The emergence of the novel ß-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic of coronavirus disease 2019 (COVID-19). Clinical studies have documented that potentially severe neurological symptoms are associated with SARS-CoV-2 infection, thereby suggesting direct CNS penetration by the virus. Prior studies have demonstrated that the destructive neurological effects of rabies virus (RABV) infections are mediated by CNS transport of the virus tightly bound to the nicotinic acetylcholine receptor (nAChR). By comparison, it has been hypothesized that a similar mechanism exists to explain the multiple neurological effects of SARS-CoV-2 via binding to peripheral nAChRs followed by orthograde or retrograde transport into the CNS. Genetic engineering of the RABV has been employed to generate novel vaccines consisting of non-replicating RABV particles expressing chimeric capsid proteins containing human immunodeficiency virus 1 (HIV-1), Middle East respiratory syndrome (MERS-CoV), Ebolavirus, and hepatitis C virus (HCV) sequences. Accordingly, we present a critical discussion that integrates lessons learned from prior RABV research and vaccine development into a working model of a SARS-CoV-2 vaccine that selectively targets and neutralizes CNS penetration of a tightly bound viral nAChR complex.
- MeSH
- Betacoronavirus chemie imunologie MeSH
- glykoprotein S, koronavirus chemie genetika imunologie MeSH
- koronavirové infekce imunologie metabolismus prevence a kontrola virologie MeSH
- lidé MeSH
- nikotinové receptory metabolismus MeSH
- pandemie MeSH
- proteinové domény MeSH
- replikace viru * MeSH
- virová pneumonie imunologie virologie MeSH
- virové vakcíny chemie imunologie metabolismus MeSH
- virus rabies genetika fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Rabies is a deadly viral disease with an extremely high fatality rate in humans. Previously, it was suggested that an enhancement of the blood-brain barrier (BBB) permeability, which allows immune cells and/or antibodies to enter the central nervous system (CNS) tissue, is critical to clear the infection. In this study, we utilised mannitol to increase BBB permeability in mice infected with highly pathogenic silver-haired bat rabies virus (SHBRV). We found that intraperitoneal injection of mannitol causes a slight, transient increase of BBB permeability in the treated mice. SHBRV-infected mice were treated with intraperitoneally administered mannitol daily from day 3 or day 4 post-infection, but no effect of this treatment on the time of disease onset, clinical signs or survival was observed. This data indicates that the increase of BBB permeability by mannitol is not efficient in promoting CNS virus clearance in SHBRV-infected mice.
- MeSH
- antigeny virové metabolismus MeSH
- centrální nervový systém účinky léků metabolismus MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- mannitol terapeutické užití MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- protilátky virové metabolismus MeSH
- rabies farmakoterapie virologie MeSH
- virus rabies účinky léků patogenita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recent studies demonstrated that inhibitors of pro-inflammatory molecular cascades triggered by rabies infection in the central nervous system (CNS) can enhance survival in mouse model and that certain antiviral compounds interfere with rabies virus replication in vitro. In this study different combinations of therapeutics were tested to evaluate their effect on survival in rabies-infected mice, as well as on viral load in the CNS. C57Bl/6 mice were infected with Silver-haired bat rabies virus (SHBRV)-18 at virus dose approaching LD50 and LD100. In one experimental group daily treatments were initiated 4 h before-, in other groups 48 or 96 h after challenge. In the first experiment therapeutic combination contained inhibitors of tumour necrosis factor-α (infliximab), caspase-1 (Ac-YVAD-cmk), and a multikinase inhibitor (sorafenib). In the treated groups there was a notable but not significant increase of survival compared to the virus infected, non-treated mice. The addition of human rabies immunoglobulins (HRIG) to the combination in the second experiment almost completely prevented mortality in the pre-exposure treatment group along with a significant reduction of viral titres in the CNS. Post-exposure treatments also greatly improved survival rates. As part of the combination with immunomodulatory compounds, HRIG had a higher impact on survival than alone. In the third experiment the combination was further supplemented with type-I interferons, ribavirin and favipiravir (T-705). As a blood-brain barrier opener, mannitol was also administered. This treatment was unable to prevent lethal consequences of SHBRV-18 infection; furthermore, it caused toxicity in treated mice, presumably due to interaction among the components. In all experiments, viral loads in the CNS were similar in mice that succumbed to rabies regardless of treatment. According to the findings, inhibitors of detrimental host response to rabies combined with antibodies can be considered among the possible therapeutic and post-exposure options in human rabies cases.
- MeSH
- antivirové látky terapeutické užití MeSH
- imunoglobuliny terapeutické užití MeSH
- imunohistochemie MeSH
- Kaplanův-Meierův odhad MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- protilátky virové imunologie MeSH
- rabies farmakoterapie imunologie MeSH
- replikace viru účinky léků MeSH
- tělesná hmotnost účinky léků MeSH
- virus rabies účinky léků imunologie patogenita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Anticipating how epidemics will spread across landscapes requires understanding host dispersal events that are notoriously difficult to measure. Here, we contrast host and virus genetic signatures to resolve the spatiotemporal dynamics underlying geographic expansions of vampire bat rabies virus (VBRV) in Peru. Phylogenetic analysis revealed recent viral spread between populations that, according to extreme geographic structure in maternally inherited host mitochondrial DNA, appeared completely isolated. In contrast, greater population connectivity in biparentally inherited nuclear microsatellites explained the historical limits of invasions, suggesting that dispersing male bats spread VBRV between genetically isolated female populations. Host nuclear DNA further indicated unanticipated gene flow through the Andes mountains connecting the VBRV-free Pacific coast to the VBRV-endemic Amazon rainforest. By combining Bayesian phylogeography with landscape resistance models, we projected invasion routes through northern Peru that were validated by real-time livestock rabies mortality data. The first outbreaks of VBRV on the Pacific coast of South America could occur by June 2020, which would have serious implications for agriculture, wildlife conservation, and human health. Our results show that combining host and pathogen genetic data can identify sex biases in pathogen spatial spread, which may be a widespread but underappreciated phenomenon, and demonstrate that genetic forecasting can aid preparedness for impending viral invasions.
- MeSH
- Bayesova věta MeSH
- biologická evoluce * MeSH
- Chiroptera virologie MeSH
- genom virový MeSH
- interakce hostitele a patogenu * MeSH
- mikrosatelitní repetice genetika MeSH
- rabies epidemiologie MeSH
- roční období MeSH
- typy dědičnosti genetika MeSH
- virus rabies genetika MeSH
- zeměpis MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Geografické názvy
- Peru epidemiologie MeSH
Nervová sústava je najkomplikovanejšou sústavou nášho organizmu a každé jej poškodenie zanecháva celoživotné následky. Rovnako ako je v neustálom vývoji veda a výskum, vyvíjajú sa aj vírusy. Ich vlastnosti a mechanizmy sa menia a prispôsobujú prostrediu, v ktorom sa nachádzajú. Z toho dôvodu je nevyhnutné študovať molekulárne vlastnosti vírusov, spôsoby, akými sa vyhýbajú imunitnej odpovedi a možnosti terapie a profylaxie. Cieľom nášho článku je podať komplexný prehľad o dvoch neuropatogénnych vírusoch rozšírených takmer po celom svete, víruse besnoty a víruse lymfocytovej choriomeningitídy a ich patogenéze, liečbe a profylaxii.
The nervous system is the most complicated system of our body and any damage leads to lifelong consequences. As well as the tireless development of science and research, evolve viruses too. Their properties and mechanisms of change adapt to the environment, in which they are located. Therefore, it is necessary to study the molecular properties of the viruses, the way they avoid the immune response, and the therapy and prophylaxis. The aim of this work is to give a comprehensive picture of two neuropathogenic viruses extended almost all over the world, rabies virus and lymphocytic choriomeningitis virus, including their pathogenesis, treatment and prophylaxis.
- MeSH
- lidé MeSH
- lymfocytární choriomeningitida * diagnóza etiologie prevence a kontrola terapie MeSH
- rabies * diagnóza etiologie prevence a kontrola terapie MeSH
- vakcína proti vzteklině dějiny farmakologie imunologie terapeutické užití MeSH
- virus lymfocytární choriomeningitidy klasifikace patogenita růst a vývoj MeSH
- virus rabies patogenita růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Although rabies incidence has fallen sharply over the past decades in Europe, the disease is still present in Eastern Europe. Oral rabies immunization of wild animal rabies has been shown to be the most effective method for the control and elimination of rabies. All rabies vaccines used in Europe are modified live virus vaccines based on the Street Alabama Dufferin (SAD) strain isolated from a naturally-infected dog in 1935. Because of the potential safety risk of a live virus which could revert to virulence, the genetic composition of three commercial attenuated live rabies vaccines was investigated in two independent laboratories using next genome sequencing. This study is the first one reporting on the diversity of variants in oral rabies vaccines as well as the presence of a mix of at least two different variants in all tested batches. The results demonstrate the need for vaccine producers to use new robust methodologies in the context of their routine vaccine quality controls prior to market release.
- MeSH
- atenuované vakcíny * MeSH
- divoká zvířata * MeSH
- genetická variace MeSH
- genom virový MeSH
- nemoci zvířat prevence a kontrola MeSH
- rabies veterinární MeSH
- RNA virová MeSH
- vakcína proti vzteklině genetika imunologie MeSH
- vakcinace veterinární MeSH
- virus rabies genetika imunologie MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
- Klíčová slova
- virus MERS-CoV,
- MeSH
- Chiroptera * virologie MeSH
- lidé MeSH
- virus Ebola MeSH
- virus Hendra MeSH
- virus Nipah MeSH
- virus rabies MeSH
- virus SARS patogenita MeSH
- zdroje nemoci * virologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- MeSH
- atenuované vakcíny terapeutické užití MeSH
- biomedicínský výzkum MeSH
- chřipka lidská epidemiologie prevence a kontrola virologie MeSH
- hemoragická horečka Ebola prevence a kontrola MeSH
- inaktivované vakcíny terapeutické užití MeSH
- lidé MeSH
- objevování léků MeSH
- očkovací programy MeSH
- příušnice prevence a kontrola MeSH
- rotavirové infekce prevence a kontrola MeSH
- rozvojové země MeSH
- sekundární imunizace MeSH
- vakcína proti příušnicím terapeutické užití MeSH
- vakcína proti rotavirům zásobování a distribuce MeSH
- vakcína proti vzteklině terapeutické užití MeSH
- vakcíny proti chřipce imunologie MeSH
- vakcíny proti ebole MeSH
- virus Ebola imunologie MeSH
- virus rabies imunologie MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Afrika MeSH
- Česká republika MeSH
- Súdán MeSH
V roce 2005 bylo na našem pracovišti ošetřeno 6 dětí, které přišly do kontaktu s netopýrem, u něhož byla prokázána infekce virem European Bat Lyssavirus 1 (EBL 1). jednalo se o první záchyt vztekliny na území ČR od roku 2002, ale od roku 1994 šlo již o čtvrtý záchyt vztekliny u netopýra. Vždy se jednalo o výskyt na jižní Moravě a o druhy netopýrů, které téměř nemigrují, z čehož plyne, že se EBL I na našem území vyskytuje endemicky. Vzteklina u netopýrů se liší od vztekliny nelétavých savců. Podle genetických analýz lze rod lyssavirus rozdělit do 6 genotypů, z nichž se v Evropě vyskytuje genotyp I (Rabies-virus) a genotypy 5 a 6 (European Bat Lyssavirus I a 2). Netopýří lyssaviry udržují své nákazové cykly pouze v populaci netopýrů, především druhu Eptesicus serotinus a rodu Myotis, ale i dalších. Ojediněle dochází k přenosu na ostatní savce. V Evropě byly popsány 4 případy onemocnění a úmrtí člověka na lyssu způsobenou některým z netopýřích lyssavirů. Netopýří lyssaviry jsou z imunologického hlediska velmi podobné klasickému viru vztekliny, takže standardně používané metody profylaxe jsou proti nim dostatečně účinné. Vzhledem k odlišnému přírodnímu rezervoáru lze ČR nadále považovat za zemi vztekliny prostou, ale kontakt s netopýry je vždy nutno z hlediska vztekliny považovat za rizikovy.
In 2005, six children were treated in our department who had been in contact with a bat infected with European bat lyssavirus 1 (EBLl). In the Czech Republic, this was the first confirmed case of rabies since 2002, but the fourth case of bat rabies since 1994. All the cases were related to Southern Moravia and bat species which almost do not migrate. This suggests only endemic prevalence of EBLl in this country. Bat rabies is different from rabies in terrestic ic mammals. Based on genetic analyses, the lyssavirus genus may be divided into 6 genotypes of which genotypes I (rabies virus), 5 (EBLl) and 6 (EBL2) are found in Europe. The infectious cycles of bat lyssaviruses are limited solely to bat populations, in particular the Eptesicus serotinus species and the Myotis genus. Transmission to other mammals is rare. In Europe, four cases of human infection and death due to rabies caused by any of bat lyssaviruses have been reported. Immunologically, bat lyssaviruses are very similar to the common rabies virus. Therefore, the standard prophylactic methods are sufficient. Because of a different natural reservoir, the Czech Republic may be still considered a rabies-free country. However, contacts with bats always pose a risk of rabies.
- MeSH
- Chiroptera MeSH
- hlášení nemocí MeSH
- infekce přenášené vektorem MeSH
- lidé MeSH
- Lyssavirus izolace a purifikace klasifikace MeSH
- rabies diagnóza epidemiologie přenos MeSH
- virus rabies izolace a purifikace patogenita MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
- Evropa MeSH
