scholarly journals A Zika virus primary isolate induces neuroinflammation, compromises the blood‐brain barrier and upregulates CXCL12 in adult macaques

2020 ◽  
Vol 30 (6) ◽  
pp. 1017-1027 ◽  
Author(s):  
Antonito T. Panganiban ◽  
Robert V. Blair ◽  
Julian B. Hattler ◽  
Diana G. Bohannon ◽  
Myrna C. Bonaldo ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Zika Virus ◽  
Brain Barrier ◽  
Primary Isolate ◽  
Blood Brain

scholarly journals Selective Disruption of the Blood–Brain Barrier by Zika Virus

2019 ◽  
Vol 10 ◽  
Author(s):  
Ana Rachel Leda ◽  
Luc Bertrand ◽  
Ibolya Edit Andras ◽  
Nazira El-Hage ◽  
Madhavan Nair ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Zika Virus ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Megan C. Mladinich ◽  
John Schwedes ◽  
Erich R. Mackow
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Zika Virus ◽  
Brain Barrier ◽  
Viral Reservoir ◽  
Zikv Infection ◽  
Viral Spread ◽  
Blood Brain ◽  
Neuronal Compartments

ABSTRACT Zika virus (ZIKV) is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB) to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC) lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59) persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs), without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α) and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7), IRF9, and IFN-stimulated genes (ISGs) 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV) persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread. IMPORTANCE ZIKV persists in patients, crossing placental and neuronal barriers, damaging neurons, and causing fetal microencephaly. We found that ZIKV persistently infects brain endothelial cells that normally protect neurons from viral exposure. hBMECs are not damaged by ZIKV infection and, analogous to persistent HCV infection, ZIKV constitutively induces and evades antiviral ISG and IFN responses to continuously replicate in hBMECs. As a result, hBMECs provide a protective niche for systemic ZIKV spread and a viral reservoir localized in the normally protective blood-brain barrier. Consistent with the spread of ZIKV into neuronal compartments, ZIKV was released basolaterally from hBMECs. Our findings define hBMEC responses that contribute to persistent ZIKV infection and potential targets for clearing ZIKV infections from hBMECs. These results further suggest roles for additional ZIKV-infected ECs to facilitate viral spread and persistence in the protected placental, retinal, and testicular compartments.

scholarly journals Zika virus crosses an in vitro human blood brain barrier model

2018 ◽  
Vol 15 (1) ◽  
Author(s):  
Judie B. Alimonti ◽  
Maria Ribecco-Lutkiewicz ◽  
Caroline Sodja ◽  
Anna Jezierski ◽  
Danica B. Stanimirovic ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Human Blood ◽  
Zika Virus ◽  
Brain Barrier ◽  
Blood Brain ◽  
Blood Brain Barrier Model ◽  
Barrier Model

scholarly journals Skeletal muscle is an early site of Zika virus replication and injury impairing myogenesis

2021 ◽  
Author(s):  
Daniel Gavino-Leopoldino ◽  
Camila Menezes Figueiredo ◽  
Mariana Oliveira Lopes da Silva ◽  
Letícia Gonçalves Barcellos ◽  
Rômulo Leão Silva Neris ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Zika Virus ◽  
Muscle Development ◽  
Brain Barrier ◽  
Zikv Infection ◽  
Viral Spread ◽  
Blood Brain

Zika virus (ZIKV) infection became a worldwide concern due to its correlation with the development of microcephaly and other neurological disorders. ZIKV neurotropism is well characterized, but the role of peripheral viral amplification to brain infection remains unknown. Here we found that ZIKV replicates in human primary skeletal muscle myoblasts, impairing its differentiation into myotubes but not interfering with the integrity of the already formed muscle fibers. Using mouse models, we showed ZIKV tropism to muscle tissue either during embryogenesis after maternal transmission or when infection occurred after birth. Interestingly, ZIKV replication in the mouse skeletal muscle started immediately after ZIKV inoculation, preceding viral RNA detection in the brain and causing no disruption to the integrity of the blood brain barrier, and remained active for more than two weeks, while replication in spleen and liver were not sustained over time. In addition, ZIKV infection of the skeletal muscle induces necrotic lesions, inflammation and fiber atrophy. We also found a reduction in the expression of regulatory myogenic factors that are essential for muscle repair after injury. Taken together our results indicate that the skeletal muscle is an early site of viral amplification and lesion that may result in late consequences in muscle development after ZIKV infection. Importance Zika Virus (ZIKV) neurotropism and its deleterious effects on central nervous system have been well characterized. But, investigations of the initial replication sites for the establishment of infection and viral spread to neural tissues remain under explored. The complete description of the range of ZIKV induced lesions and others factors that can influence the severity of the disease are necessary to prevent ZIKV deleterious effects. ZIKV has been shown to access the central nervous system without significantly affecting blood-brain barrier permeability. Here we demonstrated that skeletal muscle is an earlier site of ZIKV replication, contributing to the increase of peripheral ZIKV load. ZIKV replication in muscle promotes necrotic lesions, inflammation and also impairs myogenesis. Overall, our findings showed that skeletal muscle is involved in pathogenesis and opens new fields in the investigation of the long-term consequence of early infection.

scholarly journals Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Marion Clé ◽  
Caroline Desmetz ◽  
Jonathan Barthelemy ◽  
Marie-France Martin ◽  
Orianne Constant ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Zika Virus ◽  
Immune Cell ◽  
Leukocyte Recruitment ◽  
Brain Barrier ◽  
Local Inflammation ◽  
Zikv Infection ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT The blood-brain barrier (BBB) largely prevents toxins and pathogens from accessing the brain. Some viruses have the ability to cross this barrier and replicate in the central nervous system (CNS). Zika virus (ZIKV) was responsible in 2015 to 2016 for a major epidemic in South America and was associated in some cases with neurological impairments. Here, we characterized some of the mechanisms behind its neuroinvasion using an innovative in vitro human BBB model. ZIKV efficiently replicated, was released on the BBB parenchyma side, and triggered subtle modulation of BBB integrity as well as an upregulation of inflammatory and cell adhesion molecules (CAMs), which in turn favored leukocyte recruitment. Finally, we showed that ZIKV-infected mouse models displayed similar CAM upregulation and that soluble CAMs were increased in plasma samples from ZIKV-infected patients. Our observations suggest a complex interplay between ZIKV and the BBB, which may trigger local inflammation, leukocyte recruitment, and possible cerebral vasculature impairment. IMPORTANCE Zika virus (ZIKV) can be associated with neurological impairment in children and adults. To reach the central nervous system, viruses have to cross the blood-brain barrier (BBB), a multicellular system allowing a tight separation between the bloodstream and the brain. Here, we show that ZIKV infects cells of the BBB and triggers a subtle change in its permeability. Moreover, ZIKV infection leads to the production of inflammatory molecules known to modulate BBB integrity and participate in immune cell attraction. The virus also led to the upregulation of cellular adhesion molecules (CAMs), which in turn favored immune cell binding to the BBB and potentially increased infiltration into the brain. These results were also observed in a mouse model of ZIKV infection. Furthermore, plasma samples from ZIKV-infected patients displayed an increase in CAMs, suggesting that this mechanism could be involved in neuroinflammation triggered by ZIKV.

Zika virus and the blood-brain barrier

2021 ◽  
pp. 209-220
Author(s):  
Rishya Manikam ◽  
Soe Hui Jen ◽  
Amni Adilah Ismail ◽  
Chandramathi Samudi Raju ◽  
Shamala Devi Sekaran
Keyword(s):  
Blood Brain Barrier ◽  
Zika Virus ◽  
Brain Barrier ◽  
Blood Brain

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

2020 ◽  
Vol 11 ◽  
Author(s):  
Chi-Fen Chiu ◽  
Li-Wei Chu ◽  
I-Chen Liao ◽  
Yogy Simanjuntak ◽  
Yi-Ling Lin ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Zika Virus ◽  
Brain Barrier ◽  
Placental Barrier ◽  
Blood Brain

scholarly journals A Zika Virus Primary Isolate Induces Neuroinflammation, Compromises the Blood-Brain Barrier, and Upregulates CXCL12 in Adult Macaques

2019 ◽  
Author(s):  
Antonito T. Panganiban ◽  
Robert V. Blair ◽  
Julian B. Hattler ◽  
Diana G. Bohannon ◽  
Myrna C. Bonaldo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Virus Infection ◽  
Brain Damage ◽  
Blood Brain Barrier ◽  
Zika Virus ◽  
Brain Inflammation ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System

AbstractZika virus (ZIKV) is a neurotropic virus that can cause neuropathy in adults and fetal neurologic malformation following infection of pregnant women. We used a nonhuman primate model, the Indian-origin Rhesus macaque (IRM), to gain insight into virus-associated hallmarks of ZIKV-induced adult neuropathy. We find that the virus causes prevalent acute and chronic neuroinflammation and chronic disruption of the blood-brain barrier (BBB) in adult animals. Infection results in significant, targeted, and sustained upregulation of the chemokine, CXCL12, in the central nervous system (CNS). CXCL12 plays a key role both in regulating lymphocyte trafficking through the BBB to the CNS, and in mediating repair of damaged neural tissue including remyelination. Understanding how CXCL12 expression is controlled will likely be of central importance in the definition of ZIKV-associated neuropathy in adults.Author summaryZika virus (ZIKV) is a virus that can cause neurological problems in adults and damage to the fetal brain. Nonhuman primates (NHPs) are usually superior animal models for recapitulating human neurological disease because their brain, nervous system structure and immune response to virus infection are very similar to that of humans. We have studied the effect of ZIKV infection on the adult NHP brain and made several significant observations. Infection resulted in a high incidence of mild to moderate brain inflammation that persisted for a surprisingly long period of time. We also found that the virus disrupted the blood brain barrier, which is important for controlling transport of material from blood to the brain. It appears that the central nervous system expresses a specific substance in response to virus infection called a chemokine. This specific chemokine may be involved in virus-induced inflammation and/or in repair of virus-induced brain damage. Our data are significant since they help in understanding the mechanism of brain damage caused by ZIKV in adults.

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