scholarly journals A Functional Role for Neutralizing Antibodies in Borna Disease: Influence on Virus Tropism outside the Central Nervous System

1998 ◽  
Vol 72 (11) ◽  
pp. 8884-8892 ◽  
Author(s):  
L. Stitz ◽  
K. Nöske ◽  
O. Planz ◽  
E. Furrer ◽  
W. I. Lipkin ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rna Virus ◽  
Passive Immunization ◽  
Cns Infection ◽  
Nervous Systems ◽  
Humoral Immune ◽  
Central Nervous Systems ◽  
The Central Nervous System ◽  
And Behavior ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a negative-strand RNA virus that infects the central nervous systems (CNS) of warm-blooded animals and causes disturbances of movement and behavior. The basis for neurotropism remains poorly understood; however, the observation that the distribution of infectious virus in immunocompetent rats is different from that in immunoincompetent rats indicates a role for the immune system in BDV tropism: whereas in immunocompetent rats virus is restricted to the central, peripheral, and autonomic nervous systems, immunoincompetent rats also have virus in nonneural tissues. In an effort to examine the influence of the humoral immune response on BDV pathogenesis, we examined the effects of passive immunization with neutralizing antiserum in immunoincompetent rats. Serum transfer into immunoincompetent rats did not prevent persistent CNS infection but did result in restriction of virus to neural tissues. These results indicate that neutralizing antibodies may play a role in preventing generalized infection with BDV.

scholarly journals Mechanisms of spreading depolarization in vertebrate and insect central nervous systems

2016 ◽  
Vol 116 (3) ◽  
pp. 1117-1127 ◽  
Author(s):  
Kristin E. Spong ◽  
R. David Andrew ◽  
R. Meldrum Robertson
Keyword(s):  
Locusta Migratoria ◽  
Model Systems ◽  
Control Mechanisms ◽  
Cellular Mechanisms ◽  
Nervous Systems ◽  
Spreading Depolarization ◽  
Metathoracic Ganglion ◽  
Evolutionarily Conserved ◽  
Central Nervous Systems ◽  
The Central Nervous System

Spreading depolarization (SD) is generated in the central nervous systems of both vertebrates and invertebrates. SD manifests as a propagating wave of electrical depression caused by a massive redistribution of ions. Mammalian SD underlies a continuum of human pathologies from migraine to stroke damage, whereas insect SD is associated with environmental stress-induced neural shutdown. The general cellular mechanisms underlying SD seem to be evolutionarily conserved throughout the animal kingdom. In particular, SD in the central nervous system of Locusta migratoria and Drosophila melanogaster has all the hallmarks of mammalian SD. Locust SD is easily induced and monitored within the metathoracic ganglion (MTG) and can be modulated both pharmacologically and by preconditioning treatments. The finding that the fly brain supports repetitive waves of SD is relatively recent but noteworthy, since it provides a genetically tractable model system. Due to the human suffering caused by SD manifestations, elucidating control mechanisms that could ultimately attenuate brain susceptibility is essential. Here we review mechanisms of SD focusing on the similarities between mammalian and insect systems. Additionally we discuss advantages of using invertebrate model systems and propose insect SD as a valuable model for providing new insights to mammalian SD.

scholarly journals The Analysis of B-Cell Epitopes of Influenza Virus Hemagglutinin

Acta Naturae ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 13-20 ◽  
Author(s):  
D. N. Shcherbinin ◽  
S. V. Alekseeva ◽  
M. M. Shmarov ◽  
Yu. A. Smirnov ◽  
B. S. Naroditskiy ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cell ◽  
Broad Spectrum ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
B Cell Epitopes ◽  
Humoral Immune ◽  
Influenza Virus Hemagglutinin ◽  
Long Time ◽  
Single Domain Antibodies

Vaccination has been successfully used to prevent influenza for a long time. Influenza virus hemagglutinin (HA), which induces a humoral immune response in humans and protection against the flu, is the main antigenic component of modern influenza vaccines. However, new seasonal and pandemic influenza virus variants with altered structures of HA occasionally occur. This allows the pathogen to avoid neutralization with antibodies produced in response to previous vaccination. Development of a vaccine with the new variants of HA acting as antigens takes a long time. Therefore, during an epidemic, it is important to have passive immunization agents to prevent and treat influenza, which can be monoclonal or single-domain antibodies with universal specificity (broad-spectrum agents). We considered antibodies to conserved epitopes of influenza virus antigens as universal ones. In this paper, we tried to characterize the main B-cell epitopes of hemagglutinin and analyze our own and literature data on broadly neutralizing antibodies. We conducted a computer analysis of the best known conformational epitopes of influenza virus HAs using materials of different databases. The analysis showed that the core of the HA molecule, whose antibodies demonstrate pronounced heterosubtypic activity, can be used as a target for the search for and development of broad-spectrum antibodies to the influenza virus.

scholarly journals Optimization of the Codon Pair Usage of Human Respiratory Syncytial Virus Paradoxically Resulted in Reduced Viral Replication In Vivo and Reduced Immunogenicity

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Cyril Le Nouën ◽  
Cindy L. Luongo ◽  
Lijuan Yang ◽  
Steffen Mueller ◽  
Eckard Wimmer ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Viral Replication ◽  
Virus Replication ◽  
Neutralizing Antibodies ◽  
Rna Virus ◽  
Humoral Immune ◽  
Codon Pair ◽  
Syncytial Virus ◽  
Codon Pairs

ABSTRACT We subjected various open reading frames (ORFs) in the genome of respiratory syncytial virus (RSV) to codon pair optimization (CPO) by increasing the content of codon pairs that are overrepresented in the human genome without changing overall codon usage and amino acid sequences. CPO has the potential to increase the expression of the encoded protein(s). Four viruses were made: Max A (with CPO of NS1, NS2, N, P, M, and SH ORFs), Max B (with CPO of G and F), Max L (with CPO of L), and Max FLC (with CPO of all ORFs except M2-1 and M2-2). Because of the possibility of increased viral replication, each CPO virus was attenuated by the inclusion of a codon deletion mutation (Δ1313) and a missense mutation (I1314L) in the L polymerase. CPO had no effect on multicycle virus replication in vitro, temperature sensitivity, or specific infectivity. Max A and L, which in common had CPO of one or more ORFs of proteins of the polymerase complex, exhibited global increases in viral protein synthesis. Max B alone exhibited decreased protein synthesis, and it alone had reduced single-cycle virus replication in vitro. All CPO RSVs exhibited marginal reductions in replication in mice and hamsters. Surprisingly, the CPO RSVs induced lower levels of serum RSV-neutralizing antibodies in hamsters. This reduced immunogenicity might reflect reduced viral replication and possibly also the decrease in CpG and UpA dinucleotides as immune stimulators. Overall, our study describes paradoxical effects of CPO of an RNA virus on viral replication and the adaptive humoral immune response. IMPORTANCE Using computer algorithms and large-scale DNA synthesis, one or more ORFs of a microbial pathogen can be recoded by different strategies that involve the introduction of up to thousands of nucleotide changes without affecting amino acid coding. This approach has been used mostly to generate deoptimized viruses used as vaccine candidates. However, the effects of the converse approach of generating optimized viruses are still largely unknown. Here, various ORFs in the genome of respiratory syncytial virus (RSV) were codon pair optimized (CPO) by increasing the content of codon pairs that are overrepresented in the human genome. CPO did not affect RSV replication in multicycle replication experiments in vitro. However, replication was marginally reduced in two rodents models. In hamsters, CPO RSVs induced lower levels of serum RSV-neutralizing antibodies. Thus, CPO of an RNA virus for a mammalian host has paradoxical effects on virus replication and the adaptive humoral immune response.

scholarly journals Borna Disease Virus Glycoprotein Is Required for Viral Dissemination in Neurons

2003 ◽  
Vol 77 (22) ◽  
pp. 12222-12231 ◽  
Author(s):  
Jeffrey J. Bajramovic ◽  
Sylvia Münter ◽  
Sylvie Syan ◽  
Ulf Nehrbass ◽  
Michel Brahic ◽  
...  
Keyword(s):  
Disease Virus ◽  
Hippocampal Neurons ◽  
Neutralizing Antibodies ◽  
Rna Virus ◽  
Primary Cultures ◽  
Viral Envelope ◽  
Borna Disease Virus ◽  
Viral Particles ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a nonsegmented negative-strand RNA virus with a tropism for neurons. Infection with BDV causes neurological diseases in a wide variety of animal species. Although it is known that the virus spreads from neuron to neuron, assembled viral particles have never been visualized in the brains of infected animals. This has led to the hypothesis that BDV spreads as nonenveloped ribonucleoproteins (RNP) rather than as enveloped viral particles. We assessed whether the viral envelope glycoprotein (GP) is required for neuronal dissemination of BDV by using primary cultures of rat hippocampal neurons. We show that upon in vitro infection, BDV replicated and spread efficiently in this system. Despite rapid virus dissemination, very few infectious viral particles were detectable in the culture. However, neutralizing antibodies directed against BDV-GP inhibited BDV spread. In addition, interference with BDV-GP processing by inhibiting furin-mediated cleavage of the glycoprotein blocked virus spread. Finally, antisense treatment with peptide nucleic acids directed against BDV-GP mRNA inhibited BDV dissemination, marking BDV-GP as an attractive target for antiviral therapy against BDV. Together, our results demonstrate that the expression and correct processing of BDV-GP are necessary for BDV dissemination in primary cultures of rat hippocampal neurons, arguing against the hypothesis that the virus spreads from neuron to neuron in the form of nonenveloped RNP.

Commitment of abdominal neuroblasts in Drosophila to a male or female fate is dependent on genes of the sex-determining hierarchy

Development ◽  
1992 ◽  
Vol 114 (3) ◽  
pp. 625-642 ◽  
Author(s):  
B.J. Taylor ◽  
J.W. Truman
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Larval Instar ◽  
Genetic Regulation ◽  
S Phase ◽  
Male And Female ◽  
Nervous Systems ◽  
Neuronal Stem Cells ◽  
Central Nervous Systems ◽  
The Central Nervous System

Adult specific neurons in the central nervous system of holometabolous insects are generated by the postembryonic divisions of neuronal stem cells (neuroblasts). In the ventral nervous system of Drosophila melanogaster, sex-specific divisions by a set of abdominal neuroblasts occur during larval and early pupal stages. Animals mutant for several sex-determining genes were analyzed to determine the genetic regulation of neuroblast commitment to the male or female pattern of division and the time during development when these decisions are made. We have found that the choice of the sexual pathway taken by sex-specific neuroblasts depends on the expression of one of these genes, doublesex (dsx). In the absence of any functional dxs+ products, the sex-specific neuroblasts fail to undergo any postembryonic divisions in male or female larval nervous systems. From the analysis of intersexes generated by dominant alleles of dsx, it has been concluded that the same neuroblasts provide the sex-specific neuroblasts in both male and female central nervous systems. The time when neuroblasts become committed to generate their sex-specific divisions were identified by shifting tra-2ts flies between the male- and female-specifying temperatures at various times during larval development. Neuroblasts become determined to adopt a male or female state at the end of the first larval instar, a time when abdominal neuroblasts enter their first postembryonic S-phase.

Theiler’s Virus Infection of Perforin-Deficient Mice

1998 ◽  
Vol 72 (5) ◽  
pp. 4515-4519 ◽  
Author(s):  
Claudia Pena Rossi ◽  
Andrés McAllister ◽  
Myriam Tanguy ◽  
David Kägi ◽  
Michel Brahic
Keyword(s):  
T Cells ◽  
Fas Ligand ◽  
Cytotoxic T Cells ◽  
Viral Rna ◽  
Theiler's Virus ◽  
Nervous Systems ◽  
Central Nervous Systems ◽  
The Central Nervous System ◽  
Infected Cells ◽  
Deficient Mice

ABSTRACT Theiler’s virus, a murine picornavirus, infects the central nervous systems of C57BL/6 mice and is cleared after approximately 10 days by a process which requires CD8+ cytotoxic T cells. We used perforin-deficient C57BL/6 mice to test the role of this protein in viral clearance. Perforin-deficient mice died from viral encephalomyelitis between days 12 and 18 postinoculation. They had high levels of viral RNA in their central nervous systems until the time of death. In contrast, viral RNA had disappeared by day 11 postinoculation in wild-type C57BL/6 mice. Cytotoxic T cells can kill infected cells by two main mechanisms: the secretion of the pore-forming protein perforin or the interaction of the Fas ligand with the apoptosis-inducing Fas molecule on the target cell. Our results demonstrate that clearance of Theiler’s virus from the central nervous system in C57BL/6 mice is perforin dependent.

scholarly journals Improved delivery of broadly neutralizing antibodies by nanocapsules suppresses SHIV infection in the CNS of infant rhesus macaques

2021 ◽  
Vol 17 (7) ◽  
pp. e1009738
Author(s):  
Jing Wen ◽  
Tracy Cheever ◽  
Lan Wang ◽  
Di Wu ◽  
Jason Reed ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Acute Infection ◽  
Cns Infection ◽  
Broadly Neutralizing Antibodies ◽  
Blood Concentrations ◽  
The Central Nervous System ◽  
Shiv Infection ◽  
Hiv 1 ◽  
Infant Rhesus

Broadly neutralizing antibodies (bNAbs) directed to HIV-1 have shown promise at suppressing viremia in animal models. However, the use of bNAbs for the central nervous system (CNS) infection is confounded by poor penetration of the blood brain barrier (BBB). Typically, antibody concentrations in the CNS are extremely low; with levels in cerebrospinal fluid (CSF) only 0.1% of blood concentrations. Using a novel nanotechnology platform, which we term nanocapsules, we show effective transportation of the human bNAb PGT121 across the BBB in infant rhesus macaques upon systemic administration up to 1.6% of plasma concentration. We demonstrate that a single dose of PGT121 encased in nanocapsules when delivered at 48h post-infection delays early acute infection with SHIVSF162P3 in infants, with one of four animals demonstrating viral clearance. Importantly, the nanocapsule delivery of PGT121 improves suppression of SHIV infection in the CNS relative to controls.

Brains as Engines of Association

2019 ◽  
Author(s):  
Dale Purves
Keyword(s):  
Neural Systems ◽  
Neural Function ◽  
Trial And Error ◽  
Nervous Systems ◽  
The Past ◽  
Sensing Systems ◽  
Lifetime Experience ◽  
Survival And Reproduction ◽  
Pros And Cons ◽  
And Behavior

Brains as Engines of Association seeks an operating principle of the human brain and is divided into four parts. The first part (“What Nervous Systems Do for Animals”) is intended to set the stage for understanding the emergence of neural systems as promoting what all organisms must accomplish: survival and reproduction. The second part (“Neural Systems as Engines of Association”) lays out the general argument that biological sensing systems face a daunting problem: they cannot measure the parameters of the world in the way physical instruments can. As a result, nervous systems must make and update associations (synaptic connections) on the basis of empirical success or failure over both evolutionary and individual time. The third part (“Evidence that Neural Systems Operate Empirically”) reviews evidence accumulated over the past 20 years that supports this interpretation in vision and audition, the sensory systems that have been most studied from this or any other perspective. Finally, the fourth part (“Alternative Concepts of Neural Function”) considers the pros and cons of other interpretations of how brains operate. The overarching theme is that the nervous systems of humans and every other animal operate on the basis associations between stimuli and behavior made by trial and error over species and lifetime experience.

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