Venezuelan Equine Encephalitis Virus Variants Lacking Transcription Inhibitory Functions Demonstrate Highly Attenuated Phenotype
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ABSTRACT Alphaviruses represent a significant public health threat worldwide. They are transmitted by mosquitoes and cause a variety of human diseases ranging from severe meningoencephalitis to polyarthritis. To date, no efficient and safe vaccines have been developed against any alphavirus infection. However, in recent years, significant progress has been made in understanding the mechanism of alphavirus replication and virus-host interactions. These data have provided the possibility for the development of new rationally designed alphavirus vaccine candidates that combine efficient immunogenicity, high safety, and inability to revert to pathogenic phenotype. New attenuated variants of Venezuelan equine encephalitis virus (VEEV) designed in this study combine a variety of characteristics that independently contribute to a reduction in virulence. These constructs encode a noncytopathic VEEV capsid protein that is incapable of interfering with the innate immune response. The capsid-specific mutations strongly affect neurovirulence of the virus. In other constructs, they were combined with changes in control of capsid translation and an extensively mutated packaging signal. These modifications also affected the residual neurovirulence of the virus, but it remained immunogenic, and a single immunization protected mice against subsequent infection with epizootic VEEV. Similar approaches of attenuation can be applied to other encephalitogenic New World alphaviruses. IMPORTANCE Venezuelan equine encephalitis virus (VEEV) is an important human and animal pathogen, which causes periodic outbreaks of highly debilitating disease. Despite a continuous public health threat, no safe and efficient vaccine candidates have been developed to date. In this study, we applied accumulated knowledge about the mechanism of VEEV replication, RNA packaging, and interaction with the host to design new VEEV vaccine candidates that demonstrate exceptionally high levels of safety due to a combination of extensive modifications in the viral genome. The introduced mutations did not affect RNA replication or structural protein synthesis but had deleterious effects on VEEV neuroinvasion and virulence. In spite of dramatically reduced virulence, the designed mutants remained highly immunogenic and protected mice against subsequent infection with epizootic VEEV. Similar methodologies can be applied for attenuation of other encephalitogenic New World alphaviruses.Keywords:
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Cyclophosphamide altered not only the pathological picture of virus encephalitis, but also enhanced the invasiveness of viruses and produced fatal forms of disease to which monkeys were otherwise resistant. Normal patas monkeys infected either i.c. or intranasally (i.n.) with louping ill developed clinical encephalitis from which they recovered, but when cyclophosphamide was administered the disease proved fatal. Normal rhesus monkeys inoculated i.n. with virulent western equine encephalitis virus developed neither clinical disease nor CNS lesions, but after treatment with cyclophosphamide they developed fatal encephalitis. The viruses of louping ill, Venezuelan equine encephalitis and Western equine encephalitis when given without an immunosuppressant usually gave rise to acute inflammatory CNS pathology, but when the monkeys were given cyclophosphamide, the inflammatory reaction was replaced by a degenerative process causing both neuronal necrosis and spongy degeneration.
Immunosuppression
Encephalitis Viruses
Viral encephalitis
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Sindbis virus
Togaviridae
Alphavirus infection
Nitazoxanide
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Abstract : The clinical observations of four human cases of infection with the Venezuelan equine encephalitis virus are described. The infections occurred in the laboratory. Venezuelan equine encephalitis virus was isolated from all four patients.
Encephalitis Viruses
Veterinary virology
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The arthropod-borne encephalitides are an important cause of equine and human morbidity in the Americas. Between 1975 and 1978, 6970 human cases of arboviral encephalitis were reported in the United States of America; however, this represents only a fraction of the true incidence. St Louis encephalitis (4824 cases), California encephalitis (1035 cases), and western equine encephalitis (WEE, 947 cases) accounted for 98.5% of all reported infections. Approximately 1000-4000 cases of equine encephalitis occur annually in the United States, the majority due to WEE. In tropical America, important outbreaks of Venezuelan, eastern, and western equine encephalitis, and of Rocio encephalitis have occurred.In this article, epidemiological aspects of arboviral encephalitis outbreaks occurring within the past 5 years are reviewed. In addition, summaries of current research activities on the ecology and epidemiology of St Louis, western equine, Venezuelan equine, Rocio, and California encephalitis viruses are presented, and the problem of control of these infections is discussed.
Encephalitis Viruses
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In computational neural network models, neurons are usually allowed to excite some and inhibit other neurons, depending on the weight of their synaptic connections. The traditional way to transform such networks into networks that obey Dale's law (i.e., a neuron can either excite or inhibit) is to accompany each excitatory neuron with an inhibitory one through which inhibitory signals are mediated. However, this requires an equal number of excitatory and inhibitory neurons, whereas a realistic number of inhibitory neurons is much smaller. In this letter, we propose a model of nonlinear interaction of inhibitory synapses on dendritic compartments of excitatory neurons that allows the excitatory neurons to mediate inhibitory signals through a subset of the inhibitory population. With this construction, the number of required inhibitory neurons can be reduced tremendously.
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Venezuelan equine encephalitis virus (VEEV) is a new world alphavirus and a category B select agent. Currently, no FDA-approved vaccines or therapeutics are available to treat VEEV exposure and resultant disease manifestations. The C-terminus of the VEEV non-structural protein 3 (nsP3) facilitates cell-specific and virus-specific host factor binding preferences among alphaviruses, thereby providing targets of interest when designing novel antiviral therapeutics. In this study, we utilized an overexpression construct encoding HA-tagged nsP3 to identify host proteins that interact with VEEV nsP3 by mass spectrometry. Bioinformatic analyses of the putative interactors identified 42 small molecules with the potential to inhibit the host interaction targets, and thus potentially inhibit VEEV. Three inhibitors, tomatidine, citalopram HBr, and Z-VEID-FMK, reduced replication of both the TC-83 strain and the Trinidad donkey (TrD) strain of VEEV by at least 10-fold in astrocytoma, astroglial, and microglial cells. Further, these inhibitors reduced replication of the related New World (NW) alphavirus Eastern equine encephalitis virus (EEEV) in multiple cell types, thus demonstrating broad-spectrum antiviral activity. Time-course assays revealed all three inhibitors reduced both infectious particle production and positive-sense RNA levels post-infection. Further evaluation of the putative host targets for the three inhibitors revealed an interaction of VEEV nsP3 with TFAP2A, but not eIF2S2. Mechanistic studies utilizing siRNA knockdowns demonstrated that eIF2S2, but not TFAP2A, supports both efficient TC-83 replication and genomic RNA synthesis, but not subgenomic RNA translation. Overall, this work reveals the composition of the VEEV nsP3 proteome and the potential to identify host-based, broad spectrum therapeutic approaches to treat new world alphavirus infections.
Subgenomic mRNA
Sindbis virus
Togaviridae
Neurotropic virus
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Early and sustained treatment with interleukin-12 (IL-12) ameliorated disease in a mouse model of infection with the encephalitogenic flavivirus, St. Louis encephalitis virus (SLEV, Japanese encephalitis serogroup). However, this effect was not reproduced in murine infections with either the flavivirus tick-bore encephalitis virus (TBEV) or the alphavirus Venezuelan equine encephalitis virus (VEEV). IL-12 exacerbated TBEV disease when used in conjunction with monoclonal antibody (mAb), suggesting an enhancement of immunopathology, and was without clinical effects in VEEV infection. These data confirm the need to fully understand the pathogenesis of viral infection before cytokine intervention may be employed as a broad-spectrum antiviral therapy.
Flavivirus
Tick-borne encephalitis
Togaviridae
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Clinical findings on Venezuelan Equine Encephalitis virus infection and the teratogenic effects of several Togaviruses are described. Similarities between the intrauterine alterations induced by Venezuelan Equine Encephalitis virus and rubella virus are pointed out. Findings described by Wenger in 1967 were those of massive cerebral necrosis in fetuses of women presumably suffering of encephalitis and they are commented along with the development of an animal experimental model at the end of 1970-1980. Pathogenesis of the intrauterine infection seemed to be related to changes in the placental vessels, vascular changes in the central nervous system were also described in rats surviving Venezuelan Equine Encephalitis experimental infection; similar changes were described in the brain of children with post rubella syndrome. The need for multidisciplinary studies in the endemic areas of Venezuelan Equine Encephalitis in order to detect sequelae of the viral effects in utero is emphasized. Finally, some experimental animal models are proposed to examine diverse aspects on intrauterine effect of Venezuelan Equine Encephalitis virus.
Pathogenesis
Viral encephalitis
Encephalitis Viruses
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Eastern equine encephalitis (EEE) and Venezuelan equine encephalitis (VEE) are associated with severe morbidity and mortality in equines and humans. In the U.S., EEE is both the least frequent and the most lethal of the principal arbovirus encephalitides.
To examine features of an outbreak of encephalitis in humans and horses in Darien, an eastern province of Panama, researchers identified 19 patients with encephalitis admitted to …
Panama
Viral encephalitis
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Seventeen young boars were exposed to spontaneous infection with Japanese encephalitis virus (JEV). They manifested scrotal edema, which disappeared about 10 days later, a rise in HI antibody against JEV, two-peak pyrexia, and anorexia. Histopathological examination revealed subacute orchitis, epididymitis, funiculitis, and nonpurulent encephalitis.These changes were marked 1-5 days after the appearance of scrotal edema. Organization of the testis, low and insufficient spermatogenesis, and nonpurulent encephalitis were noticed over a period from 7 to 41 days after the appearance of scrotal edema.
Epididymitis
Orchitis
Anorexia
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