scholarly journals Interactions and Signal Transduction Pathways Involved during Central Nervous System Entry by Neisseria meningitidis across the Blood–Brain Barriers

2020 ◽  
Vol 21 (22) ◽  
pp. 8788
Author(s):  
Julia Borkowski ◽  
Horst Schroten ◽  
Christian Schwerk
Keyword(s):  
Signal Transduction ◽  
Central Nervous System ◽  
Nervous System ◽  
Neisseria Meningitidis ◽  
Severe Disease ◽  
Blood Stream ◽  
Brain Parenchyma ◽  
Host Cells ◽  
Signal Transduction Pathways ◽  
Blood Brain

The Gram-negative diplococcus Neisseria meningitidis, also called meningococcus, exclusively infects humans and can cause meningitis, a severe disease that can lead to the death of the afflicted individuals. To cause meningitis, the bacteria have to enter the central nervous system (CNS) by crossing one of the barriers protecting the CNS from entry by pathogens. These barriers are represented by the blood–brain barrier separating the blood from the brain parenchyma and the blood–cerebrospinal fluid (CSF) barriers at the choroid plexus and the meninges. During the course of meningococcal disease resulting in meningitis, the bacteria undergo several interactions with host cells, including the pharyngeal epithelium and the cells constituting the barriers between the blood and the CSF. These interactions are required to initiate signal transduction pathways that are involved during the crossing of the meningococci into the blood stream and CNS entry, as well as in the host cell response to infection. In this review we summarize the interactions and pathways involved in these processes, whose understanding could help to better understand the pathogenesis of meningococcal meningitis.

scholarly journals Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Blake H. Albright ◽  
Katherine E. Simon ◽  
Minakshi Pillai ◽  
Garth W. Devlin ◽  
Aravind Asokan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Sialic Acid ◽  
Blood Brain Barrier ◽  
Viral Vectors ◽  
Variable Region ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

ABSTRACT Central nervous system (CNS) transduction by systemically administered recombinant adeno-associated viral (AAV) vectors requires crossing the blood-brain barrier (BBB). We recently mapped a structural footprint on the AAVrh.10 capsid, which, when grafted onto the AAV1 capsid (AAV1RX), enables viral transport across the BBB; however, the underlying mechanisms remain unknown. Here, we establish through structural modeling that this footprint overlaps in part the sialic acid (SIA) footprint on AAV1. We hypothesized that altered SIA-capsid interactions may influence the ability of AAV1RX to transduce the CNS. Using AAV1 variants with altered SIA footprints, we map functional attributes of these capsids to their relative SIA dependence. Specifically, capsids with ablated SIA binding can penetrate and transduce the CNS with low to moderate efficiency. In contrast, AAV1 shows strong SIA dependency and does not transduce the CNS after systemic administration and, instead, transduces the vasculature and the liver. The AAV1RX variant, which shows an intermediate SIA binding phenotype, effectively enters the brain parenchyma and transduces neurons at levels comparable to the level of AAVrh.10. In corollary, the reciprocal swap of the AAV1RX footprint onto AAVrh.10 (AAVRX1) attenuated CNS transduction relative to that of AAVrh.10. We conclude that the composition of residues within the capsid variable region 1 (VR1) of AAV1 and AAVrh.10 profoundly influences tropism, with altered SIA interactions playing a partial role in this phenotype. Further, we postulate a Goldilocks model, wherein optimal glycan interactions can influence the CNS transduction profile of AAV capsids. IMPORTANCE Understanding how viruses cross the blood-brain barrier can provide insight into new approaches to block infection by pathogens or the ability to exploit these pathways for designing new recombinant viral vectors for gene therapy. In this regard, modulation of virus-carbohydrate interactions by mutating the virion shell can influence the ability of recombinant viruses to cross the vascular barrier, enter the brain, and enable efficient gene transfer to neurons.

scholarly journals Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gabriela C Olivera ◽  
Emily C Ross ◽  
Christiane Peuckert ◽  
Antonio Barragan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Cortical Capillaries ◽  
The Brain

The cellular barriers of the central nervous system proficiently protect the brain parenchyma from infectious insults. Yet, the single-celled parasite Toxoplasma gondii commonly causes latent cerebral infection in humans and other vertebrates. Here, we addressed the role of the cerebral vasculature in the passage of T. gondii to the brain parenchyma. Shortly after inoculation in mice, parasites mainly localized to cortical capillaries, in preference over post-capillary venules, cortical arterioles or meningeal and choroidal vessels. Early invasion to the parenchyma (days 1-5) occurred in absence of a measurable increase in blood-brain barrier (BBB) permeability, perivascular leukocyte cuffs or hemorrhage. However, sparse focalized permeability elevations were detected adjacently to replicative parasite foci. Further, T. gondii triggered inflammatory responses in cortical microvessels and endothelium. Pro- and anti-inflammatory treatments of mice with LPS and hydrocortisone, respectively, impacted BBB permeability and parasite loads in the brain parenchyma. Finally, pharmacological inhibition or Cre/loxP conditional knockout of endothelial focal adhesion kinase (FAK), a BBB intercellular junction regulator, facilitated parasite translocation to the brain parenchyma. The data reveal that the initial passage of T. gondii to the central nervous system occurs principally across cortical capillaries. The integrity of the microvascular BBB restricts parasite transit, which conversely is exacerbated by the inflammatory response.

scholarly journals The diverse cellular responses of the choroid plexus during infection of the central nervous system

2018 ◽  
Vol 314 (2) ◽  
pp. C152-C165 ◽  
Author(s):  
Alexa N. Lauer ◽  
Tobias Tenenbaum ◽  
Horst Schroten ◽  
Christian Schwerk
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Choroid Plexus ◽  
Inflammatory Cell ◽  
Regulation Of Gene Expression ◽  
Immunological Response ◽  
Cellular Responses ◽  
Host Cells ◽  
Signal Transduction Pathways ◽  
The Central Nervous System

The choroid plexus (CP) is responsible for the production of a large amount of the cerebrospinal fluid (CSF). As a highly vascularized structure, the CP also presents a significant frontier between the blood and the central nervous system (CNS). To seal this border, the epithelium of the CP forms the blood-CSF barrier, one of the most important barriers separating the CNS from the blood. During the course of infectious disease, cells of the CP can experience interactions with intruding pathogens, especially when the CP is used as gateway for entry into the CNS. In return, the CP answers to these encounters with diverse measures. Here, we will review the distinct responses of the CP during infection of the CNS, which include engaging of signal transduction pathways, the regulation of gene expression in the host cells, inflammatory cell response, alterations of the barrier, and, under certain circumstances, cell death. Many of these actions may contribute to stage an immunological response against the pathogen and subsequently help in the clearance of the infection.

scholarly journals Central nervous system delivery of molecules across the blood-brain barrier

2021 ◽  
pp. 104952
Author(s):  
Fabien Gosselet ◽  
Rodrigo Azevedo Loiola ◽  
Anna Roig ◽  
Anna Rosell ◽  
Maxime Culot
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain
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