scholarly journals Retrograde, Transneuronal Spread of Pseudorabies Virus in Defined Neuronal Circuitry of the Rat Brain Is Facilitated by gE Mutations That Reduce Virulence

1999 ◽  
Vol 73 (5) ◽  
pp. 4350-4359 ◽  
Author(s):  
M. Yang ◽  
J. P. Card ◽  
R. S. Tirabassi ◽  
R. R. Miselis ◽  
L. W. Enquist
Keyword(s):  
Brain Stem ◽  
Rat Brain ◽  
Pseudorabies Virus ◽  
Animal Species ◽  
Wild Type ◽  
Neuronal Circuitry ◽  
Brain Infection ◽  
Virion Envelope ◽  
The Brain ◽  
Stomach Musculature

ABSTRACT The pseudorabies virus (PRV) gE gene encodes a multifunctional membrane protein found in infected cell membranes and in the virion envelope. Deletion of the gE gene results in marked attenuation of the virus in almost every animal species tested that is permissive for PRV. A common inference is that gE mutants are less virulent because they have reduced ability to spread from cell to cell; e.g., gE mutants infect fewer cells and, accordingly, animals live longer. In this report, we demonstrate that this inference does not hold in a rat experimental model for virus invasion of the brain. We find that animals infected with gE mutants live longer despite extensive retrograde, transneuronal spread of virus in the rat brain. In this model of brain infection, virus is injected into the stomach musculature and virions spread to the brain in long axons of brain stem neurons that give rise to the tenth cranial nerve (the vagus). The infection then spreads from neuron to neuron in well-defined, and physically separated, areas of the brain involved in autonomic regulation of the viscera. We examined the progression of infection of five PRV strains in this circuitry: the wild-type PRV-Becker strain, the attenuated PRV-Bartha vaccine strain, and three gE mutants isogenic with the PRV-Becker strain. By 60 to 67 h after infection, all PRV-Becker-infected animals were dead. Analysis of Becker-infected rats killed prior to virus-induced death demonstrated that the virus had established an infection only in the primary vagal neurons connected directly to the stomach and synaptically linked neurons in the immediate vicinity of the caudal brain stem. There was little spread to other neurons in the vagus circuitry. In contrast, rats infected with PRV-Bartha or PRV-Becker gE mutants survived to at least 96 h and exhibited few overt signs of disease. Despite this long survival and the lack of symptoms, brains of animals sacrificed at this time revealed extensive transsynaptic infection not only of the brain stem but also of areas of the forebrain synaptically linked to neurons in the brain stem. This finding provides evidence that the gE protein plays a role in promoting symptoms of infection and death in animals that is independent of neuron-to-neuron spread during brain infection. When this early virulence function is not active, animals live longer, resulting in more extensive spread of virus in the brain.

scholarly journals Transneuronal tracing of neural pathways that regulate hindlimb muscle blood flow

2007 ◽  
Vol 292 (4) ◽  
pp. R1532-R1541 ◽  
Author(s):  
T.-K. Lee ◽  
J. H. Lois ◽  
J. H. Troupe ◽  
T. D. Wilson ◽  
B. J. Yates
Keyword(s):  
Blood Flow ◽  
Brain Stem ◽  
Pseudorabies Virus ◽  
Muscle Blood Flow ◽  
Ventrolateral Medulla ◽  
Cell Group ◽  
Sympathetic Outflow ◽  
Survival Times ◽  
Left And Right ◽  
The Brain

Despite considerable interest in the neural mechanisms that regulate muscle blood flow, the descending pathways that control sympathetic outflow to skeletal muscles are not adequately understood. The present study mapped these pathways through the transneuronal transport of two recombinant strains of pseudorabies virus (PRV) injected into the gastrocnemius muscles in the left and right hindlimbs of rats: PRV-152 and PRV-BaBlu. To prevent PRV from being transmitted to the brain stem via motor circuitry, a spinal transection was performed just below the L2 level. Infected neurons were observed bilaterally in all of the areas of the brain that have previously been shown to contribute to regulating sympathetic outflow: the medullary raphe nuclei, rostral ventrolateral medulla (RVLM), rostral ventromedial medulla, A5 adrenergic cell group region, locus coeruleus, nucleus subcoeruleus, and the paraventricular nucleus of the hypothalamus. The RVLM, the brain stem region typically considered to play the largest role in regulating muscle blood flow, contained neurons infected following the shortest postinoculation survival times. Approximately half of the infected RVLM neurons were immunopositive for tyrosine hydroxylase, indicating that they were catecholaminergic. Many (47%) of the RVLM neurons were dually infected by the recombinants of PRV injected into the left and right hindlimb, suggesting that the central nervous system has a limited capacity to independently regulate blood flow to left and right hindlimb muscles.

scholarly journals Susceptibility of CCR5-Deficient Mice to Genital Herpes Simplex Virus Type 2 Is Linked to NK Cell Mobilization

2007 ◽  
Vol 81 (8) ◽  
pp. 3704-3713 ◽  
Author(s):  
Manoj Thapa ◽  
William A. Kuziel ◽  
Daniel J. J. Carr
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Herpes Simplex ◽  
Nk Cells ◽  
Brain Stem ◽  
Nk Cell ◽  
Wild Type ◽  
Simplex Virus ◽  
The Brain

ABSTRACT Following genital herpes simplex virus type 2 (HSV-2) exposure, NK cells and T cells are mobilized to sites of infection to control viral replication and spread. The present investigation sought to determine the role of the chemokine receptor CCR5 in this process. Mice deficient in CCR5 (CCR5−/−) displayed a significant reduction in cumulative survival following infection in comparison to wild-type, HSV-2-infected controls. Associated with decreased resistance to viral infection, CCR5−/− mice yielded significantly more virus and expressed higher levels of tumor necrosis factor alpha, CXCL1, CCL2, CCL3, and CCL5 in the vagina, spinal cord, and/or brain stem than did wild-type mice. Whereas there was no difference in absolute number of leukocytes (CD45high), CD4 T cells, or CD8 T cells residing in the draining lymph nodes, spleen, spinal cord, or brain stem comparing HSV-2-infected wild-type to CCR5−/− mice prior to or after infection, there were significantly more NK cells (NK1.1+ CD3−) residing in the brain stem and spleen of infected wild-type mice. Functionally, NK activity from cells isolated from the brain stem of HSV-2-infected wild-type mice was greater than that from HSV-2-infected CCR5−/− mice. In addition, antibody-mediated depletion of NK cells resulted in an increase in HSV-2 levels in the vaginal, spinal cord, and brain stem tissue of wild-type but not CCR5−/− mice. Collectively, the absence of CCR5 expression significantly impacts the ability of the host to control genital HSV-2 infection, inflammation, and spread associated with a specific reduction in NK cell expansion, infiltration, and activity in the nervous system.

Superior Laryngeal Nerve Brain Stem Evoked Response in the Cat

1997 ◽  
Vol 106 (2) ◽  
pp. 101-108 ◽  
Author(s):  
Young-Ho Kim ◽  
Kwang-Moon Kim ◽  
Won Pyo Hong ◽  
Hong Yoon Kim
Keyword(s):  
Brain Stem ◽  
Animal Species ◽  
Near Field ◽  
Superior Laryngeal Nerve ◽  
Laryngeal Nerve ◽  
Evoked Response ◽  
Internal Branch ◽  
Brain Stem Evoked Response ◽  
The Waves ◽  
The Brain

The generator sources of each wave of the laryngeal brain stem evoked response (LBR) have yet to be precisely demonstrated, although this has been studied in several animal species. This study was carried out to record the near-field brain stem activity as well as the far-field brain stem activity in the cat under the same experimental setup, and to search for the generator sources of the waves. Under general anesthesia, the LBR tracings were recorded adjacent to and within the brain stem following direct electrical stimulation of the internal branch of the superior laryngeal nerve. Reproducible positive and negative waves were detected by the far- and near-field techniques. Mean latencies, configurations, and reproducibility of each wave were demonstrated. From these results, we speculate on the generator sources of each wave.

Aromaticl-amino acid decar☐ylase in the rat brain: Immunocytochemical localization in neurons of the brain stem

Neuroscience ◽  
1984 ◽  
Vol 11 (3) ◽  
pp. 691-713 ◽  
Author(s):  
C.B. Jaeger ◽  
D.A. Ruggiero ◽  
V.R. Albert ◽  
D.H. Park ◽  
T.H. Joh ◽  
...  
Keyword(s):  
Amino Acid ◽  
Brain Stem ◽  
Rat Brain ◽  
Immunocytochemical Localization ◽  
The Brain

scholarly journals Peripheral Immunization Blocks Lethal Actions of Vesicular Stomatitis Virus within the Brain

2009 ◽  
Vol 83 (22) ◽  
pp. 11540-11549 ◽  
Author(s):  
Koray Ozduman ◽  
Guido Wollmann ◽  
Sebastian A. Ahmadi ◽  
Anthony N. van den Pol
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Direct Injection ◽  
Neurological Impairment ◽  
Wild Type ◽  
Recombinant Viruses ◽  
Brain Infection ◽  
Vesicular Stomatitis ◽  
Attenuated Viruses ◽  
The Brain ◽  
Prototype Virus

ABSTRACT Vesicular stomatitis virus (VSV) is the prototype virus for 75 or more negative-strand RNA viruses in the rhabdovirus family. Some of these viruses, including VSV, can cause neurological impairment or death upon brain infection. VSV has shown promise in the prevention and treatment of disease as a vaccine vector and an oncolytic virus, but infection of the brain remains a concern. Three VSV variants, the wild-type-related VSV-G/GFP and two attenuated viruses, VSV-CT1 and VSV-CT9-M51, were compared for neuroinvasiveness and neuromorbidity. In nonimmunized mice, direct VSV-G/GFP injection into the brain invariably resulted in lethal encephalitis; in contrast, partial survival was seen after direct injection of the attenuated VSV strains. In addition, both attenuated VSV strains showed significantly reduced neuroinvasiveness after intranasal inoculation of young postnatal day 16 mice. Of the three tested variants, VSV-CT9-M51 generated the lowest degree of neuropathology. Despite its attenuated state, peripheral inoculations of VSV-CT9-M51 targeted and killed human glioblastoma implanted into the mouse brain. Importantly, we show here that intranasal or intramuscular immunization prevents the lethal effects of subsequent VSV-G/GFP, VSV-CT1, and VSV-CT9-M51 injections into the brain. These results indicate that attenuated recombinant viruses show reduced neurovirulence and that peripheral immunization blocks the lethal actions of all VSVs tested.

scholarly journals Infectivity of a Pseudorabies Virus Mutant Lacking Attachment Glycoproteins C and D

1998 ◽  
Vol 72 (9) ◽  
pp. 7341-7348 ◽  
Author(s):  
Axel Karger ◽  
Jerg Schmidt ◽  
Thomas C. Mettenleiter
Keyword(s):  
Receptor Binding ◽  
Pseudorabies Virus ◽  
Cell Clone ◽  
Plaque Formation ◽  
Wild Type ◽  
Virion Protein ◽  
Gene Encoding ◽  
Mdbk Cells ◽  
Virion Envelope ◽  
Virus Mutant

ABSTRACT Initiation of herpesvirus infection requires attachment of virions to the host cell followed by fusion of virion envelope and cellular cytoplasmic membrane during penetration. In several alphaherpesviruses, glycoprotein C (gC) is the primary attachment protein, interacting with cell-surface heparan sulfate proteoglycans. Secondary binding is mediated by gD, which, normally, is also required for penetration. Recently, we described the isolation of a gD-negative infectious pseudorabies virus (PrV) mutant, PrV gD− Pass (J. Schmidt, B. G. Klupp, A. Karger, and T. C. Mettenleiter, J. Virol. 71:17–24, 1997). In PrV gD− Pass, attachment and penetration occur in the absence of gD. To assess the importance of specific attachment for infectivity of PrV gD− Pass, the gene encoding gC was deleted, resulting in mutant PrV gCD− Pass. Deletion of both known attachment proteins reduced specific infectivity compared to wild-type PrV by more than 10,000-fold. Surprisingly, the virus mutant still retained significant infectivity and could be propagated on normal noncomplementing cells, indicating the presence of another receptor-binding virion protein. Selection of bovine kidney (MDBK) cells resistant to infection by PrV gCD− Pass resulted in the isolation of a cell clone, designated NB, which was susceptible to infection by wild-type PrV but refractory to infection by either PrV gCD− Pass or PrV gD− Pass, a defect which could partially be overcome by polyethylene glycol (PEG)-induced membrane fusion. However, even after PEG-induced infection plaque formation of PrV gCD− Pass or PrV gD− Pass did not ensue in NB cells. Also, phenotypic gD complementation of PrV gCD− Pass or PrV gD−Pass rescued the defect in infection of NB cells but did not restore plaque formation. Glycosaminoglycan analyses of MDBK and NB cells yielded identical results, and NB cells were normally susceptible to infection by other alphaherpesviruses as well as vesicular stomatitis virus. Infectious center assays after PEG-induced infection of NB cells with PrV gD− Pass on MDBK cells indicated efficient exit of virions from infected NB cells. Together, our data suggest the presence of another receptor and receptor-binding virion protein which can mediate PrV entry and cell-to-cell spread in MDBK cells.

Autoradiographic localization of opiate receptors in rat brain. II. The brain stem

1977 ◽  
Vol 129 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Samir F. Atweh ◽  
Michael J. Kuhar
Keyword(s):  
Brain Stem ◽  
Rat Brain ◽  
Opiate Receptors ◽  
The Brain

Neuroanatomic organization of the parasympathetic bronchomotor system in developing sheep

1997 ◽  
Vol 273 (1) ◽  
pp. R121-R133 ◽  
Author(s):  
J. J. Perez Fontan ◽  
C. R. Velloff
Keyword(s):  
Brain Stem ◽  
Pseudorabies Virus ◽  
Respiratory Muscles ◽  
Ventrolateral Medulla ◽  
Solitary Tract ◽  
Preganglionic Neurons ◽  
Vagal Innervation ◽  
Ventral Medullary Surface ◽  
Trachealis Muscle ◽  
The Brain

We applied two complementary retrograde labeling techniques to characterize the organization of the brain stem neuronal network responsible for the vagal innervation of the trachealis muscle in developing sheep. Single neuronal labeling produced by injections of the beta-subunit of cholera toxin into the muscle in newborn lambs showed that airway vagal preganglionic neurons are located exclusively in the nucleus ambiguous and nucleus of the solitary tract. Transneuronal labeling produced by similar injections of the Bartha strain of the pseudorabies virus in sheep fetuses demonstrated that these airway vagal preganglionic neurons receive inputs from a small number of neurons in brain stem areas known to participate in premotor control of the respiratory muscles (ventral respiratory group), chemoreception (nucleus of the solitary tract and ventral medullary surface), and cardiovascular and respiratory regulation (raphe nuclei, ventrolateral medulla, and noradrenergic groups of the medulla and pons). We conclude that the vagal preganglionic neurons that project to airway smooth muscle are already integrated in the control of breathing before birth in sheep.

scholarly journals Function of Torsin AAA+ ATPases in Pseudorabies Virus Nuclear Egress

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 738
Author(s):  
Julia E. Hölper ◽  
Barbara G. Klupp ◽  
G. W. Gant Luxton ◽  
Kati Franzke ◽  
Thomas C. Mettenleiter
Keyword(s):  
Nuclear Membrane ◽  
Pseudorabies Virus ◽  
Gene Knockout ◽  
Early Time ◽  
Wild Type ◽  
Mutant Proteins ◽  
Nuclear Egress ◽  
Cytoplasmic Transport ◽  
Virion Envelope ◽  
Aaa Atpases

Newly assembled herpesvirus nucleocapsids traverse the intact nuclear envelope by a vesicle-mediated nucleo-cytoplasmic transport for final virion maturation in the cytoplasm. For this, they bud at the inner nuclear membrane resulting in primary enveloped particles in the perinuclear space (PNS) followed by fusion of the primary envelope with the outer nuclear membrane (ONM). While the conserved viral nuclear egress complex orchestrates the first steps, effectors of fusion of the primary virion envelope with the ONM are still mostly enigmatic but might include cellular proteins like SUN2 or ESCRT-III components. Here, we analyzed the influence of the only known AAA+ ATPases located in the endoplasmic reticulum and the PNS, the Torsins (Tor), on nuclear egress of the alphaherpesvirus pseudorabies virus. For this overexpression of wild type and mutant proteins as well as CRISPR/Cas9 genome editing was applied. Neither single overexpression nor gene knockout (KO) of TorA or TorB had a significant impact. However, TorA/B double KO cells showed decreased viral titers at early time points of infection and an accumulation of primary virions in the PNS pointing to a delay in capsid release during nuclear egress.

scholarly journals Two Modes of Pseudorabies Virus Neuroinvasion and Lethality in Mice

2004 ◽  
Vol 78 (23) ◽  
pp. 12951-12963 ◽  
Author(s):  
Elizabeth E. Brittle ◽  
Ashley E. Reynolds ◽  
L. W. Enquist
Keyword(s):  
Nervous System ◽  
Immune Responses ◽  
Pseudorabies Virus ◽  
Infectious Virus ◽  
Skin Lesions ◽  
Cns Infection ◽  
Wild Type ◽  
Behavioral Abnormalities ◽  
Virulent Strains ◽  
The Brain

ABSTRACT We describe two distinct modes of neuroinvasion and lethality after murine flank inoculation with virulent and attenuated strains of pseudorabies virus (PRV). Mice infected with virulent (e.g., PRV-Becker, PRV-Kaplan, or PRV-NIA3) strains self-mutilate their flank skin in response to virally induced pruritus, die rapidly with no identifiable symptoms of central nervous system (CNS) infection such as behavioral abnormalities, and have little infectious virus or viral antigen in the brain. In distinct contrast, animals infected with an attenuated PRV vaccine strain (PRV-Bartha) survive approximately three times longer than wild-type PRV-infected animals, exhibit severe CNS abnormalities, and have an abundance of infectious virus in the brain at the time of death. Interestingly, these animals have no skin lesions and do not appear pruritic at any time during infection. The severe pruritus and relatively earlier time until death induced by wild-type PRV infection may reflect the peripheral nervous system (PNS) and immune responses to infection rather than a fatal, virally induced CNS pathology. Based on previously characterized afferent (sensory) and efferent (motor) neuronal pathways that innervate the skin, we deduced that wild-type virulent strains transit through the PNS via both afferent and efferent routes, whereas PRV-Bartha travels by only efferent routes in the PNS en route to the brain.

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