Bolivian hemorrhagic fever (BHF) caused by Machupo virus (MACV) is a New World arenavirus having a reported mortality rate of 25-35%. The BHF starts with fever, followed by headache, and nausea which rapidly progresses to severe hemorrhagic phase within 7 days of disease onset. One of the key promoters for MACV viral entry into the cell followed by viral propagation is performed by the viral glycoprotein (GPC). GPC is post-transcriptionally cleaved into GP1, GP2 and a signal peptide. These proteins all take part in the viral infection in host body. Therefore, GPC protein is an ideal target for developing therapeutics against MACV infection. In this study, GPC protein was considered to design a multi-epitope, multivalent vaccine containing antigenic and immunogenic CTL and HTL epitopes. Different structural validations and physicochemical properties were analysed to validate the vaccine. Docking and molecular dynamics simulations were conducted to understand the interactions of the vaccine with various immune receptors. Finally, the vaccine was codon optimised in silico and along with which immune simulation studies was performed in order to evaluate the vaccine's effectiveness in triggering an efficacious immune response against MACV.
- MeSH
- americká hemoragická horečka * imunologie prevence a kontrola MeSH
- arenaviry Nového světa imunologie MeSH
- epitopy imunologie chemie MeSH
- lidé MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- virové vakcíny * imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Increased glucose uptake and utilization via aerobic glycolysis are among the most prominent hallmarks of tumor cell metabolism. Accumulating evidence suggests that similar metabolic changes are also triggered in many virus-infected cells. Viral propagation, like highly proliferative tumor cells, increases the demand for energy and macromolecular synthesis, leading to high bioenergetic and biosynthetic requirements. Although significant progress has been made in understanding the metabolic changes induced by viruses, the interaction between host cell metabolism and arenavirus infection remains unclear. Our study sheds light on these processes during lymphocytic choriomeningitis virus (LCMV) infection, a model representative of the Arenaviridae family. METHODS: The impact of LCMV on glucose metabolism in MRC-5 cells was studied using reverse transcription-quantitative PCR and biochemical assays. A focus-forming assay and western blot analysis were used to determine the effects of glucose deficiency and glycolysis inhibition on the production of infectious LCMV particles. RESULTS: Despite changes in the expression of glucose transporters and glycolytic enzymes, LCMV infection did not result in increased glucose uptake or lactate excretion. Accordingly, depriving LCMV-infected cells of extracellular glucose or inhibiting lactate production had no impact on viral propagation. However, treatment with the commonly used glycolytic inhibitor 2-deoxy-D-glucose (2-DG) profoundly reduced the production of infectious LCMV particles. This effect of 2-DG was further shown to be the result of suppressed N-linked glycosylation of the viral glycoprotein. CONCLUSIONS: Although our results showed that the LCMV life cycle is not dependent on glucose supply or utilization, they did confirm the importance of N-glycosylation of LCMV GP-C. 2-DG potently reduces LCMV propagation not by disrupting glycolytic flux but by inhibiting N-linked protein glycosylation. These findings highlight the potential for developing new, targeted antiviral therapies that could be relevant to a wider range of arenaviruses.
A key aim in wildlife disease ecology is to understand how host and parasite characteristics influence parasite transmission and persistence. Variation in host population density can have strong impacts on transmission and outbreaks, and theory predicts particular transmission-density patterns depending on how parasites are transmitted between individuals. Here, we present the results of a study on the dynamics of Morogoro arenavirus in a population of multimammate mice (Mastomys natalensis). This widespread African rodent, which is also the reservoir host of Lassa arenavirus in West Africa, is known for its strong seasonal density fluctuations driven by food availability. We investigated to what degree virus transmission changes with host population density and how the virus might be able to persist during periods of low host density. A seven-year capture-mark-recapture study was conducted in Tanzania where rodents were trapped monthly and screened for the presence of antibodies against Morogoro virus. Observed seasonal seroprevalence patterns were compared with those generated by mathematical transmission models to test different hypotheses regarding the degree of density dependence and the role of chronically infected individuals. We observed that Morogoro virus seroprevalence correlates positively with host density with a lag of 1-4 months. Model results suggest that the observed seasonal seroprevalence dynamics can be best explained by a combination of vertical and horizontal transmission and that a small number of animals need to be infected chronically to ensure viral persistence. Transmission dynamics and viral persistence were best explained by the existence of both acutely and chronically infected individuals and by seasonally changing transmission rates. Due to the presence of chronically infected rodents, rodent control is unlikely to be a feasible approach for eliminating arenaviruses such as Lassa virus from Mastomys populations.
- MeSH
- Arenavirus imunologie MeSH
- hustota populace MeSH
- infekce viry z čeledi Arenaviridae epidemiologie MeSH
- myši MeSH
- nemoci hlodavců epidemiologie MeSH
- protilátky virové MeSH
- séroepidemiologické studie MeSH
- zdroje nemoci veterinární MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Tanzanie MeSH
Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8+ T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses. Antigen stimulation and inflammation induced SPTLC2 expression, and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress, and CD8+ T cell death. Protective CD8+ T cell responses in HSAN-I patient PBMCs and Sptlc2-deficient mice were restored by supplementing with sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Therefore, SPTLC2 underpins protective immunity by translating extracellular stimuli into intracellular anabolic signals and antagonizes ER stress to promote T cell metabolic fitness.
- MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- cytokiny biosyntéza MeSH
- dědičné senzorické a autonomní neuropatie genetika MeSH
- kultivované buňky MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfocytární choriomeningitida imunologie virologie MeSH
- mTORC1 metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- proliferace buněk MeSH
- serin-C-palmitoyltransferasa genetika MeSH
- sfingolipidy biosyntéza MeSH
- signální transdukce imunologie MeSH
- stres endoplazmatického retikula genetika imunologie MeSH
- virus lymfocytární choriomeningitidy imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: Parasite evolution is hypothesized to select for levels of parasite virulence that maximise transmission success. When host population densities fluctuate, low levels of virulence with limited impact on the host are expected, as this should increase the likelihood of surviving periods of low host density. We examined the effects of Morogoro arenavirus on the survival and recapture probability of multimammate mice (Mastomys natalensis) using a seven-year capture-mark-recapture time series. Mastomys natalensis is the natural host of Morogoro virus and is known for its strong seasonal density fluctuations. RESULTS: Antibody presence was negatively correlated with survival probability (effect size: 5-8% per month depending on season) but positively with recapture probability (effect size: 8%). CONCLUSIONS: The small negative correlation between host survival probability and antibody presence suggests that either the virus has a negative effect on host condition, or that hosts with lower survival probability are more likely to obtain Morogoro virus infection, for example due to particular behavioural or immunological traits. The latter hypothesis is supported by the positive correlation between antibody status and recapture probability which suggests that risky behaviour might increase the probability of becoming infected.
- MeSH
- analýza přežití MeSH
- Arenavirus imunologie izolace a purifikace MeSH
- chování zvířat MeSH
- infekce viry z čeledi Arenaviridae mortalita veterinární MeSH
- Murinae * MeSH
- nemoci hlodavců mortalita virologie MeSH
- protilátky virové krev MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: In order to optimize net transmission success, parasites are hypothesized to evolve towards causing minimal damage to their reservoir host while obtaining high shedding rates. For many parasite species however this paradigm has not been tested, and conflicting results have been found regarding the effect of arenaviruses on their rodent host species. The rodent Mastomys natalensis is the natural reservoir host of several arenaviruses, including Lassa virus that is known to cause Lassa haemorrhagic fever in humans. Here, we examined the effect of three arenaviruses (Gairo, Morogoro and Lassa virus) on four parameters of wild-caught Mastomys natalensis: body mass, head-body length, sexual maturity and fertility. After correcting for the effect of age, we compared these parameters between arenavirus-positive (arenavirus RNA or antibody) and negative animals using data from different field studies in Guinea (Lassa virus) and Tanzania (Morogoro and Gairo viruses). RESULTS: Although the sample sizes of our studies (1297, 749 and 259 animals respectively) were large enough to statistically detect small differences in body conditions, we did not observe any adverse effects of these viruses on Mastomys natalensis. We did find that sexual maturity was significantly positively related with Lassa virus antibody presence until a certain age, and with Gairo virus antibody presence in general. Gairo virus antibody-positive animals were also significantly heavier and larger than antibody-free animals. CONCLUSION: Together, these results suggest that the pathogenicity of arenaviruses is not severe in M. natalensis, which is likely to be an adaptation of these viruses to optimize transmission success. They also suggest that sexual behaviour might increase the probability of M. natalensis to become infected with arenaviruses.
- MeSH
- Arenavirus izolace a purifikace MeSH
- infekce přenášené vektorem * MeSH
- infekce viry z čeledi Arenaviridae patologie veterinární virologie MeSH
- Murinae fyziologie virologie MeSH
- přenašečství patologie veterinární virologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Guinea MeSH
- Tanzanie MeSH
Many emerging infections are RNA virus spillovers from animal reservoirs. Reservoir identification is necessary for predicting the geographic extent of infection risk, but rarely are taxonomic levels below the animal species considered as reservoir, and only key circumstances in nature and methodology allow intrinsic virus-host associations to be distinguished from simple geographic (co-)isolation. We sampled and genetically characterized in detail a contact zone of two subtaxa of the rodent Mastomys natalensis in Tanzania. We find two distinct arenaviruses, Gairo and Morogoro virus, each spatially confined to a single M. natalensis subtaxon, only co-occurring at the contact zone's centre. Inter-subtaxon hybridization at this centre and a continuum of quality habitat for M. natalensis show that both viruses have the ecological opportunity to spread into the other substaxon's range, but do not, strongly suggesting host-intrinsic barriers. Such barriers could explain why human cases of another M. natalensis-borne arenavirus, Lassa virus, are limited to West Africa.
- MeSH
- Arenavirus klasifikace metabolismus fyziologie MeSH
- druhová specificita MeSH
- fylogeografie MeSH
- horečka Lassa virologie MeSH
- lidé MeSH
- Murinae virologie MeSH
- nemoci hlodavců virologie MeSH
- virus Lassa fyziologie MeSH
- zdroje nemoci virologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Tanzanie 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
- vakcína proti vzteklině dějiny farmakologie imunologie terapeutické užití MeSH
- virus lymfocytární choriomeningitidy klasifikace patogenita růst a vývoj MeSH
- virus vztekliny patogenita růst a vývoj MeSH
- vzteklina * diagnóza etiologie prevence a kontrola terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Despite its near pan-African range, the Natal multimammate mouse, Mastomys natalensis, carries the human pathogen Lassa virus only in West Africa, while the seemingly non-pathogenic arenaviruses Mopeia, Morogoro, and Luna have been detected in this semi-commensal rodent in Mozambique/Zimbabwe, Tanzania and Zambia, respectively. Here, we describe a novel arenavirus in M. natalensis from Gairo district of central Tanzania, for which we propose the name "Gairo virus". Surprisingly, the virus is not closely related with Morogoro virus that infects M. natalensis only 90km south of Gairo, but clusters phylogenetically with Mobala-like viruses that infect non-M. natalensis host species in Central African Republic and Ethiopia. Despite the evolutionary distance, Gairo virus shares basic ecological features with the other M. natalensis-borne viruses Lassa and Morogoro. Our data show that M. natalensis, carrying distantly related viruses even in the same geographical area, is a potent reservoir host for a variety of arenaviruses.
- MeSH
- Arenavirus klasifikace genetika izolace a purifikace MeSH
- fylogeneze MeSH
- genetická variace * MeSH
- infekce viry z čeledi Arenaviridae imunologie veterinární virologie MeSH
- molekulární sekvence - údaje MeSH
- Murinae imunologie virologie MeSH
- nemoci hlodavců imunologie virologie MeSH
- protilátky virové imunologie MeSH
- virus Lassa klasifikace genetika izolace a purifikace MeSH
- zdroje nemoci virologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Tanzanie MeSH
Původci virových hemoragických horeček jsou obalené RNA viry z čeledí Filoviridae (viry Ebola a Marburg), Arenaviridae (viry Lassa, Lujo, Junin, Machupo, Guanarito), Bunyaviridae (hantaviry, viry krymsko-konžské hemoragické horečky a horečky Rift Valley) a Flaviviridae (viry žluté zimnice a omské hemoragické horečky). Tyto nákazy představují skupinu akutních systémových horečnatých onemocnění podobného klinického obrazu, která bývají často doprovázena rozvojem šokového stavu s následným multiorgánovým selháním. Infekce se vyskytují na všech kontinentech mimo Antarktidy a patří mezi typické zoonózy a nákazy s přírodní ohniskovostí. Přenos přímým kontaktem s nemocným nebo jeho tělesnými tekutinami je významný zejména u horeček Lassa, Ebola, Marburg a krymsko-konžské hemoragické horečky. Přestože riziko infekce pro turisty je nízké, patří tato onemocnění mezi obávaná pro jejich závažný klinický průběh a nedostupnost cílené léčby. Současná rozsáhlá epidemie horečky Ebola v západní Africe ukazuje, že tyto infekce mohou představovat zdravotnický problém s globálními důsledky. Dalším potenciálním rizikem by mohlo být zneužití těchto patogenů jako zbraní hromadného ničení. Péče o pacienty s podezřením na tyto infekce vyžaduje dodržování přísných bariérových opatření a hospitalizaci na vysoce specializovaném oddělení.
Viral haemorrhagic fevers are caused by enveloped RNA viruses that belong to the families Filoviridae (Ebola, Marburg), Arenaviridae (Lassa, Lujo, Junin, Machupo, Guanarito), Bunyaviridae (hantaviruses, Crimean-Congo haemorrhagic fever and Rift Valley fever virus) and Flaviviridae (yellow fever, Omsk haemorrhagic fever virus). These infections manifest as acute systemic febrile illnesses with severe clinical course followed by development of shock syndrome and subsequent multiorgan dysfunction syndrome. Viral haemorrhagic fevers are widespread and present in all continents with the exception of Antarctica and represent typical zoonotic infections with natural foci. The potential for direct human-to-human transmission is significant in Lassa, Ebola, Marburg and Crimean-Congo haemorrhagic fevers. Although the risk of transmission to tourists is relatively low, these infections are feared for their severe clinical course and unavailable specific treatment. Current Ebola outbreak in western Africa shows that these infections represent a significant public health problem. The potential risk represents the use of these pathogens as weapons of mass destruction. Provision of medical care for patients with viral haemorrhagic fever should be restricted to specialized centres.
- MeSH
- antivirové látky farmakologie MeSH
- Arenavirus klasifikace patogenita MeSH
- diferenciální diagnóza MeSH
- Flavivirus patogenita MeSH
- hemoragické horečky virové * diagnóza epidemiologie etiologie klasifikace patologie prevence a kontrola terapie MeSH
- infekce RNA viry * diagnóza epidemiologie klasifikace patologie prevence a kontrola terapie MeSH
- infekce viry z čeledi Arenaviridae dějiny klasifikace MeSH
- infekce viry z čeledi Bunyaviridae dějiny klasifikace MeSH
- infekce viry z čeledi Filoviridae dějiny klasifikace MeSH
- infekce viry z rodu Flavivirus dějiny klasifikace MeSH
- lidé MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
