Synergistic Roles of Antibody and Interferon in Noncytolytic Clearance of Sindbis Virus from Different Regions of the Central Nervous System

ABSTRACT Sindbis virus (SINV) is an alphavirus that causes infection of neurons and encephalomyelitis in adult immunocompetent mice. Recovery can occur without apparent neurological damage. To better define the factors facilitating noncytolytic clearance of SINV in different regions of the central nervous system (CNS) and the roles of innate and adaptive immune responses at different times during infection, we have characterized SINV infection and clearance in the brain, brain stem, and spinal cords of severe combined immunodeficiency (SCID) and C57BL/6 (wild-type [WT]) mice and mice deficient in beta interferon (IFN-β) (BKO), antibody (μMT), IFN-γ (GKO), IFN-γ receptor (GRKO), and both antibody and IFN-γ (μMT/GKO). WT mice cleared infectious virus by day 8, while SCID mice had persistent virus replication at all sites. For 3 days after infection, BKO mice had higher titers at all sites than WT mice, despite similar IFN-α production, but cleared virus similarly. GKO and GRKO mice cleared infectious virus from all sites by days 8 to 10 and, like WT mice, displayed transient reactivation at 12 to 22 days. μMT mice did not clear virus from the brain, and clearance from the brain stem and lumbar spinal cord was delayed, followed by reactivation. Eighty-one days after infection, μMT/GKO mice had not cleared virus from any site, but titers were lower than for SCID mice. These studies show that IFN-β is independently important for early control of CNS virus replication, that antiviral antibody is critical for clearance from the brain, and that both antibody and IFN-γ contribute to prevention of reactivation after initial clearance.

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Visna-Maedi-Like Disease Associated with an Ovine Retrovirus Infection in a Corriedale Sheep

Veterinary Pathology ◽

10.1177/030098588001700503 ◽

1980 ◽

Vol 17 (5) ◽

pp. 544-552 ◽

Cited By ~ 11

Author(s):

W. D. Sheffield ◽

O. Narayan ◽

J. D. Strandberg ◽

R. J. Adams

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Stem ◽

Virus Replication ◽

Lymphoid Hyperplasia ◽

Cervical Cord ◽

Pathologic Examination ◽

The Central Nervous System ◽

Retrovirus Infection ◽

The Brain

A visna-maedi-like disease was found in a Corriedale sheep from which a retrovirus sharing the group antigen of visna-progressive pneumonia virus was isolated from lung, brain, and spleen. Clinically, the sheep had acute neurologic signs and dyspnea. Pathologic examination showed lesions similar to both visna and maedi. In the lung, there was a patchy interstitial pneumonia with marked lymphoid hyperplasia. Changes in the central nervous system were necrotizing nonsuppurative encephalitis of the brain stem, poliomyelitis of the cervical cord, and ependymitis and subependymal gliosis of the ventricles. Histologically, the central nervous system lesions seemed to have arisen sequentially, perhaps in response to bursts of virus replication as the agent underwent possible antigenic mutation. The severe lesions in both the central nervous system and lungs suggested a virus strain with dual tropism.

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NEUROLOGIC DISEASES IN INFANCY AND CHILDHOOD

PEDIATRICS ◽

10.1542/peds.19.5.949 ◽

1957 ◽

Vol 19 (5) ◽

pp. 949-957

Author(s):

William A. Hawke ◽

John S. Prichard

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Stem ◽

Developmental Patterns ◽

Basic Emotions ◽

Neurologic Diseases ◽

Neurologic Disorders ◽

Infancy And Childhood ◽

The Central Nervous System ◽

The Brain

THE SEMINAR was conducted in four 3-hour sessions and aimed to cover the more important features of pediatric neurology. DEVELOPMENT Dr. Hawke reviewed the normal development of the central nervous system in the infant and child which is so important in the assessment of neurologic disorders in this age group. It was noted that the nervous system was particularly immature and changing rapidly in the first 2 years of life. Development was related to myelination and it was emphasized that this was not a steady process but a pattern of sequences of rapid and slow growth. Motor and sensory development appeared to develop from above and to proceed downward, so that eye-control develops before hand- and legcontrol. Development was related to three functioning levels of the central nervous system—the brain stem, the archipallium, and the neopallium. It was observed that the newborn baby functioned at the brain stem level, and to illustrate this an example was given of the hydranencephalic baby which behaves perfectly normally for the first few weeks of life. The anchipallium, which includes part of the temporal lobe, the cingulate gyrus and basal ganglia, supervenes on the brain stem and may be considered responsible for the basic emotions and some primitive motor and sensory control. The neopallium, which includes most of the cerebral hemisphere, becomes dominant in primates. Its function is intellectual rather than emotional and is responsible for skills, discrimination and fine movements. The clinical application of these developmental patterns are innumerable but illustrations were given of changes in physical signs in static brain lesions.

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Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection

Journal of Virology ◽

10.1128/jvi.00143-15 ◽

2015 ◽

Vol 89 (10) ◽

pp. 5602-5614 ◽

Cited By ~ 95

Author(s):

Fang Li ◽

Yueyun Wang ◽

Lan Yu ◽

Shengbo Cao ◽

Ke Wang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Japanese Encephalitis Virus ◽

Inflammatory Cytokines ◽

Japanese Encephalitis ◽

Cytokines And Chemokines ◽

The Central Nervous System ◽

Ifn Γ ◽

Bbb Permeability ◽

The Brain

ABSTRACTJapanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage.In vitrostudies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB.IMPORTANCEJapanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate that JEV gains entry into the CNS prior to BBB disruption. Furthermore, it is not JEV infectionper se, but the inflammatory cytokines/chemokines induced by JEV infection that inhibit the expression of TJ proteins and ultimately result in the enhancement of BBB permeability. Neutralization of gamma interferon (IFN-γ) ameliorated the enhancement of BBB permeability in JEV-infected mice, suggesting that IFN-γ could be a potential therapeutic target. This study would lead to identification of potential therapeutic avenues for the treatment of JEV infection.

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The Innate Immune Adaptor Molecule MyD88 Restricts West Nile Virus Replication and Spread in Neurons of the Central Nervous System

Journal of Virology ◽

10.1128/jvi.01026-10 ◽

2010 ◽

Vol 84 (23) ◽

pp. 12125-12138 ◽

Cited By ~ 76

Author(s):

Kristy J. Szretter ◽

Stephane Daffis ◽

Jigisha Patel ◽

Mehul S. Suthar ◽

Robyn S. Klein ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

West Nile Virus ◽

Virus Replication ◽

Independent Effect ◽

Type I ◽

Rna Helicases ◽

West Nile ◽

The Central Nervous System ◽

The Brain

ABSTRACT Type I interferons (IFN-α/β) control viral infection by triggering the expression of genes that restrict transcription, translation, replication, and assembly. Many viruses induce IFN responses after recognition by cytoplasmic or endosomal RNA sensors (RIG-I-like RNA helicases [RLR] and Toll-like receptors [TLR]), which signal through the cognate adaptor signaling molecules IPS-1, TRIF, and MyD88. Recent studies have demonstrated that IPS-1-dependent induction of IFN-α/β downstream of RLR recognition restricts West Nile virus (WNV) infection in many cell types, whereas TRIF-dependent TLR3 signaling limits WNV replication in neurons. Here, we examined the contribution of MyD88 signaling to the control of WNV by evaluating IFN induction and virus replication in genetically deficient cells and mice. MyD88 − / − mice showed increased lethality after WNV infection and elevated viral burden primarily in the brain, even though little effect on the systemic type I IFN response was observed. Intracranial inoculation studies corroborated these findings, as WNV spread more rapidly in the central nervous system of MyD88 − / − mice, and this phenotype preceded the recruitment of inflammatory leukocytes. In vitro, increased WNV replication was observed in MyD88 − / − macrophages and subsets of neurons but not in myeloid dendritic cells. MyD88 had an independent effect on recruitment of monocyte-derived macrophages and T cells into the brain that was associated with blunted induction of the chemokines that attract leukocytes. Our experiments suggest that MyD88 restricts WNV by inhibiting replication in subsets of cells and modulating expression of chemokines that regulate immune cell migration into the central nervous system.

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Vagovagal reflex control of digestion: afferent modulation by neural and "endoneurocrine" factors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.268.1.g1 ◽

1995 ◽

Vol 268 (1) ◽

pp. G1-G10 ◽

Cited By ~ 24

Author(s):

R. C. Rogers ◽

D. M. McTigue ◽

G. E. Hermann

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Stem ◽

Neural Control ◽

Dorsal Vagal Complex ◽

The Central Nervous System ◽

Small Intestinal ◽

Reflex Control ◽

Control Circuits ◽

The Brain

Vagovagal reflex control circuits in the dorsal vagal complex of the brain stem provide overall coordination of gastric, small intestinal, and pancreatic digestive functions. The neural components forming these reflex circuits are under substantial descending neural control. By adjusting the excitability of the differing components of the reflex, significant alterations in digestion control can be produced by the central nervous system. Additionally, the dorsal vagal complex is situated within a circumventricular region without a "blood-brain barrier." As a result, vagovagal reflex circuitry is also exposed to humoral influences, which can profoundly alter digestive functions by acting directly on brain stem neurons.

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Differential Regulation of Interferon Regulatory Factor (IRF)-7 and IRF-9 Gene Expression in the Central Nervous System during Viral Infection

Journal of Virology ◽

10.1128/jvi.79.12.7514-7527.2005 ◽

2005 ◽

Vol 79 (12) ◽

pp. 7514-7527 ◽

Cited By ~ 49

Author(s):

Shalina S. Ousman ◽

Jianping Wang ◽

Iain L. Campbell

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

Viral Infection ◽

Mononuclear Cells ◽

Lymphocytic Choriomeningitis ◽

The Central Nervous System ◽

Ifn Γ ◽

The Brain ◽

Lcmv Infection

ABSTRACT Interferon regulatory factors (IRFs) are a family of transcription factors involved in the regulation of the interferons (IFNs) and other genes that may have an essential role in antiviral defense in the central nervous system, although this is currently not well defined. Therefore, we examined the regulation of IRF gene expression in the brain during viral infection. Several IRF genes (IRF-2, -3, -5, -7, and -9) were expressed at low levels in the brain of uninfected mice. Following intracranial infection with lymphocytic choriomeningitis virus (LCMV), expression of the IRF-7 and IRF-9 genes increased significantly by day 2. IRF-7 and IRF-9 gene expression in the brain was widespread at sites of LCMV infection, with the highest levels in infiltrating mononuclear cells, microglia/macrophages, and neurons. IRF-7 and IRF-9 gene expression was increased in LCMV-infected brain from IFN-γ knockout (KO) but not IFN-α/βR KO animals. In the brain, spleen, and liver or cultured glial and spleen cells, IRF-7 but not IRF-9 gene expression increased with delayed kinetics in the absence of STAT1 but not STAT2 following LCMV infection or IFN-α treatment, respectively. The stimulation of IRF-7 gene expression by IFN-α in glial cell culture was prevented by cycloheximide. Thus, (i) many of the IRF genes were expressed constitutively in the mouse brain; (ii) the IRF-7 and IRF-9 genes were upregulated during viral infection, a process dependent on IFN-α/β but not IFN-γ; and (iii) IRF-7 but not IRF-9 gene expression can be stimulated in a STAT1-independent but STAT2-dependent fashion via unidentified indirect pathways coupled to the activation of the IFN-α/β receptor.

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A Suspected New Storage Disease in Cattle

Veterinary Pathology ◽

10.1177/030098588201900604 ◽

1982 ◽

Vol 19 (6) ◽

pp. 616-622 ◽

Cited By ~ 6

Author(s):

W. J. Hartley ◽

R. F. Webb

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Stem ◽

Storage Disease ◽

Nerve Fibers ◽

Myelinated Nerve ◽

Myelinated Nerve Fibers ◽

The Central Nervous System ◽

Motor Columns ◽

The Brain

A suspected storage disease occurred in 50% of a group of five- to seven-month-old Hereford calves in one of four years following the same mating procedure. Lesions were confined to the central nervous system and consisted of multiple intraneuronal, cytoplasmic laminated cytosomes in restricted areas of the brain stem, together with extensive loss of myelinated nerve fibers in the motor columns of the cord.

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The effect of undernutrition on the postnatal development of the brain and cord in pigs

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1967.0003 ◽

1967 ◽

Vol 166 (1005) ◽

pp. 396-407 ◽

Cited By ~ 40

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Brain Stem ◽

The Body ◽

Chronological Age ◽

Absolute Amount ◽

The Central Nervous System ◽

One Year ◽

The Brain

Sucking pigs about 2 weeks old were held back by undernutrition so that they weighed only 5 to 6 kg when they were a year of age. The brain and cord developed during this time to the size to be expected in a normal pig about 10 weeks old but, although they remained immature for their chronological age, the effect on the various constituents was not uniform. The accumulation of cholesterol was less retarded than that of DNA.P or the increase in brain weight. During rehabilitation on a highly satisfactory diet the final body w eight reached at 3 1/2 years was 80 % of that to be expected in an adult pig and was equivalent only to that of a normal pig two years old. The central nervous system grew to the appropriate size for the body. The percentage of cholesterol in the central nervous system rose during rehabilitation, but, particularly in the forebrain, brain stem and spinal cord, remained subnormal for the chronological age. The deficiency of DNA- P in the rehabilitated brain was even greater, and the absolute amount finally corresponded to that found in the brain of a norm alanimal only one year of age.

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