.

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Super Resolution Microscopy and Deep Learning Identify Zika Virus Reorganization of the Endoplasmic Reticulum

10.1101/2020.05.12.091611 ◽

2020 ◽

Author(s):

Rory K. M. Long ◽

Kathleen P. Moriarty ◽

Ben Cardoen ◽

Guang Gao ◽

A. Wayne Vogl ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Deep Learning ◽

Viral Replication ◽

Zika Virus ◽

Deep Neural Networks ◽

Super Resolution ◽

Zikv Infection ◽

Subcellular Organelle ◽

Infected Cells ◽

Super Resolution Microscopy

AbstractThe endoplasmic reticulum (ER) is a complex subcellular organelle composed of diverse structures such as tubules, sheets and tubular matrices. Flaviviruses such as Zika virus (ZIKV) induce reorganization of endoplasmic reticulum (ER) membranes to facilitate viral replication. Here, using 3D super resolution microscopy, ZIKV infection is shown to induce the formation of dense tubular matrices associated with viral replication in the central ER. Viral non-structural proteins NS4B and NS2B associate with replication complexes within the ZIKV-induced tubular matrix and exhibit distinct ER distributions outside this central ER region. Deep neural networks trained to identify ZIKV-infected versus mock-infected cells successfully identified ZIKV-induced central ER tubular matrices as a determinant of viral infection. Super resolution microscopy and deep learning are therefore able to identify and localize morphological features of the ER and may be of use to screen for inhibitors of infection by ER-reorganizing viruses.

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Zika virus is transmitted in neural progenitor cells via cell-to-cell spread and infection is inhibited by the autophagy inducer trehalose

Journal of Virology ◽

10.1128/jvi.02024-20 ◽

2020 ◽

pp. JVI.02024-20

Author(s):

Alex E Clark ◽

Zhe Zhu ◽

Florian Krach ◽

Jeremy N Rich ◽

Gene W. Yeo ◽

...

Keyword(s):

Viral Replication ◽

Progenitor Cells ◽

Zika Virus ◽

Neural Progenitor Cells ◽

Neutralizing Antibody ◽

Neural Progenitor ◽

Health Concern ◽

Free Virus ◽

Zikv Infection ◽

Infected Cells

Zika virus (ZIKV) is a mosquito-borne human pathogen that causes congenital Zika syndrome and neurological symptoms in some adults. There are currently no approved treatments or vaccines for ZIKV, and exploration of therapies targeting host processes could avoid viral development of drug resistance. The purpose of our study was to determine if the non-toxic and widely used disaccharide trehalose, which showed antiviral activity against Human Cytomegalovirus (HCMV) in our previous work, could restrict ZIKV infection in clinically relevant neural progenitor cells (NPCs). Trehalose is known to induce autophagy, the degradation and recycling of cellular components. Whether autophagy is proviral or antiviral for ZIKV is controversial and depends on cell type and specific conditions used to activate or inhibit autophagy. We show here that trehalose treatment of NPCs infected with recent ZIKV isolates from Panama and Puerto Rico significantly reduces viral replication and spread. In addition, we demonstrate that ZIKV infection in NPCs spreads primarily cell-to-cell as an expanding infectious center, and NPCs are infected via contact with infected cells far more efficiently than by cell-free virus. Importantly, ZIKV was able to spread in NPCs in the presence of neutralizing antibody.Importance Zika virus causes birth defects and can lead to neurological disease in adults. While infection rates are currently low, ZIKV remains a public health concern with no treatment or vaccine available. Targeting a cellular pathway to inhibit viral replication is a potential treatment strategy that avoids development of antiviral resistance. We demonstrate in this study that the non-toxic autophagy-inducing disaccharide trehalose reduces spread and output of ZIKV in infected neural progenitor cells (NPCs), the major cells infected in the fetus. We show that ZIKV spreads cell-to-cell in NPCs as an infectious center and that NPCs are more permissive to infection by contact with infected cells than by cell-free virus. We find that neutralizing antibody does not prevent the spread of the infection in NPCs. These results are significant in demonstrating anti-ZIKV activity of trehalose and in clarifying the primary means of Zika virus spread in clinically relevant target cells.

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Super resolution microscopy and deep learning identify Zika virus reorganization of the endoplasmic reticulum

Scientific Reports ◽

10.1038/s41598-020-77170-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rory K. M. Long ◽

Kathleen P. Moriarty ◽

Ben Cardoen ◽

Guang Gao ◽

A. Wayne Vogl ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Deep Learning ◽

Viral Replication ◽

Viral Infection ◽

Zika Virus ◽

Deep Neural Networks ◽

Super Resolution ◽

Zikv Infection ◽

Infected Cells ◽

Super Resolution Microscopy

AbstractThe endoplasmic reticulum (ER) is a complex subcellular organelle composed of diverse structures such as tubules, sheets and tubular matrices. Flaviviruses such as Zika virus (ZIKV) induce reorganization of ER membranes to facilitate viral replication. Here, using 3D super resolution microscopy, ZIKV infection is shown to induce the formation of dense tubular matrices associated with viral replication in the central ER. Viral non-structural proteins NS4B and NS2B associate with replication complexes within the ZIKV-induced tubular matrix and exhibit distinct ER distributions outside this central ER region. Deep neural networks trained to distinguish ZIKV-infected versus mock-infected cells successfully identified ZIKV-induced central ER tubular matrices as a determinant of viral infection. Super resolution microscopy and deep learning are therefore able to identify and localize morphological features of the ER and allow for better understanding of how ER morphology changes due to viral infection.

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Pregnant Women Infected with Zika Virus Show Higher Viral Load and Immunoregulatory Cytokines Profile with CXCL10 Increase

Viruses ◽

10.3390/v13010080 ◽

2021 ◽

Vol 13 (1) ◽

pp. 80

Author(s):

Elizabeth Camacho-Zavala ◽

Clara Santacruz-Tinoco ◽

Esteban Muñoz ◽

Rommel Chacón-Salinas ◽

Ma Isabel Salazar-Sanchez ◽

...

Keyword(s):

Viral Load ◽

Inflammatory Response ◽

Pregnant Women ◽

Inflammatory Cytokines ◽

Zika Virus ◽

Epidemiological Surveillance ◽

Congenital Defects ◽

Serum Samples ◽

Zikv Infection ◽

Anti Inflammatory

Background: Zika virus (ZIKV) infection during pregnancy usually shows only mild symptoms and is frequently subclinical. However, it can be vertically transmitted to the fetus, causing microcephaly and other congenital defects. During pregnancy, the immune environment modifications can alter the response to viruses in general and ZIKV in particular. Objective: To describe the role of pregnancy in the systemic pro- and anti-inflammatory response during symptomatic ZIKV infection. Materials and Methods: A multiplex assay was used to measure 25 cytokines, chemokines, and receptors in 110 serum samples from pregnant and nonpregnant women with and without ZIKV infection with and without symptoms. Samples were collected through an epidemiological surveillance system. Results: Samples from pregnant women with ZIKV infection showed a higher viral load but had similar profiles of inflammatory markers as compared with nonpregnant infected women, except for CXCL10 that was higher in infected pregnant women. Notably, the presence of ZIKV in pregnancy favored a regulatory profile by significantly increasing anti-inflammatory cytokines such as interleukin (IL)-10, receptors IL-1RA, and IL-2R, but only those pro-inflammatory cytokines such as IL-6, interferon (IFN)-α, IFN-γ and IL-17 that are essential for the antiviral response. Interestingly, there were no differences between symptomatic and weakly symptomatic ZIKV-infected groups. Conclusion: Our results revealed a systemic anti-inflammatory cytokine and chemokine profile that could participate in the control of the virus. The anti-inflammatory response in pregnant women infected with ZIKA was characterized by high CXCL10, a cytokine that has been correlated with congenital malformations.

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Decidual NK cells kill Zika virus–infected trophoblasts

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2115410118 ◽

2021 ◽

Vol 118 (47) ◽

pp. e2115410118

Author(s):

Sumit Sen Santara ◽

Ângela C. Crespo ◽

Sachin Mulik ◽

Cristian Ovies ◽

Selma Boulenouar ◽

...

Keyword(s):

Er Stress ◽

Natural Killer ◽

Zika Virus ◽

First Trimester ◽

Receptor Ligands ◽

Zikv Infection ◽

Pregnant Mice ◽

Infected Cells ◽

Spread Of Infection ◽

Cellular Immune

Zika virus (ZIKV) during pregnancy infects fetal trophoblasts and causes placental damage and birth defects including microcephaly. Little is known about the anti-ZIKV cellular immune response at the maternal–fetal interface. Decidual natural killer cells (dNK), which directly contact fetal trophoblasts, are the dominant maternal immune cells in the first-trimester placenta, when ZIKV infection is most hazardous. Although dNK express all the cytolytic molecules needed to kill, they usually do not kill infected fetal cells but promote placentation. Here, we show that dNK degranulate and kill ZIKV-infected placental trophoblasts. ZIKV infection of trophoblasts causes endoplasmic reticulum (ER) stress, which makes them dNK targets by down-regulating HLA-C/G, natural killer (NK) inhibitory receptor ligands that help maintain tolerance of the semiallogeneic fetus. ER stress also activates the NK activating receptor NKp46. ZIKV infection of Ifnar1−/− pregnant mice results in high viral titers and severe intrauterine growth restriction, which are exacerbated by depletion of NK or CD8 T cells, indicating that killer lymphocytes, on balance, protect the fetus from ZIKV by eliminating infected cells and reducing the spread of infection.

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Coordination of Zika Virus Infection and Viroplasm Organization by Microtubules and Microtubule-Organizing Centers

Cells ◽

10.3390/cells10123335 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3335

Author(s):

Rebecca A. Buchwalter ◽

Sarah C. Ogden ◽

Sara B. York ◽

Li Sun ◽

Chunfeng Zheng ◽

...

Keyword(s):

Zika Virus ◽

Infectious Virus ◽

Virus Production ◽

Health Concern ◽

Zikv Infection ◽

Virus Particles ◽

Microtubule Organizing Centers ◽

Infected Cells ◽

Congenital Microcephaly ◽

A Site

Zika virus (ZIKV) became a global health concern in 2016 due to its links to congenital microcephaly and other birth defects. Flaviviruses, including ZIKV, reorganize the endoplasmic reticulum (ER) to form a viroplasm, a compartment where virus particles are assembled. Microtubules (MTs) and microtubule-organizing centers (MTOCs) coordinate structural and trafficking functions in the cell, and MTs also support replication of flaviviruses. Here we investigated the roles of MTs and the cell’s MTOCs on ZIKV viroplasm organization and virus production. We show that a toroidal-shaped viroplasm forms upon ZIKV infection, and MTs are organized at the viroplasm core and surrounding the viroplasm. We show that MTs are necessary for viroplasm organization and impact infectious virus production. In addition, the centrosome and the Golgi MTOC are closely associated with the viroplasm, and the centrosome coordinates the organization of the ZIKV viroplasm toroidal structure. Surprisingly, viroplasm formation and virus production are not significantly impaired when infected cells have no centrosomes and impaired Golgi MTOC, and we show that MTs are anchored to the viroplasm surface in these cells. We propose that the viroplasm is a site of MT organization, and the MTs organized at the viroplasm are sufficient for efficient virus production.

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Zika Virus-Induced Neuronal Apoptosis via Increased Mitochondrial Fragmentation

Frontiers in Microbiology ◽

10.3389/fmicb.2020.598203 ◽

2020 ◽

Vol 11 ◽

Author(s):

Shu Yang ◽

Kirill Gorshkov ◽

Emily M. Lee ◽

Miao Xu ◽

Yu-Shan Cheng ◽

...

Keyword(s):

Cell Death ◽

Zika Virus ◽

Neuronal Apoptosis ◽

Mitochondrial Dynamics ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Mitochondrial Fragmentation ◽

Zikv Infection ◽

Mitofusin 2 ◽

Infected Cells

The 2015 to 2016 outbreak of Zika virus (ZIKV) infections in the Americas coincided with a dramatic increase in neurodevelopmental abnormalities, including fetal microcephaly, in newborns born to infected women. In this study, we observed mitochondrial fragmentation and disrupted mitochondrial membrane potential after 24 h of ZIKV infection in human neural stem cells and the SNB-19 glioblastoma cell line. The severity of these changes correlated with the amount of ZIKV proteins expressed in infected cells. ZIKV infection also decreased the levels of mitofusin 2, which modulates mitochondria fusion. Mitochondrial division inhibitor 1 (Mdivi-1), a small molecule inhibiting mitochondria fission, ameliorated mitochondria disruptions and reduced cell death in ZIKV-infected cells. Collectively, this study suggests that abnormal mitochondrial fragmentation contributes to ZIKV-induced neuronal cell death; rebalancing mitochondrial dynamics of fission-fusion could be a therapeutic strategy for drug development to treat ZIKV-mediated neuronal apoptosis.

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THE ROLE OF OXIDATIVE STRESS IN THE ETIOPATHOGENESIS OF DEPRESSION

Trakia Journal of Sciences ◽

10.15547/tjs.2019.01.013 ◽

2019 ◽

Vol 17 (1) ◽

pp. 81-93 ◽

Cited By ~ 1

Author(s):

D. Komsiiska ◽

Y. Petkov

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Central Nervous System ◽

Omega 3 Fatty Acids ◽

Omega 3 ◽

Cytotoxic Effects ◽

Negative Effect ◽

The Central Nervous System ◽

The Brain

In recent years, the role of oxidative stress in the etiopathogenesis of depression has been increasingly discussed. The mechanisms by which stress has a negative effect on the brain are not yet fully understood. Free radicals cause rapid damage to certain cellular macromolecules that may be involved in cytotoxic effects in the central nervous system. The effectiveness of new types of supplementation therapy with antioxidants - vitamins A, E, C, Omega-3 fatty acids, Coenzyme Q10 and Zn are being studied.

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