scholarly journals Measles Virus Bearing Measles Inclusion Body Encephalitis-Derived Fusion Protein Is Pathogenic after Infection via the Respiratory Route

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Cyrille Mathieu ◽  
Marion Ferren ◽  
Eric Jurgens ◽  
Claire Dumont ◽  
Ksenia Rybkina ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Animal Models ◽  
Fusion Protein ◽  
Inclusion Body ◽  
Measles Virus ◽  
Antiviral Treatment ◽  
Single Amino Acid ◽  
Cns Infection ◽  
Viral Fusion

ABSTRACTA clinical isolate of measles virus (MeV) bearing a single amino acid alteration in the viral fusion protein (F; L454W) was previously identified in two patients with lethal sequelae of MeV central nervous system (CNS) infection. The mutation dysregulated the viral fusion machinery so that the mutated F protein mediated cell fusion in the absence of known MeV cellular receptors. While this virus could feasibly have arisen via intrahost evolution of the wild-type (wt) virus, it was recently shown that the same mutation emerged under the selective pressure of small-molecule antiviral treatment. Under these conditions, a potentially neuropathogenic variant emerged outside the CNS. While CNS adaptation of MeV was thought to generate viruses that are less fit for interhost spread, we show that two animal models can be readily infected with CNS-adapted MeV via the respiratory route. Despite bearing a fusion protein that is less stable at 37°C than the wt MeV F, this virus infects and replicates in cotton rat lung tissue more efficiently than the wt virus and is lethal in a suckling mouse model of MeV encephalitis even with a lower inoculum. Thus, either during lethal MeV CNS infection or during antiviral treatmentin vitro, neuropathogenic MeV can emerge, can infect new hosts via the respiratory route, and is more pathogenic (at least in these animal models) than wt MeV.IMPORTANCEMeasles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.

scholarly journals Measles fusion complexes from central nervous system clinical isolates: decreased interaction between hemagglutinin and fusion proteins

2021 ◽  
Author(s):  
Cyrille Mathieu ◽  
Tiago Nascimento Figueira ◽  
Amanda R Decker ◽  
Marion Ferren ◽  
Francesca Tiziana Bovier ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Viral Entry ◽  
Measles Virus ◽  
Single Amino Acid ◽  
Cns Infection ◽  
Wild Type ◽  
Single Amino Acid Change ◽  
The Central Nervous System ◽  
H Protein

Measles virus (MeV) viral entry is mediated by a fusion complex comprised of a receptor-binding protein (hemagglutinin, H) and a fusion protein (F). The wild-type H/F complex requires interaction with specific proteinaceous receptors (CD150/SLAM and nectin-4) in order to be activated. In contrast, the H/F complexes isolated from viruses infecting the central nervous system (CNS) do not require a specific receptor. A single amino acid change in the F protein (L454W) was previously identified in two patients with lethal sequelae of MeV CNS infection, and the F bearing this mutation mediates fusion even without the H protein. We show here that viruses bearing the L454W fusion complex are less efficient than wt virus at targeting receptor-expressing cells and that this defect is associated with a decreased interaction between the H and the F proteins.

scholarly journals Measles Virus Mutants Possessing the Fusion Protein with Enhanced Fusion Activity Spread Effectively in Neuronal Cells, but Not in Other Cells, without Causing Strong Cytopathology

2014 ◽  
Vol 89 (5) ◽  
pp. 2710-2717 ◽  
Author(s):  
Shumpei Watanabe ◽  
Shinji Ohno ◽  
Yuta Shirogane ◽  
Satoshi O. Suzuki ◽  
Ritsuko Koga ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Fusion Protein ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Neuronal Cells ◽  
Extracellular Domain ◽  
Fusion Activity ◽  
F Protein ◽  
The Central Nervous System

ABSTRACTSubacute sclerosing panencephalitis (SSPE) is caused by persistent measles virus (MV) infection in the central nervous system (CNS). Since human neurons, its main target cells, do not express known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), it remains to be understood how MV infects and spreads in them. We have recently reported that fusion-enhancing substitutions in the extracellular domain of the MV fusion (F) protein (T461I and S103I/N462S/N465S), which are found in multiple SSPE virus isolates, promote MV spread in human neuroblastoma cell lines and brains of suckling hamsters. In this study, we show that hyperfusogenic viruses with these substitutions also spread efficiently in human primary neuron cultures without inducing syncytia. These substitutions were found to destabilize the prefusion conformation of the F protein trimer, thereby enhancing fusion activity. However, these hyperfusogenic viruses exhibited stronger cytopathology and produced lower titers at later time points in SLAM- or nectin 4-expressing cells compared to the wild-type MV. Although these viruses spread efficiently in the brains of SLAM knock-in mice, they did not in the spleens. Taken together, the results suggest that enhanced fusion activity is beneficial for MV to spread in neuronal cells where no cytopathology occurs, but detrimental to other types of cells due to strong cytopathology. Acquisition of enhanced fusion activity through substitutions in the extracellular domain of the F protein may be crucial for MV's extensive spread in the CNS and development of SSPE.IMPORTANCESubacute sclerosing panencephalitis (SSPE) is a fatal disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). Its cause is not well understood, and no effective therapy is currently available. Recently, we have reported that enhanced fusion activity of MV through the mutations in its fusion protein is a major determinant of efficient virus spread in human neuronal cells and brains of suckling hamsters. In this study, we show that those mutations render the conformation of the fusion protein less stable, thereby making it hyperfusogenic. Our results also show that enhanced fusion activity is beneficial for MV to spread in the CNS but detrimental to other types of cells in peripheral tissues, which are strongly damaged by the virus. Our findings provide important insight into the mechanism for the development of SSPE after MV infection.

scholarly journals Molecular Features of the Measles Virus Viral Fusion Complex That Favor Infection and Spread in the Brain

mBio ◽  
2021 ◽  
Author(s):  
Cyrille Mathieu ◽  
Francesca T. Bovier ◽  
Marion Ferren ◽  
Nicole A. P. Lieberman ◽  
Camilla Predella ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Measles Virus ◽  
Subacute Sclerosing Panencephalitis ◽  
Viral Fusion ◽  
Systemic Immune Response ◽  
Molecular Features ◽  
The Face ◽  
The Brain

Measles virus (MeV) infection can cause serious complications in immunocompromised individuals, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE), another severe central nervous system (CNS) complication, develop even in the face of a systemic immune response.

scholarly journals 045 Primary cutibacterium acnes central nervous system infection causing focal seizures: an unusual presentation of a rare disease

2019 ◽  
Vol 90 (e7) ◽  
pp. A15.2-A15
Author(s):  
Sophie E Waller ◽  
Sarah Browning ◽  
Elizabeth Pepper
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Infection ◽  
Cns Infection ◽  
Delayed Presentation ◽  
Pathogenic Potential ◽  
Focal Seizures ◽  
Device Infection ◽  
Cutibacterium Acnes ◽  
Neurosurgical Intervention

IntroductionCutibacterium acnes is a Gram positive, anaerobic bacterium of low pathogenic potential that forms part of the normal cutaneous flora. Although most often identified as a contaminant in culture of microbiological specimens, it is commonly implicated in both postoperative wound and implantable device infection. Neurosurgical device infections secondary to C. acnes are well recognised and are likely secondary to bacterial contamination from the skin during surgery. Indolent infection characterised by delayed presentation of weeks to months following intervention is common. C. acnes infection involving the central nervous system (CNS) in the absence of previous neurosurgical intervention is rare, but has been described following dental or mastoid infections and following facial trauma. A further case series has reported de novo C. acnes CNS infection occurring in the absence of these recognised risk factors, but with clinical features of meningitis being common to all.Methods and resultsWe describe a unique case of primary C. acnes extra-dural collection in a previously well patient with no neurosurgical history presenting with sub-acute focal seizures and progressive focal leptomeningeal thickening on MRI.ConclusionC. acnes CNS infection can occur in the immunocompetent and in the absence of neurosurgical intervention.

scholarly journals Metagenomic Next-Generation Sequencing for Pathogen Detection and Transcriptomic Analysis in Pediatric Central Nervous System Infections

2021 ◽  
Author(s):  
Nanda Ramchandar ◽  
Nicole G Coufal ◽  
Anna S Warden ◽  
Benjamin Briggs ◽  
Toni Schwarz ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Next Generation Sequencing ◽  
Usual Care ◽  
Transcriptomic Analysis ◽  
Cns Infection ◽  
Metagenomic Sequencing ◽  
Next Generation ◽  
Cns Infections ◽  
Generation Sequencing

Abstract Background Pediatric central nervous system (CNS) infections are potentially life-threatening and may incur significant morbidity. Identifying a pathogen is important, both in terms of guiding therapeutic management, but also in characterizing prognosis. Usual care testing by culture and PCR is often unable to identify a pathogen. We examined the systematic application of metagenomic next-generation sequencing (mNGS) for detecting organisms and transcriptomic analysis of cerebrospinal fluid (CSF) in children with CNS infections. Methods We conducted a prospective multi-site study that aimed to enroll all children with a CSF pleocytosis and suspected CNS infection admitted to one of three tertiary pediatric hospitals during the study timeframe. After usual care testing had been performed, the remaining CSF was sent for mNGS and transcriptomic analysis. Results We screened 221 and enrolled 70 subjects over a 12-month recruitment period. A putative organism was isolated from CSF in 25 (35.7%) subjects by any diagnostic modality. mNGS of the CSF samples identified a pathogen in 20 (28.6%) subjects, which were also all identified by usual care testing. The median time to result was 38 hours. Conclusion Metagenomic sequencing of CSF has the potential to rapidly identify pathogens in children with CNS infections.

scholarly journals Central nervous system involvement in Chagas' disease: an updating

1993 ◽  
Vol 35 (2) ◽  
pp. 111-116 ◽  
Author(s):  
José Eymard Homem Pittella
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Chagas Disease ◽  
Acute Phase ◽  
Central Nervous System Involvement ◽  
Cns Infection ◽  
Cns Involvement ◽  
Anatomical Basis ◽  
Immunosuppressed Patients ◽  
Acute Form

A review was made of the available literature on central nervous system (CNS) involvement in Chagas' disease. Thirty-one works concerning the acute nervous form and 17 others dealing with the chronic nervous form, all presenting neuropathologic studies, were critically analysed. Based on this analysis, an attempt was made to establish the possible natural history of CNS involvement in Chagas' disease. Among others, the following facts stand out: 1) the initial, acute phase of Trypanosoma cruzi infection is usually asymptomatic and subclinical; 2) only a small percentage of cases develop encephalitis in the acute phase of Chagas' disease; 3) the symptomatic acute forms accompanied by chagasic encephalitis are grave, with death ensuing in virtually all cases as a result of the brain lesions per se or of acute chagasic myocarditis, this being usually intense and always present; 4) individuals with the asymptomatic acute form and with the mild symptomatic acute form probably have no CNS infection or, in some cases, they may have discrete encephalitis in sparse foci. In the latter case, regression of the lesions may be total, or residual inflammatory nodules of relative insignificance may persist. Thus, no anatomical basis exists that might characterize the existence of a chronic nervous form of Chagas' disease; 5) reactivation of the CNS infection in the chronic form of Chagas' disease is uncommon and occurs only in immunosuppressed patients.

scholarly journals Morbillivirus Infection of the Mouse Central Nervous System Induces Region-Specific Upregulation of MMPs and TIMPs Correlated to Inflammatory Cytokine Expression

2001 ◽  
Vol 75 (17) ◽  
pp. 8268-8282 ◽  
Author(s):  
Seng-Thuon Khuth ◽  
Hideo Akaoka ◽  
Axel Pagenstecher ◽  
Olivier Verlaeten ◽  
Marie-Françoise Belin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mouse Model ◽  
Neurological Disorders ◽  
Dynamic Balance ◽  
Brain Structures ◽  
Cytokine Expression ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Cns Infection ◽  
Necrosis Factor Alpha

ABSTRACT Viral infection of the central nervous system (CNS) can result in perturbation of cell-to-cell communication involving the extracellular matrix (ECM). ECM integrity is maintained by a dynamic balance between the synthesis and proteolysis of its components, mainly as a result of the action of matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). An MMP/TIMP imbalance may be critical in triggering neurological disorders, in particular in virally induced neural disorders. In the present study, a mouse model of brain infection using a neurotropic strain of canine distemper virus (CDV) was used to study the effect of CNS infection on the MMP/TIMP balance and cytokine expression. CDV replicates almost exclusively in neurons and has a unique pattern of expression (cortex, hypothalamus, monoaminergic nuclei, hippocampus, and spinal cord). Here we show that although several mouse brain structures were infected, they exhibited a differential pattern in terms of MMP, TIMP, and cytokine expression, exemplified by (i) a large increase in pro-MMP9 levels, in particular in the hippocampus, which occurred mainly in neurons and was associated with in situ gelatinolytic activity, (ii) specific and significant upregulation of MT1-MMP mRNA expression in the cortex and hypothalamus, (iii) an MMP/TIMP imbalance, suggested by the upregulation of TIMP-1 mRNA in the cortex, hippocampus, and hypothalamus and of TIMP-3 mRNA in the cortex, and (iv) a concomitant region-specific large increase in expression of Th1-like cytokines, such as gamma interferon, tumor necrosis factor alpha, and interleukin 6 (IL-6), contrasting with weaker induction of Th2-like cytokines, such as IL-4 and IL-10. These data indicate that an MMP/TIMP imbalance in specific brain structures, which is tightly associated with a local inflammatory process as shown by the presence of immune infiltrating cells, differentially impairs CNS integrity and may contribute to the multiplicity of late neurological disorders observed in this viral mouse model.

scholarly journals Clinical Analysis of Intravenous and Oral Sequential Treatment With Voriconazole for Candida Central Nervous System Infection in Six Premature Infants

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Zhu ◽  
Xiaohui Gong ◽  
Zhiling Li ◽  
Danni Wang ◽  
Chongbing Yan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Side Effects ◽  
Blood Culture ◽  
Kidney Function ◽  
Premature Infants ◽  
Sequential Treatment ◽  
Cns Infection ◽  
Significant Difference ◽  
Liver And Kidney

Objective: The aim of the study was to observe the clinical efficacy and safety of intravenous and oral sequential treatment with voriconazole for Candida central nervous system (CNS) infection in premature infants.Methods: The study included retrospective analysis of the clinical data of six premature infants with Candida CNS infection admitted to the neonatology department in Shanghai Children’s Hospital between November 2016 and November 2019. By reviewing the characteristics of voriconazole based on the literature, it showed that infants without gastrointestinal dysfunction could be effectively treated by intravenous and oral sequential therapy with voriconazole (both 7 mg/kg/dose, every 12 h). Clinical manifestations, the time required for the cerebrospinal fluid (CSF), blood culture, nonspecific infection markers such as platelets and C-reactive protein (CRP) to turn normal, and drug-related side effects were observed and recorded in the process of treatment. All data were statistically analyzed by T test and Mann–Whitney U test.Results: A total of six premature infants were diagnosed with Candida CNS infection, two cases were diagnosed by a positive CSF culture and four cases were clinically diagnosed. Blood culture was positive for Candida in five cases. Among the 6 patients, 4 cases were Candida albicans and 2 cases were Candida parapsilosis. All the six cases were cured. After 3–5 days of treatment, symptoms such as lethargy, apnea, and feeding intolerance were improved and disappeared; a repeated blood culture turned negative in 3–7 days; CSF returned to normal in 15 ± 9 days on an average. Brain abscess, meningeal inflammation, and other infectious lesions were cleared on cranial magnetic resonance imaging (MRI) after treatment. The average total course of voriconazole was 61 ± 29 days, and the average oral treatment was 28 ± 15 days. No Candida recurrence was found during the treatment, and no drug-related side effects such as skin rash, liver and kidney function impairment, or visual abnormalities were found. The white blood cells, CSF glucose/plasma glucose ratio, and protein in CSF were significantly improved after the treatment (p < 0.05). No statistically significant difference was identified in the liver and kidney function indexes (p > 0.05).Conclusion: Voriconazole is a relatively safe and effective alternative treatment for Candida CNS infection in preterm infants. No severe drug-related side effects were detected.

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