Flavivirus Encephalitis

Kimura, Takashi; Sasaki, Michihito; Okumura, Megumi J.; Kim, E.; Sawa, Hirofumi

doi:10.1177/0300985810372507

Cited by 76 publications

(52 citation statements)

References 114 publications

(179 reference statements)

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“…Pathologic changes in mouse brains as well as clinical signs are similar of those observed in humans [35,36,37]. In agreement with previous findings, virus recovered from infectious clones displayed lower mortality than the original cell culture derived Oshima 5–10 strain which induces high mortality in mice following intra-peritoneal inoculation [34].…”

Section: Resultssupporting

confidence: 85%

Attenuation of Tick-Borne Encephalitis Virus Using Large-Scale Random Codon Re-encoding

et al. 2015

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Large-scale codon re-encoding (i.e. introduction of a large number of synonymous mutations) is a novel method of generating attenuated viruses. Here, it was applied to the pathogenic flavivirus, tick-borne encephalitis virus (TBEV) which causes febrile illness and encephalitis in humans in forested regions of Europe and Asia. Using an infectious clone of the Oshima 5–10 strain ("wild-type virus"), a cassette of 1.4kb located in the NS5 coding region, was modified by randomly introducing 273 synonymous mutations ("re-encoded virus"). Whilst the in cellulo replicative fitness of the re-encoded virus was only slightly reduced, the re-encoded virus displayed an attenuated phenotype in a laboratory mouse model of non-lethal encephalitis. Following intra-peritoneal inoculation of either 2.105 or 2.106 TCID50 of virus, the frequency of viraemia, neurovirulence (measured using weight loss and appearance of symptoms) and neuroinvasiveness (detection of virus in the brain) were significantly decreased when compared with the wild-type virus. Mice infected by wild-type or re-encoded viruses produced comparable amounts of neutralising antibodies and results of challenge experiments demonstrated that mice previously infected with the re-encoded virus were protected against subsequent infection by the wild-type virus. This constitutes evidence that a mammalian species can be protected against infection by a virulent wild-type positive-stranded RNA virus following immunisation with a derived randomly re-encoded strain. Our results demonstrate that random codon re-encoding is potentially a simple and effective method of generating live-attenuated vaccine candidates against pathogenic flaviviruses.

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Section: Resultssupporting

confidence: 85%

Attenuation of Tick-Borne Encephalitis Virus Using Large-Scale Random Codon Re-encoding

et al. 2015

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“…In both KFDV- and AHFV-infected mice, intestinal lesions included inflammation of enteric nerve plexi, associated with neuronal degeneration and depletion. This finding has also been reported in mouse models of West Nile virus [10], [19]. …”

Section: Discussionsupporting

confidence: 84%

Kyasanur Forest Disease Virus Infection in Mice Is Associated with Higher Morbidity and Mortality than Infection with the Closely Related Alkhurma Hemorrhagic Fever Virus

et al. 2014

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BackgroundKyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic fever virus (AHFV) are closely related members of the Flavivirus genus and are important causes of human disease in India and the Arabian Peninsula, respectively. Despite high genetic similarity, the viruses have distinctly different host ranges and ecologies. Human cases of KFDV or AHFV develop a spectrum of disease syndromes ranging from liver pathology to neurologic disease. Case reports suggest KFDV is more commonly associated with hepatic and gastrointestinal manifestations whereas AHFV is more commonly associated with neurologic disease.Methodology/Principal FindingsInoculation of three immunocompetent laboratory mouse strains revealed that KFDV was consistently more lethal than AHFV. In subsequent studies utilizing C57BL/6J mice, we demonstrated that KFDV infection was associated with higher viral loads and significantly higher mortality. KFDV-infected mice rapidly developed more severe disease than AHFV-infected mice, as evidenced by significant abnormalities on clinical chemistry panels and more severe pathology in the brain and gastrointestinal tract.Conclusions/SignificanceInfections of C57BL/6J mice with KFDV or AHFV resulted in clinical disease syndromes that closely approximate the diseases seen in human cases. Despite high genetic similarity, there were clear differences in survival, viral kinetics, clinical chemistry data and histology. These results suggest that distinct mouse models for AHFV and KFDV are necessary in order to gain a better understanding of the unique pathogenesis of each virus, as well as to provide platforms for testing promising vaccines and therapeutics.

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“…Histological changes in the brain were characterized by glial cell proliferation, formation of lymphocyte perivascular cuffing and neuronal degeneration. These changes were all reminiscent of those observed in rodent infection models with virus such as JEV [21-23], WNV [24], DENV [25] and YFV [26]. Viral antigens were detected in neural cells of the brain, and the development of clinical symptoms coincided with progressive inflammatory infiltration.…”

Section: Discussionmentioning

confidence: 71%

Duck Tembusu virus exhibits neurovirulence in BALB/c mice

Zhang

et al. 2013

Virol J

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BackgroundDuck Tembusu virus is a member of the Ntaya group in the genus Flavivirus. The virus has been responsible for severe duck egg-drop syndrome in China since 2010. Its emergence and rapid spread have caused great economic loss for the poultry industry. The epidemiology of the virus infection and the potential threat to public health is of great concern because of the infective and zoonotic nature of flaviviruses.ResultsIn this study, the pathogenicity of duck Tembusu virus in BALB/c mice was investigated. Infected mice developed clinical signs, including loss of appetite, ruffled hair, weight loss, disorientation, blindness and paralysis of hind limbs from six days post- infection following intracerebral inoculation. Morbidity was 100%, with mortality ranging from 20 to 80% in three- to eight-week-old mice. High virus titers were recovered from the brain, and the virus was distributed in several organs. Histologically, there was widespread non-suppurative encephalitis in the brain. Lymphocyte depletion in the spleen was observed, along with fatty degeneration in the liver and kidney.ConclusionsOur results demonstrate, for the first time, that duck Tembusu virus is highly neurovirulent in BALB/c mice. The mouse model used in this work was able to produce Tembusu virus infection and could be useful for elucidating some of the aspects of the pathophysiology of other flavivirus infections.

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Flavivirus Encephalitis

Cited by 76 publications

References 114 publications

Attenuation of Tick-Borne Encephalitis Virus Using Large-Scale Random Codon Re-encoding

Attenuation of Tick-Borne Encephalitis Virus Using Large-Scale Random Codon Re-encoding

Kyasanur Forest Disease Virus Infection in Mice Is Associated with Higher Morbidity and Mortality than Infection with the Closely Related Alkhurma Hemorrhagic Fever Virus

Duck Tembusu virus exhibits neurovirulence in BALB/c mice

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