Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injuryin vitrothrough type I interferon signaling

ABSTRACT Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative strains also demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit (NVU), differentially rendering brain endothelial cells, pericytes, and astrocytes permissive to viral replication. Transmission and immunoelectron microscopy revealed early events in virus internalization and Cav-1 association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS and that IFN differentially restricts this process at the BBB. IMPORTANCE VEEV, WEEV, and eastern equine encephalitis virus (EEEV) are emerging infectious diseases in the Americas, and they have caused several major outbreaks in the human and horse population during the past few decades. Shortly after infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. Neuroinvasion has been associated with virus entry into the CNS directly from the bloodstream; however, the underlying molecular mechanisms have remained largely unknown. Here, we demonstrate that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPases within brain endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower viral burdens in the brain than in similarly infected wild-type animals. These studies identify a potentially targetable pathway to limit neuroinvasion by alphaviruses.

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Type II iodothyronine deiodinase protein in chicken choroid plexus: additional perspectives on T3 supply in the avian brain

Journal of Endocrinology ◽

10.1677/joe.1.05743 ◽

2004 ◽

Vol 183 (1) ◽

pp. 235-241 ◽

Cited By ~ 20

Author(s):

C H J Verhoelst ◽

V M Darras ◽

S A Roelens ◽

G M Artykbaeva ◽

S Van der Geyten

Keyword(s):

Epithelial Cells ◽

Choroid Plexus ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Type I ◽

Mrna Levels ◽

Type Ii ◽

Iodothyronine Deiodinase ◽

Blood Brain ◽

D2 Protein

It is widely accepted that type II iodothyronine deiodinase (D2) is mostly present in the brain, where it maintains the homeostasis of thyroid hormone (TH) levels. Although intensive studies have been performed on activity and mRNA levels of the deiodinases, very little is known about their expression at the protein level due to the lack of specific antisera. The current study reports the production of a specific D2 polyclonal antiserum and its use in the comparison of D2 protein distribution with that of type I (D1) and type III (D3) deiodinase protein in the choroid plexus at the blood–brain barrier level. Immunocytochemistry showed very high D2 protein expression in the choroid plexus, especially in the epithelial cells, whereas the D1 and D3 proteins were absent. Furthermore, dexamethasone treatment led to an up-regulation of the D2 protein in the choroid plexus. The expression of D2 protein in the choroid plexus led to a novel insight into the working mechanism of the uptake and transport of thyroid hormones along the blood–brain barrier in birds. It is hypothesized that D2 allows the prohormone thyroxine (T4) to be converted into the active 3,5,3′-triiodothyronine (T3). Within the choroidal epithelial cells. T3 is subsequently bound to its carrier protein, transthyretin (TTR), to allow transport through the cerebrospinal fluid. Neurons can thus not only be provided with a sufficient T3 level via the aid of the astrocytes, as was hypothesized previously based on in situ hybridization data, but also by means of T4 deiodination by D2, directly at the blood–brain barrier level.

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Non-clinical evaluation of a blood-brain barrier-penetrating enzyme for the treatment of mucopolysaccharidosis type I

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2018.12.205 ◽

2019 ◽

Vol 126 (2) ◽

pp. S83-S84

Author(s):

Sachiho Kida ◽

Masafumi Kinoshita ◽

Satowa Tanaka ◽

Miho Okumura ◽

Yuri Koshimura ◽

...

Keyword(s):

Blood Brain Barrier ◽

Clinical Evaluation ◽

Brain Barrier ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I ◽

Blood Brain

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The Blood-Brain Barrier Interface in Diabetes Mellitus: Dysfunctions, Mechanisms and Approaches to Treatment

Current Pharmaceutical Design ◽

10.2174/1381612826666200325110014 ◽

2020 ◽

Vol 26 (13) ◽

pp. 1438-1447 ◽

Cited By ~ 3

Author(s):

William A. Banks

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Growth Factor ◽

Matrix Metalloproteinases ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Type I ◽

Type Ii ◽

P Glycoprotein ◽

Blood Brain

Diabetes mellitus (DM) is one of the most common diseases in the world. Among its effects are an increase in the risk of cognitive impairment, including Alzheimer’s disease, and blood-brain barrier (BBB) dysfunction. DM is characterized by high blood glucose levels that are caused by either lack of insulin (Type I) or resistance to the actions of insulin (Type II). The phenotypes of these two types are dramatically different, with Type I animals being thin, with low levels of leptin as well as insulin, whereas Type II animals are often obese with high levels of both leptin and insulin. The best characterized change in BBB dysfunction is that of disruption. The brain regions that are disrupted, however, vary between Type I vs Type II DM, suggesting that factors other than hyperglycemia, perhaps hormonal factors such as leptin and insulin, play a regionally diverse role in BBB vulnerability or protection. Some BBB transporters are also altered in DM, including P-glycoprotein, lowdensity lipoprotein receptor-related protein 1, and the insulin transporter as other functions of the BBB, such as brain endothelial cell (BEC) expression of matrix metalloproteinases (MMPs) and immune cell trafficking. Pericyte loss secondary to the increased oxidative stress of processing excess glucose through the Krebs cycle is one mechanism that has shown to result in BBB disruption. Vascular endothelial growth factor (VEGF) induced by advanced glycation endproducts can increase the production of matrix metalloproteinases, which in turn affects tight junction proteins, providing another mechanism for BBB disruption as well as effects on P-glycoprotein. Through the enhanced expression of the redox-related mitochondrial transporter ABCB10, redox-sensitive transcription factor NF-E2 related factor-2 (Nrf2) inhibits BEC-monocyte adhesion. Several potential therapies, in addition to those of restoring euglycemia, can prevent some aspects of BBB dysfunction. Carbonic anhydrase inhibition decreases glucose metabolism and so reduces oxidative stress, preserving pericytes and blocking or reversing BBB disruption. Statins or N-acetylcysteine can reverse the BBB opening in some models of DM, fibroblast growth factor-21 improves BBB permeability through an Nrf2-dependent pathway, and nifedipine or VEGF improves memory in DM models. In summary, DM alters various aspects of BBB function through a number of mechanisms. A variety of treatments based on those mechanisms, as well as restoration of euglycemia, may be able to restore BBB functions., including reversal of BBB disruption.

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Blood Brain Barrier Breakdown Following Topical Aldara Treatment

10.14293/s2199-1006.1.sor-.ppzk5eg.v1 ◽

2020 ◽

Author(s):

Maria Suessmilch ◽

Julie-Myrtille Bourgognon ◽

Jonathan Cavanagh

Keyword(s):

Blood Brain Barrier ◽

Topical Application ◽

Immune Cell ◽

Hippocampal Neurogenesis ◽

The Body ◽

Brain Inflammation ◽

Brain Barrier ◽

Type I ◽

Blood Brain ◽

The Brain

Brain inflammation markers are present in several psychiatric and neurodegenerative disorders like major depressive disorder, Alzheimers disease and schizophrenia. Inflammation is also linked to sickness behaviour (social withdrawal, decreased appetite, impaired concentration, irritability), a mechanism by which the body redirects its resources to fight infection and encourage wound healing. The topical application of Aldara triggers systemic type I and II interferon and pro-inflammatory cytokine production, immune cell infiltration into the skin and hyperkeratosis and has been used as a model of psoriasis since 2009(1). We have recently reported that Imiquimod, the active component of Aldara, can enter the brain within 4 hours of topical application(2) and induces a transcriptional interferon and chemokine response in the brain, along with the infiltration of immune cells, a reduction in hippocampal neurogenesis and a reduction in burrowing behaviour(3). To allow us to understand the mechanisms of immune cell entry into the brain following topical Aldara treatment, we investigated blood brain barrier (BBB) integrity using a number of experimental techniques.

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miR-143 Regulates Lysosomal Enzyme Transport across the Blood-Brain Barrier and Transforms CNS Treatment for Mucopolysaccharidosis Type I

Molecular Therapy ◽

10.1016/j.ymthe.2020.06.011 ◽

2020 ◽

Vol 28 (10) ◽

pp. 2161-2176

Author(s):

Yi Lin ◽

Xiaohong Wang ◽

Kevin P. Rose ◽

Mei Dai ◽

Jingfen Han ◽

...

Keyword(s):

Blood Brain Barrier ◽

Lysosomal Enzyme ◽

Brain Barrier ◽

Type I ◽

Mucopolysaccharidosis Type ◽

Mucopolysaccharidosis Type I ◽

Blood Brain ◽

Enzyme Transport

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MRI phenotypes in MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000530 ◽

2019 ◽

Vol 6 (2) ◽

pp. e530 ◽

Cited By ~ 10

Author(s):

Christopher C. Hemond ◽

Brian C. Healy ◽

Shahamat Tauhid ◽

Maria A. Mazzola ◽

Francisco J. Quintana ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Lesion Volume ◽

Type I ◽

Type Ii ◽

Hyperintense Lesion ◽

Cross Sectional ◽

Type Iv ◽

Blood Brain ◽

Conversion Rates

ObjectiveTo classify and immunologically characterize persons with MS based on brain lesions and atrophy and their associated microRNA profiles.MethodsCerebral T2-hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) were quantified and used to define MRI phenotypes as follows: type I: low T2LV, low atrophy; type II: high T2LV, low atrophy; type III: low T2LV, high atrophy; type IV: high T2LV, high atrophy, in a large cross-sectional cohort (n = 1,088) and a subset with 5-year lngitudinal follow-up (n = 153). Serum miRNAs were assessed on a third MS cohort with 2-year MRI phenotype stability (n = 98).ResultsOne-third of the patients had lesion-atrophy dissociation (types II or III) in both the cross-sectional and longitudinal cohorts. At 5 years, all phenotypes had progressive atrophy (p < 0.001), disproportionally in type II (BPF −2.28%). Only type IV worsened in physical disability. Types I and II showed a 5-year MRI phenotype conversion rate of 33% and 46%, whereas III and IV had >90% stability. Type II switched primarily to IV (91%); type I switched primarily to II (47%) or III (37%). Baseline higher age (p = 0.006) and lower BPF (p < 0.001) predicted 5-year phenotype conversion. Each MRI phenotype demonstrated an miRNA signature whose underlying biology implicates blood-brain barrier pathology: hsa.miR.22.3p, hsa.miR.361.5p, and hsa.miR.345.5p were the most valid differentiators of MRI phenotypes.ConclusionsMRI-defined MS phenotypes show high conversion rates characterized by the continuation of either predominant neurodegeneration or inflammation and support the partial independence of these 2 measures. MicroRNA signatures of these phenotypes suggest a role for blood-brain barrier integrity.

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Viral Pathogen-Associated Molecular Patterns Regulate Blood-Brain Barrier Integrity via Competing Innate Cytokine Signals

mBio ◽

10.1128/mbio.01476-14 ◽

2014 ◽

Vol 5 (5) ◽

Cited By ~ 88

Author(s):

Brian P. Daniels ◽

David W. Holman ◽

Lillian Cruz-Orengo ◽

Harsha Jujjavarapu ◽

Douglas M. Durrant ◽

...

Keyword(s):

Pattern Recognition ◽

West Nile Virus ◽

Tight Junction ◽

Blood Brain Barrier ◽

Innate Immune ◽

Brain Barrier ◽

Type I ◽

West Nile ◽

Blood Brain ◽

Molecular Patterns

ABSTRACT Pattern recognition receptor (PRR) detection of pathogen-associated molecular patterns (PAMPs), such as viral RNA, drives innate immune responses against West Nile virus (WNV), an emerging neurotropic pathogen. Here we demonstrate that WNV PAMPs orchestrate endothelial responses to WNV via competing innate immune cytokine signals at the blood-brain barrier (BBB), a multicellular interface with highly specialized brain endothelial cells that normally prevents pathogen entry. While Th1 cytokines increase the permeability of endothelial barriers, type I interferon (IFN) promoted and stabilized BBB function. Induction of innate cytokines by pattern recognition pathways directly regulated BBB permeability and tight junction formation via balanced activation of the small GTPases Rac1 and RhoA, which in turn regulated the transendothelial trafficking of WNV. In vivo, mice with attenuated type I IFN signaling or IFN induction (Ifnar −/− Irf7 −/− ) exhibited enhanced BBB permeability and tight junction dysregulation after WNV infection. Together, these data provide new insight into host-pathogen interactions at the BBB during neurotropic viral infection. IMPORTANCE West Nile virus (WNV) is an emerging pathogen capable of infecting the central nervous system (CNS), causing fatal encephalitis. However, the mechanisms that control the ability of WNV to cross the blood-brain barrier (BBB) and access the CNS are unclear. In this study, we show that detection of WNV by host tissues induces innate immune cytokine expression at the BBB, regulating BBB structure and function and impacting transendothelial trafficking of WNV. This regulatory effect is shown to happen rapidly following exposure to virus, to occur independently of viral replication within BBB cells, and to require the signaling of cytoskeletal regulatory Rho GTPases. These results provide new understanding of host-pathogen interactions at the BBB during viral encephalitis.

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Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo

mBio ◽

10.1128/mbio.00819-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 31

Author(s):

Florian Douam ◽

Yentli E. Soto Albrecht ◽

Gabriela Hrebikova ◽

Evita Sadimin ◽

Christian Davidson ◽

...

Keyword(s):

Blood Brain Barrier ◽

Yellow Fever ◽

Vaccine Strain ◽

Brain Barrier ◽

Type I ◽

Type Iii ◽

Blood Brain ◽

Type Iii Ifn ◽

Type Iii Interferon

ABSTRACT Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR−/−) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR−/−) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR−/− λR−/− mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies. IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies.

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Exacerbated brain edema in a rat streptozotocin model of hyperglycemic ischemic stroke: Evidence for involvement of blood–brain barrier Na–K–Cl cotransport and Na/H exchange

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18770844 ◽

2018 ◽

Vol 39 (9) ◽

pp. 1678-1692 ◽

Cited By ~ 7

Author(s):

Natalie Y Yuen ◽

Olga V Chechneva ◽

Yi-Je Chen ◽

Yi-Chen Tsai ◽

Logan K Little ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Cerebral Edema ◽

Artery Occlusion ◽

Brain Barrier ◽

Microvascular Endothelial Cell ◽

Type I ◽

Edema Formation ◽

Blood Brain ◽

Na Uptake

Cerebral edema is exacerbated in diabetic ischemic stroke through poorly understood mechanisms. We showed previously that blood–brain barrier (BBB) Na–K–Cl cotransport (NKCC) and Na/H exchange (NHE) are major contributors to edema formation in normoglycemic ischemic stroke. Here, we investigated whether hyperglycemia-exacerbated edema involves changes in BBB NKCC and NHE expression and/or activity and whether inhibition of NKCC or NHE effectively reduces edema and injury in a type I diabetic model of hyperglycemic stroke. Cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundances and activities were determined by Western blot, radioisotopic flux and microspectrofluorometric methods. Cerebral edema and Na in rats subjected to middle cerebral artery occlusion (MCAO) were assessed by nuclear magnetic resonance methods. Hyperglycemia exposures of 1-7d significantly increased CMEC NKCC and NHE abundance and activity. Subsequent exposure to ischemic factors caused more robust increases in NKCC and NHE activities than in normoglycemic CMEC. MCAO-induced edema and brain Na uptake were greater in hyperglycemic rats. Intravenous bumetanide and HOE-642 significantly attenuated edema, brain Na uptake and ischemic injury. Our findings provide evidence that BBB NKCC and NHE contribute to increased edema in hyperglycemic stroke, suggesting that these Na transporters are promising therapeutic targets for reducing damage in diabetic stroke.

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