Studies on the pathogenesis of and propagation of enterovirus 71 in poliomyelitis-like disease in monkeys

Hashimoto, Isao; Hagiwara, Akio

doi:10.1007/bf00691653

Cited by 20 publications

(11 citation statements)

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“…To investigate the clinical course and the pathological changes of the disease, monkey experiments were performed, and it was found that cynomolgus, rhesus, or green monkeys were susceptible to EV71 infection after subcutaneous, intraspinal or intracerebral inoculations [Hashimoto et al, 1978;Chumakov et al, 1979;Hashimoto and Hagiwara, 1982]. In particular, intraspinal inoculation of cynomolgus monkeys with several EV71 isolates consistently resulted in complete flaccid paralysis and virus-related lesions in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Nagata

Shimizu

Ami

et al. 2002

Journal of Medical Virology

113

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Among the enteroviruses, polioviruses and enterovirus 71 (EV71) are two major neurotropic viruses causing serious neurological manifestations. While polioviruses are being eradicated globally by vaccination, EV71 still has the potential to cause a large outbreak such as that in Taiwan in 1998, in which there were many fatalities. In this study, we determined the neurovirulence of EV71 by neuropathological analysis of cynomolgus monkeys after experimental infection with five EV71 strains, which were isolated from individual patients with fatal encephalitis; meningitis; and hand, foot, and mouth disease. After intraspinal inoculation, the monkeys developed neurological manifestations within 1-6 days post-inoculation, irrespective of the inoculated strains. These manifestations included not only pyramidal tract signs such as flaccid paralysis, but also extrapyramidal tract signs such as tremor and ataxia. Histological and viral examinations confirmed virus replication in the spinal cord, brainstem, cerebellar cortex, and dentate nuclei, and cerebrum. The strains isolated during the 1970s and 1990s showed no particular differences with respect to neurotropism. Thus, it is clear that EV71 has a wider neurotropism than that of polioviruses.

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Section: Introductionmentioning

confidence: 99%

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Nagata

Shimizu

Ami

et al. 2002

Journal of Medical Virology

113

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“…Since the 1970s, HFMD outbreaks with significant mortality have been reported throughout the world, including in Bulgaria in 1975 [44 deaths (7)], Hungary in 1978 [47 deaths (8) Appropriate animal models are needed to better understand EV71 neuropathogenesis and to facilitate the development of effective vaccines and drugs. EV71-infected cynomolgus monkeys developed neurological complications similar to those observed in human cases, including ataxia, tremor, and flaccid paralysis (11)(12)(13)(14)(15), and pathological lesions were observed in the spinal cord, brainstem, cerebellar dentate nucleus, and other parts of the brain (14,15). However, the use of monkeys to model EV71 infection is difficult for both ethical and economic reasons.…”

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confidence: 98%

Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

Fujii¹,

Nagata

Sato

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

150

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Enterovirus 71 (EV71) typically causes mild hand-foot-and-mouth disease in children, but it can also cause severe neurological disease. Recently, epidemic outbreaks of EV71 with significant mortality have been reported in the Asia-Pacific region, and EV71 infection has become a serious public health concern worldwide. However, there is little information available concerning EV71 neuropathogenesis, and no vaccines or anti-EV71 drugs have been developed. Previous studies of this disease have used monkeys and neonatal mice that are susceptible to some EV71 strains as models. The monkey model is problematic for ethical and economical reasons, and mice that are more than a few weeks old lose their susceptibility to EV71. Thus, the development of an appropriate small animal model would greatly contribute to the study of this disease. Mice lack EV71 susceptibility due to the absence of a receptor for this virus. Previously, we identified the human scavenger receptor class B, member 2 (hSCARB2) as a cellular receptor for EV71. In the current study, we generated a transgenic (Tg) mouse expressing hSCARB2 with an expression profile similar to that in humans. Tg mice infected with EV71 exhibited ataxia, paralysis, and death. The most severely affected cells were neurons in the spinal cord, brainstem, cerebellum, hypothalamus, thalamus, and cerebrum. The pathological features in these Tg mice were generally similar to those of EV71 encephalomyelitis in humans and experimentally infected monkeys. These results suggest that this Tg mouse could represent a useful animal model for the study of EV71 infection.picornavirus | neurotropism | viral receptor E nterovirus 71 (EV71) is a human enterovirus species A of the genus Enterovirus within the Picornaviridae family, and it is known to be one of the causative agents of hand-foot-and-mouth disease (HFMD) (1, 2). HFMD is generally considered to be a mild exanthematous disease. However, in some infants and young children, after a few days of prodromal illness, HFMD caused predominantly by EV71 can be complicated by neurological manifestations, including ataxia, tremor, myoclonus, polio-like paralysis, encephalomyelitis, cardiopulmonary failure, and death (3, 4). In humans with fatal EV71 encephalomyelitis, inflammation and viral antigens in neurons were observed mainly in the spinal cord, brainstem, hypothalamus, cerebellar dentate nucleus, and cerebrum (5, 6). Since the 1970s, HFMD outbreaks with significant mortality have been reported throughout the world, including in Bulgaria in 1975 [44 deaths (7) Appropriate animal models are needed to better understand EV71 neuropathogenesis and to facilitate the development of effective vaccines and drugs. EV71-infected cynomolgus monkeys developed neurological complications similar to those observed in human cases, including ataxia, tremor, and flaccid paralysis (11-15), and pathological lesions were observed in the spinal cord, brainstem, cerebellar dentate nucleus, and other parts of the brain (14,15). However, the use of monkeys to mod...

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“…E71 has also been known to cause central nervous system (CNS) disease in man (3,11,12). E71 has been reported to be capable of causing paralysis as a result of characteristic CNS lesions after subcutaneous injection (6), oral administration (7) and intraspinal injection (8) in cynomolgus monkeys. In monkeys infected with E71 specific immunofluorescence was detected in the degenerating nerve cells in the anterior horns of the CNS, although no virus antigen was detected in the supporting tissues, vascular endothelium or inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

“…Ultrathin sections of the CNS and cultured CMK cells were cut by an LKB-ultramicrotome equipped with a diamond knife and mounted on 200-mesh copper grids, stained with lead citrate, and examined in a JEM-100 CX electron microscope. The indirect immunofluorescent technique was essentially the same as in the previous study (7,8). The rabbit anti-E71 hyperimmune serum was prepared in a rabbit.…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural changes of motoneurons in monkeys infected with enterovirus 71

Hashimoto

Hagiwara

Uchino

1985

Archives of Virology

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Tissues of the central nervous system (CNS) of cynomolgus monkeys were examined by electron microscopy after intraspinal inoculation of enterovirus 71 (E71). A characteristic finding was the appearance of numerous membrane-bound vesicles (Mbvs) in affected motoneurons. Similar Mbvs were also present in E71-infected cynomolgus monkey kidney (CMK) cells in culture. Virus-like particles were found within or around Mbvs in motoneurons as well as in infected CMK cells in culture. Neither Mbvs nor E71 antigens as detected by immunofluorescence were found in supporting tissues, vascular endothelium, or inflammatory cells. Quite similar findings had been seen in poliovirus infections. It was suggested that the appearance of Mbvs in the cytoplasm of motoneuron is the direct results of virus multiplication in E71 infection as in poliovirus infection.

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Studies on the pathogenesis of and propagation of enterovirus 71 in poliomyelitis-like disease in monkeys

Cited by 20 publications

References 19 publications

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71

Transgenic mouse model for the study of enterovirus 71 neuropathogenesis

Ultrastructural changes of motoneurons in monkeys infected with enterovirus 71

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