Semliki Forest Virus: Cause of a Fatal Case of Human Encephalitis

Willems, Wulf R.; Kaluza, G.; Boschek, C. B.; Bauer, Heinz; Hager, H.; Schütz, Hansjörg; Feistner, Helmut

doi:10.1126/science.424742

Cited by 74 publications

(38 citation statements)

References 5 publications

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“…It is known that the scientist was working with virus supernatant from BHK cells, but the route of infection is unknown. Seroconversion in laboratory workers is, however, common [46].…”

Section: Semliki Forest Virusmentioning

confidence: 99%

The Pathogenesis of Alphaviruses

Atkins

2013

ISRN Virology

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Alphaviruses are enveloped single-stranded positive sense RNA viruses of the family Togaviridae. e genus alphavirus contains nine viruses, which are of medical, theoretical, or economic importance, and which will be considered. Sindbis virus (SINV) and Semliki Forest (SFV), although of some medical importance, have largely been studied as models of viral pathogenicity. In mice, SINV and SFV infect neurons in the central nervous system and virulent strains induce lethal encephalitis, whereas avirulent strains of SFV induce demyelination. SFV infects the developing foetus and can be teratogenic. Venezuelan Equine Encephalitis virus, Eastern Equine Encephalitis virus, and Western Equine Encephalitis virus can induce encephalitis in horses and humans. ey are prevalent in the Americas and are mosquito transmitted. Ross River virus, Chikungunya virus (CHIKV), and O'nyong-nyong virus (ONNV) are prevalent in Australasia, Africa and Asia, and Africa, respectively. ONNV virus is transmitted by Anopheles mosquitoes, while the other alphaviruses are transmitted by culicine mosquitoes. CHIKV has undergone adaptation to a new mosquito host which has increased its host range beyond Africa. Salmonid alphavirus is of economic importance in the farmed salmon and trout industry. It is postulated that future advances in research on alphavirus pathogenicity will come in the �eld of innate immunity.

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“…It is known that the scientist was working with virus supernatant from BHK cells, but the route of infection is unknown. Seroconversion in laboratory workers is, however, common [46].…”

Section: Semliki Forest Virusmentioning

confidence: 99%

The Pathogenesis of Alphaviruses

Atkins

2013

ISRN Virology

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“…Human SFV infections are associated with a disease characterized by headache, fever, myalgia, and arthralgia of variable severity (14,15). One fatal case of SFV encephalitis in a laboratory worker has been reported (16).…”

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confidence: 99%

Attenuation of Semliki Forest Virus Neurovirulence by MicroRNA-Mediated Detargeting

Ylösmäki

Martikainen

Hinkkanen

et al. 2013

J Virol

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cArtificial target sequences for tissue-specific miRNAs have recently been introduced as a new means for altering the tissue tropism of viral replication. This approach can be used to improve the safety of oncolytic viruses for cancer virotherapy by restricting their replication in unwanted tissues, such as the liver. Semliki Forest virus (SFV) is a positive-strand RNA virus and, similar to the related alphaviruses, like Sindbis virus, has potential as a gene therapy vector and an oncolytic virotherapy agent, but this potential is limited by the neurovirulence of these alphaviruses. Here, we have generated a replicative SFV4 carrying six tandem targets for the neuron-specific miR124 between the viral nonstructural protein 3 and 4 (nsp3 and nsp4) genes. When administered intraperitoneally into adult BALB/c mice, SFV4-miRT124 displayed an attenuated spread into the central nervous system (CNS) and greatly increased survival. Peripheral replication was not affected, indicating neuron-specific attenuation. Moreover, a strong protective SFV immunity was elicited in these animals. Intracranial infection of adult mice with SFV4-miRT124 showed greatly reduced infection of neurons in the brain but led to the infection of oligodendrocytes in the corpus callosum. Taken together, our data show that miR124-mediated attenuation of neurovirulence is a feasible and promising strategy for generating safer oncolytic alphavirus virotherapy agents. M icroRNAs (miRNAs) are small noncoding RNA molecules that have important regulatory roles in gene expression by targeting mRNAs for cleavage or translational repression. Incomplete sequence complementarity between the miRNA and the target mRNA can induce translational repression without mRNA degradation, whereas a higher degree of sequence complementarity leads to catalytic degradation of the target mRNA (1). The human genome encodes more than 1,000 miRNAs, and over 50% of cellular mRNAs have been estimated to be under miRNA regulation (2). miRNAs have important regulatory roles in development, cell proliferation, differentiation, apoptosis, and stress responses, explaining why dysregulation of miRNA expression is associated with many diseases, most notably cancer (3). miRNA targeting has recently been used to modify replicative tropism of both RNA and DNA viruses (4-10). By tissue-specific targeting the expression of viral genes that account for viral replication/ pathogenicity, it is possible to generate rationally attenuated live vaccine viruses and safer oncolytic viruses for the treatment of cancer. For example, Edge et al. developed a tumor-specific vesicular stomatitis virus (VSV) by inserting 3 copies of Let7 miRNA target elements in the 3= untranslated region of the VSV genomic RNA (5). Likewise, by inserting four copies of muscle-specific miRNA target elements into the coxsackievirus A21 genome, Kelly et al. could prevent lethal myositis developing in mice infected with the miRNA-targeted coxsackievirus A21 without compromising the tumor cell-killing potency of this virus (7)....

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“…(1) SAGV itself is quite safe without any cases of human illness so far. In the cases of SINV and SFV, it has been reported that some isolates are pathogenic for humans (16,17,32). (2) No translational enhancer in the capsid region has been detected for SAGV, making it possible to express a foreign gene without including additional residues derived from the Nterminal region of the capsid protein.…”

Section: Pseudovirion Formation For Expression and Purification Of Gfmentioning

confidence: 99%

Engineering of a Sagiyama Alphavirus RNA‐Based Transient Expression Vector

Yamaguchi

Shirako

2002

Microbiology and Immunology

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Sagiyama virus (SAGV), a strain of Getah virus in the genus Alphavirus in the family Togaviridae, has a broad host range in vertebrates and invertebrates but is not pathogenic for humans. We engineered the SAGV genome as an efficient transient expression vector using the full‐length infectious cDNA clone pSAG2 as the background. A green fluorescent protein (GFP) gene was used as a reporter gene and expressed from a subgenomic mRNA. When the GFP gene was placed downstream of the intact capsid protein gene or an internally deleted capsid protein gene encoding the N‐terminal 9 amino acids and C‐terminal 149 amino acids, autoproteolysis occurred efficiently at the boundary site to release GFP from the N‐terminally‐fused capsid‐protease domain. GFP was also expressed efficiently without the 5′‐terminal region of the capsid protein gene, suggesting that SAGV capsid protein gene does not have a translation enhancer sequence. To provide structural proteins for pseudovirion formation, a nonviable mutant construct, pSAG2.3L, which contains a Gly‐to‐Leu substitution at the − 2 position of the nsP3/4 cleavage site, was used as a helper. GFP was expressed up to 50 μg from 1 × 106 BHK21 cells after inoculation of pseudovirions. The C6/36 mosquito cell was also a suitable host for a large scale expression of GFP using pseudovirions. In addition to high‐level transient expression, safeness of SAGV should give an advantage over other alphavirus expression vectors.

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Semliki Forest Virus: Cause of a Fatal Case of Human Encephalitis

Cited by 74 publications

References 5 publications

The Pathogenesis of Alphaviruses

The Pathogenesis of Alphaviruses

Attenuation of Semliki Forest Virus Neurovirulence by MicroRNA-Mediated Detargeting

Engineering of a Sagiyama Alphavirus RNA‐Based Transient Expression Vector

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