Virus spread and initial pathological changes in the nervous system in genital herpes simplex virus type 2 infection in mice

Summary Mice were infected by the vaginal route with the MS strain of herpes simplex virus type 2 (HSV-2). Serial vaginal cultures were used to confirm infection and to select mice for this study. Two mice were killed by perfusion on days 2–6 post infection (p.i.) and lumbar and sacral cord with cauda were fixed and embedded for electron microscopy. Semithin Epon-sections were stained for viral antigen using a rabbit anti-HSV-2 antiserum and the Avidin-Biotin (ABC) method. Thin sections from antigen-positive blocks were examined by electron microscopy, and the number and types of infected cells detected by these two methods were compared. A good correlation was found between detection of infected cells by these methods. Infected cells included neurons of dorsal root ganglia and spinal cord, satellite cells of dorsal root ganglia, non-myelinating Schwann cells, astrocytes, oligodendrocytes and arachnoidal cells. Infected cells were first detected in the cauda on day 3 p.i. and in the spinal cord on day 5 p.i. The temporal and spatial distribution of infected cells was consistent with neural spread to and within the CNS. The pathological lesions showed a good correlation with the distribution and number of infected cells and are probably due to a direct virus effect. The similar sensitivity of the Epon-ABC method to electron microscopy in detecting infected cells indicates that this method may have useful applications in both experimental and diagnostic work.     

Sendai virus vector-mediated brain-derived neurotrophic factor expression ameliorates memory deficits and synaptic degeneration in a transgenic mouse model of Alzheimer's disease

Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.     

Theiler's virus in brain cell cultures: lysis of neurons and oligodendrocytes and persistence in astrocytes and macrophages

The mechanisms of persistence and of demyelination in Theiler's virus (TV)-induced chronic neurologic disease (a murine model for multiple sclerosis) are, as yet, disputed. We investigated the tropism and persistence of TV in brain cell culture to better understand the pathogenesis of this disease. Using anti-genic markers to identify specific cells in culture, we have demonstrated that TV infects, lytically, neurons and oligodendrocytes and persistently astrocytes and macrophages. These results suggest that host cell factors play a key role in the mechanism of demyelination and the persistence of TV in the nervous system.     

Cerebrospinal fluid shunt infection: risk factors and long-term follow-up

Introduction Shunt infection (SI) is an enduring problem in pediatric neurosurgery. Its occurrence is variable in the different series that were published, according to the definition retained. In addition, long-term data, which could help to evaluate the incidence of delayed SI, as well as the developmental outcome after SI, are scarce in the literature.Materials and methods We reviewed retrospectively children shunted for hydrocephalus during the last 20 years to evaluate the incidence of SI, including late SI, the risk factors and sources of contamination, and the late outcome after SI.Results We treated 1,173 patients who were followed-up for a mean duration of 7.0 years. During that period, 158 patients presented with a total number of 190 episodes of infection, 19 of which occurred more than 1 year after surgery. The infection rates per patient and per procedure were 13.6 and 5.9%, respectively. Age below 4 months at shunt insertion [odds ratio (OR)=1.81], antenatal diagnosis (OR=2.23), myelomeningocele (OR=2.14), and post-hemorrhagic hydrocephalus (OR=1.98) were significantly correlated with SI. SI was mostly due to intraoperative contamination; however, delayed SI was mostly caused by blood-borne contamination and abdominal sepsis. The mortality related to SI was 10.1%; the Glasgow Outcome Score, as well as schooling, was significantly and independently affected by SI.Conclusion Long-term follow-up of shunted children is necessary to evaluate the real incidence of SI and the functional outcome after SI.     

Characteristics of cloned cerebrovascular endothelial cells following infection with Theiler's virus II. Persistent infection

Cloned cerebrovascular endothelial cells (CVE) persistently infected with Theiler's virus (PI-CVE) have been established and characterized. The CVE were derived from strains of mice that are susceptible (SJL/J and CBA) and resistant (BALB/c) to Theiler's virus-induced demyelination (TVID). The cells were persistently infected with either the BeAn or GDVII strains of Theiler's virus in vitro and studied at various passage levels for infectious virus, viral antigen and the expression of major histocompatibility complex (MHC) Class I and II antigens. The virus replicated to lower titers than in acutely infected CVE and appeared to be more cell-associated. Flow cytometric analysis revealed that 18–39% of the PI-CVE contained viral antigen. Persistently infected CVE derived from SJL/J and CBA mice expressed high levels of MHC Class I, whereas BALB/c PI-CVE did not. MHC Class II was upregulated by IFN-γ in SJL/J PI-CVE albeit at a slightly lower level than in uninfected CVE. In addition, the PI-CVE demonstrated increased levels of mRNA for IL-1β when compared to uninfected CVE.     

开颅术后神经系统感染的危险因素及临床干预

目的探讨开颅术后神经系统感染的危险因素,并提出临床干预措施,以降低神经系统感染的发生率。方法选取2015-01—2016-11在平煤神马医疗集团总医院行开颅手术的患者234例,回顾性分析所有患者的临床资料,按照术后是否发生神经系统感染分为实验组41例和对照组193例,分析神经系统感染的危险因素及临床干预措施。结果通过对2组潜在危险因素对比发现,神经系统感染的发生与60岁老年人、手术时间≥4h、放置引流管、术前未预防性应用抗生素、≥2次手术、术中发生脑脊液漏及实施脑室体外引流术有关,差异有统计学意义(P0.05)。通过多因素分析发现,手术时间、留置引流管、术中脑脊液漏、脑室体外引流术是开颅术后神经系统感染的独立危险因素,术前预防性应用抗生素是保护因素,差异有统计学意义(P0.05)。结论开颅术后神经系统感染的危险因素主要有年龄60岁、手术时间≥4h、放置引流管、手术次数≥2次、术前未预防性应用抗生素、术中发生脑脊液漏及实施脑室体外引流术。通过术前加强营养、增加患者身体抵抗力、预防性应用抗生素、术中严格执行无菌原则、术后严密监测病情变化等降低开颅术后神经系统感染的发生率。一旦发生神经系统感染可进行控制颅内感染、心理护理、保持大便通畅及五官护理等降低神经系统感染的病死率。     

Practical Considerations for the Use of Pseudorabies Virus in Transneuronal Studies of Neural Circuitry

The development of neurotrophic alpha herpesviruses for transneuronal analysis of neuronal circuitry has emerged from interdisciplinary characterizations of the viral life cycle and the defense response mounted by the nervous system to contain and eliminate the infection. Important findings from a number of fields have combined to provide compelling evidence that these viruses, when used appropriately, are powerful probes of multisynaptic circuits. These studies have also revealed that a number of variables can influence the outcome of infection and should be considered in designing and interpreting data derived from studies employing this experimental approach. The purpose of this paper is to review the literature that has established this experimental approach as a viable method for transynaptic analysis of neuronal circuitry and to define the factors that should be considered in applying this technology.     

Targets of herpes simplex virus type 1 infection in a mouse corneal model

Summary In animal models, spread of herpes simplex virus type 1 (HSV-1) from epithelial replication sites to the peripheral and central nervous system is known from analysis of individually dissected tissues. To examine virus spread in undissociated tissues, corneas of adult mice were inoculated with HSV-1. After 1 to 13 days groups of mice were perfused with formalin, and decalcified blocks of head and neck were embedded in paraffin. At intervals, serial sections were screened for HSV antigen. On days 1 and 2, viral antigen was restricted to cornea and conjunctiva but by days 3 and 4 was also seen in autonomic ganglia and the trigeminal system. On day 6, HSV antigen reached its maximum extent; infected sites included the trigeminal complex (ganglion, root, peripheral ophthalmic and maxillary branches and spinal nucleus and tract), ehtmoid sinus and olfactory buld, visual system, and autonomic ganglia (ciliary, pterygopalatine and superior cervical). Antigen progressively diminished on days 8 and 10, and was not detected on day 13. This method demonstrates a broader range of infected tissues and suggests a more complex pattern of HSV spread than has been previously recognized. Virus appears to reach the intracranial compartment by four different neural routes. When effects of higher and lower corneal inoculation doses were compared, a lower dose resulted in lower peak HSV titers in trigeminal ganglion and brain stem and later virus appearance in these tissues. Thus, dose may influence the kinetics of HSV spread from the peripheral inoculation site to the CNS.Supported in part by U.S.U.H.S. grant, R07396. the opinions or assertions contained herein are the private views of the authors and should not be construed as official or necessarily reflecting the views of the Uniformed Services University of the Health Sciences or Department of Defense. There is no objection to its presentation and/or publication     

Measles virus infection and multiple sclerosis

Summary In 159 patients out of 161 with multiple sclerosis (MS), a significant rise in the level of measles hemagglutination inhibition (HI) antibody was found in the serum and in 92 MS patients the occurrence of measles HI antibody in the CSF was significantly more frequent. MS patients showed CSF humoral response against measles virus by neutralizing test (NV) (76%) more often than by hemagglutination test (37%). CSF FA antibody was found in 60%. In the serum of MS patients the presence of NV, HAd, FA, and GP-RNP was observed. 87% of MS patients showed lowered serum: CSF NV or HI antibody ratios and 78% had a diminished FA antibody ratio. Longitudinal study of serum HI measles virus antibody showed no substantial changes over longer period of the disease. Higher CSF measles antibody titer was found in more disabled patients with a malignant course of the disease (P<0.001). It is concluded that either peristent infection with proviruses or nonspecific stimulation of certain clones in individuals with genetic susceptibility provides for an excessive synthesis of humoral viral antibodies in MS.

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Zusammenfassung Bei 159 von 161 Multiple Sklerose-Patienten wurde im Serum eine signifikante Erhöhung des Titers der Masern-Hämagglutinationshemmungsantikörper gefunden. Bei 92 MS-Patienten erschien das Vorhandensein von Masern-Hämagglutinationshemmungsantikörper im Serum signifikant häufiger als bei Vergleichspersonen. Multiple Sklerose-Patienten zeigten beim Neutralisierungstest im Serum häufiger eine humorale Antwort gegen Masernvirus Hämolysin (76%) als beim Hämagglutinisierungstest (37%). FA-Liquorantikörper wurden in 60% gefunden. Im Serum von MS-Patienten wurde das Vorhandensein von NV, HAD, FA und GPRNP (s. Text) beobachtet. 87% der MS-Patienten zeigten eine erniedrigte Serum-Liquor-Relation der NV- und HI-Antikörper, und 78% hatten eine erniedrigte FA-Antikörper-Relation. Eine Studie der Serum HI-Masernvirusantikörper zeigte keine nennenswerte Veränderung über eine längere Zeitperiode. Höhere Masernantikörpertiter im Liquor wurden bei Patienten mit besonders ausgeprägter Behinderung und einem bösartigen Verlauf der Krankheit (P<0,001) gefunden. Es wurde der Schluß gezogen, daß bei MS-Patienten entweder eine persistierende Infektion mit Provirus oder eine nichtspezifische Stimulierung gewisser Kloni bei Individuen mit genetisch verankerter Empfänglichkeit zu einer übertriebenen Synthese von humoralen Virusantikörpern führt.

     

Spread of vesicular stomatitis virus along the visual pathways after retinal infection in the mouse

Summary Vesicular stomatitis virus (VSV) was injected into the left eyeball of 3-week-old mice and it infected the retinal ganglion cells. The infection spread rapidly along the visual pathways to the postsynaptic neurons in the contralateral superior collicle (SC) and lateral geniculate body (LGB). The distributional pattern of the viral immunoreactivity indicated an anterograde axonal transport of the infectious material. A subsequent spread to the ganglion cells of the right retina further indicated retrograde axonal VSV transport. Within the retina the infection spread from the ganglion cells to the pigment epithelium. Although a transneuronal spread of the VSV infection was observed, no VSV budding from or uptake in synaptic membranes was demonstrated ultrastructurally in the retina or the superior collicle. In the retina virions budded from the perikaryal and dendritic plasma membranes of the ganglion cells as well as from the nerve cell bodies of the inner and outer nuclear layers, but not from the receptor segments. In the superior collicle budding was also observed from the plasma membranes of nerve cell bodies and dendrites. In contrast, the intraocular injection of Sendai virus caused a limited retinal ganglion cell infection, with no further propagation in the retina or to the SC or LGB.     

Ventriculosubgaleal shunt in the management of recurrent ventriculoperitoneal shunt infection

The use of a ventriculosubgaleal shunt for temporary treatment of hydrocephalus in a child with multiple recurrent shunt infections related to eczema in the neck is described. Further shunt infection was avoided, the eczema cleared, and a permanent ventriculoperitoneal shunt was inserted successfully after 2 months.     

Nervous system involvement after infection with COVID-19 and other coronaviruses

Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage. Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases. It is reported that CoV can be found in the brain or cerebrospinal fluid. The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system. Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.     

Dopaminergic neurotransmission in chronic herpes simplex virus brain infection in rabbits

Summary In this study we have examined brain concentrations of monoamine neurotransmitters and striatal and mesencephalic D-2 receptors in a chronic model of herpes simplex virus (HSV) encephalitis. The HSV-inoculated rabbits were killed two months after inoculation. Dopamine (DA), noradrenaline, serotonin and their metabolites were determined in the substantia nigra, caudate nucleus, putamen, nucleus accumbens, and olfactory tubercles using HPLC with electrochemical detection. The B_max and K_d values of D-2 receptors were studied in the striatum and in the mesencephalon using³H-spiroperidol as ligand.The animals showed rotational behaviour, consisting of posture tilting to the inoculated side and circling in the same direction during the first week, then slowly subsiding. Compared with controls, the concentration of homovanillic acid (HVA) was reduced in the ascending DA system on both sides. Neither in the number nor affinity of D-2 receptors were there any differences between the HSV-inoculated and control rabbits.The decreased HVA concentrations suggest that dopaminergic hypofunction can develop as a consequence of previously experienced acute HSV brain infection.     

Effect of persistent mouse hepatitis virus infection on MHC Class I expression in murine astrocytes

Neurotropic strains of mouse hepatitis virus (MHV) have been used extensively for the study of viral pathogenesis in the central nervous system (CNS), serving as models for human neurological diseases such as multiple sclerosis (MS). MHV strains A59 and JHMV both cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. In acute disease, CNS damage is most likely the result of lytic infection in neurons and oligodendrocytes, and death can be prevented by the adoptive transfer of Class I-restricted CD8+ T cells. However, in later stages of the disease induced by some MHV strains, virus tends to be restricted to astrocytes in a nonlytic infection, and the immune response appears to contribute to CNS damage. These data lead us to suggest that the astrocyte may play a central role in the neuropathogenesis of MHV infection. Consistent with this possibility, A59 has been reported to induce the expression of Class I molecules of the major histocompatibility complex (MHC) in glial cells following infection in vivo and in vitro. In this communication, we have examined the influence of persistent infection by both A59 and JHMV on MHC Class I expression in primary murine astrocytes. Persistence was characterized by the presence of intracellular viral antigen and mRNA in the absence of detectable infectious virus particles. Under these conditions, JHMV, but not A59, inhibited constitutive expression of the H-2 K^b molecule, with the magnitude of inhibition increasing with postinfection time. A59 was not able to induce Class I during persistence, presumably due to the lack of infectious virus particles. Class I expression was restored by the addition of gamma-interferon (IFN-γ) to astrocytes persistently infected with either A59 or JHMV. Thus, Class I inhibition is not a permanent consequence of JHMV persistence, and persistence does not interfere with normal signalling pathways for Class I induction. © 1995 Wiley-Liss, Inc.     

Impact of Theiler's virus infection on hippocampal neuronal progenitor cells: differential effects in two mouse strains

M. Jafari, V. Haist, W. Baumgärtner, S. Wagner, V. M. Stein, A. Tipold, H. Wendt and H. Potschka (2012) Neuropathology and Applied Neurobiology 38, 647–664 Impact of Theiler's virus infection on hippocampal neuronal progenitor cells: differential effects in two mouse strains Aims: Disease‐associated alterations in hippocampal neurogenesis are discussed as an important factor contributing to long‐term consequences of central nervous system diseases. Therefore, the study aimed to determine the impact of Theiler's murine encephalomyelitis virus infection on hippocampal cell proliferation, neuronal progenitor cells and neurogenesis as well as the influence of microglia on respective disease‐associated alterations. Methods: The impact of the infection was evaluated in two mouse strains which differ in the disease course, with an acute polioencephalitis followed by virus elimination in C57BL/6 mice and a chronic demyelinating disease in SJL/J mice. Results: Infection with the low neurovirulent BeAn strain did not exert significant acute effects regardless of the mouse strain. In the chronic phase, the number of neuronal progenitor cells and early postmitotic neurones was significantly reduced in infected SJL/J mice, whereas no long‐term alterations were observed in C57BL/6 mice. A contrasting course of microglia activation was observed in the two mouse strains, with an early increase in the number of activated microglia cells in SJL/J mice and a delayed increase in C57BL/6 mice. Quantitative analysis did not confirm a correlation between the number of activated microglia and the number of neuronal progenitor cells and early postmitotic neurones. However, flow cytometric analyses revealed alterations in the functional state of microglial cells which might have affected the generation of neuronal progenitor cells. Conclusions: Theiler's murine encephalomyelitis virus infection can exert delayed effects on the hippocampal neuronal progenitor population with long‐term alterations evident 3 months following infection. These alterations proved to depend on strain susceptibility and might contribute to detrimental consequences of virus encephalitis such as cognitive impairment.     

The impact of antibiotic-impregnated catheters on shunt infection in children and neonates

Introduction Infection remains a significant problem with cerebrospinal fluid (CSF) diversion procedures. Antibiotic-impregnated shunt catheters (AIS) have been introduced to prevent infection, mainly in the early post-operative period when most infections occur. We evaluate the impact on infection rates in children following the introduction of catheters impregnated with rifampicin and clindamycin. Materials and methods The study was a retrospective analysis of all paediatric shunt procedures undertaken after the introduction of AIS systems in 2003. All procedures where a complete AIS system was implanted were included. For the purpose of analysis, shunt procedures were classified as de novo (group 1), clean revision (group 2) and following external ventricular drainage with either sterile CSF (group 3) or infected CSF (group 4). Results were compared to a historical cohort of shunt procedures undertaken before the introduction of AIS catheters. Results A total of 214 AIS were implanted in 150 children between October 2003 and December 2006. There were 4 infections in group 1 (8.5%), 6 infections in group 2 (5.3%) and 11 infections in groups 3 and 4 (20%). The historical control group comprised 77 shunts in 65 children. The infection rate in neonatal de novo shunts reduced from 27 to 10.4% following the introduction of AIS catheters. Conclusions AIS catheters can reduce the number of shunt infections seen in clinical practice in certain subgroups. This has had a significant impact on the neonatal hydrocephalic population. The high risk of shunt infection after a period of external ventricular drainage raises the issue of emergence of bacterial resistance.