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
- Hemorrhagic Fever, American * immunology prevention & control MeSH
- Arenaviruses, New World immunology MeSH
- Epitopes immunology chemistry MeSH
- Humans MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Viral Vaccines * immunology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article 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.
Rodents are a speciose group of mammals with strong zoonotic potential. Some parts of Africa are still underexplored for the occurrence of rodent-borne pathogens, despite this high potential. Angola is at the convergence of three major biogeographical regions of sub-Saharan Africa, each harbouring a specific rodent community. This rodent-rich area is, therefore, strategic for studying the diversity and evolution of rodent-borne viruses. In this study we examined 290 small mammals, almost all rodents, for the presence of mammarenavirus and hantavirus RNA. While no hantavirus was detected, we found three rodent species positive for distinct mammarenaviruses with a particularly high prevalence in Namaqua rock rats (Micaelamys namaquensis). We characterised four complete virus genomes, which showed typical mammarenavirus organisation. Phylogenetic and genetic distance analyses revealed: (i) the presence of a significantly divergent strain of Luna virus in Angolan representatives of the ubiquitous Natal multimammate mouse (Mastomys natalensis), (ii) a novel Okahandja-related virus associated with the Angolan lineage of Micaelamys namaquensis for which we propose the name Bitu virus (BITV) and (iii) the occurrence of a novel Mobala-like mammarenavirus in the grey-bellied pygmy mouse (Mus triton) for which we propose the name Kwanza virus (KWAV). This high virus diversity in a limited host sample size and in a relatively small geographical area supports the idea that Angola is a hotspot for mammarenavirus diversity.
- MeSH
- Arenaviridae classification genetics MeSH
- Phylogeny MeSH
- Genome, Viral MeSH
- Arenaviridae Infections veterinary MeSH
- Geography, Medical MeSH
- Rodent Diseases epidemiology virology MeSH
- Prevalence MeSH
- RNA, Viral MeSH
- Whole Genome Sequencing MeSH
- Disease Reservoirs virology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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 immunology MeSH
- Population Density MeSH
- Arenaviridae Infections epidemiology MeSH
- Mice MeSH
- Rodent Diseases epidemiology MeSH
- Antibodies, Viral MeSH
- Seroepidemiologic Studies MeSH
- Disease Reservoirs veterinary MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Tanzania 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-Positive T-Lymphocytes immunology MeSH
- Cytokines biosynthesis MeSH
- Hereditary Sensory and Autonomic Neuropathies genetics MeSH
- Cells, Cultured MeSH
- Middle Aged MeSH
- Humans MeSH
- Lymphocytic Choriomeningitis immunology virology MeSH
- Mechanistic Target of Rapamycin Complex 1 metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Cell Proliferation MeSH
- Serine C-Palmitoyltransferase genetics MeSH
- Sphingolipids biosynthesis MeSH
- Signal Transduction immunology MeSH
- Endoplasmic Reticulum Stress genetics immunology MeSH
- Lymphocytic choriomeningitis virus immunology MeSH
- Animals MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Survival Analysis MeSH
- Arenavirus immunology isolation & purification MeSH
- Behavior, Animal MeSH
- Arenaviridae Infections mortality veterinary MeSH
- Murinae * MeSH
- Rodent Diseases mortality virology MeSH
- Antibodies, Viral blood MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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 isolation & purification MeSH
- Disease Vectors * MeSH
- Arenaviridae Infections pathology veterinary virology MeSH
- Murinae physiology virology MeSH
- Carrier State pathology veterinary virology MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Guinea MeSH
- Tanzania 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 classification metabolism physiology MeSH
- Species Specificity MeSH
- Phylogeography MeSH
- Lassa Fever virology MeSH
- Humans MeSH
- Murinae virology MeSH
- Rodent Diseases virology MeSH
- Lassa virus physiology MeSH
- Disease Reservoirs virology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Tanzania 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
- Humans MeSH
- Lymphocytic Choriomeningitis * diagnosis etiology prevention & control therapy MeSH
- Rabies Vaccines history pharmacology immunology therapeutic use MeSH
- Lymphocytic choriomeningitis virus classification pathogenicity growth & development MeSH
- Rabies virus pathogenicity growth & development MeSH
- Rabies * diagnosis etiology prevention & control therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review 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 classification genetics isolation & purification MeSH
- Phylogeny MeSH
- Genetic Variation * MeSH
- Arenaviridae Infections immunology veterinary virology MeSH
- Molecular Sequence Data MeSH
- Murinae immunology virology MeSH
- Rodent Diseases immunology virology MeSH
- Antibodies, Viral immunology MeSH
- Lassa virus classification genetics isolation & purification MeSH
- Disease Reservoirs virology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Tanzania MeSH
