Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation

Nagata, Noriyo; Iwasaki, Takuya; Ami, Yasushi; Tano, Yoshio; Harashima, Ayako; Suzaki, Yuriko; Sato, Yuko; Hasegawa, Hideki; Sata, Tetsutaro; Miyamura, Tatsuo; Shimizu, Hiroyuki

doi:10.1099/vir.0.79883-0

Cited by 97 publications

(92 citation statements)

References 33 publications

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“…In the reported mouse and cynomolgus monkey studies, the animals died of paralysis and encephalomyelitis without lesions in the lung tissue. 19,27 This result is consistent with the fact that damaged neurons and inflammation were concentrated in the motor area. 28,29 However, damaged neurons and inflammation were also found in motor areas of human autopsy cases and our infected rhesus monkeys.…”

Section: Discussionsupporting

confidence: 78%

“…These data are seemly different than observations from the murine and cynomolgus monkey models, in which no obvious pathological lesions were found in non-CNS organs. 27,29 The reason for these differences is unclear. A human autopsy report indicated that the patient had pulmonary edema and inflammation in the lungs.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, studies in cynomolgus monkeys and mice revealed that no EV71 replication occurred in the main organs of the animals, except for the CNS. 27,29 However, it can be argued that oral infection with the strain adapted to mice was capable of inducing virus distribution in some organs, including the heart, lungs and kidneys in mice; 32 infection with the ts strain via the intravenous route in cynomolgus monkeys 27 and infection via the intracerebral, intramuscular, intraperitoneal and subcutaneous routes in mice did not yield a similar distribution of the virus. 29 Our results indicate that virus was present in some organs of the monkeys that were infected via the intravenous and intratracheal routes.…”

Section: Discussionmentioning

confidence: 99%

“…6,26,27 These symptoms suggest the presence of lesions in the CNS of the monkeys. In this study, physical examination of the monkeys that were infected via these four routes revealed that the muscle tension in the limbs was in the normal range, and no herpes-like skin lesions were observed on the hands, feet or mouths.…”

Section: Clinical Manifestations Of Ev71 Infection In Rhesus Monkeys mentioning

confidence: 99%

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Pathogenesis study of enterovirus 71 infection in rhesus monkeys

Zhang

Cui

Liu

et al. 2011

Laboratory Investigation

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Enterovirus 71 (EV71), a major pathogen that is responsible for causing hand-foot-and-mouth disease (HFMD) worldwide, is a member of the Human Enterovirus species A, family Picornaviridae. HFMD that is caused by EV71 is usually characterized by vesicular lesions on the skin and oral mucosa and high morbidity rates in children; additionally, occasional fatal cases have been reported involving brainstem encephalitis and myelitis associated with cardiopulmonary collapse. Although viral pathogenesis in humans is unclear, previous animal studies have indicated that EV71, inoculated via various routes, is capable of targeting and injuring the central nervous system (CNS). We report here the pathogenic process of systemic EV71 infection in rhesus monkeys after inoculation via intracerebral, intravenous, respiratory and digestive routes. Infection with EV71 via these routes resulted in different rates of targeting to and injury of the CNS. Intracerebral inoculation resulted in pulmonary edema and hemorrhage, along with impairment of neurons. However, intravenous and respiratory inoculations resulted in a direct infection of the CNS, accompanied by obvious inflammation of lung tissue, as shown by impairment of the alveoli structure and massive cellular infiltration around the terminal bronchioles and small vessels. These pathological changes were associated with a peak of viremia and dynamic viral distribution in organs over time in the infected monkeys. Our results suggest that the rhesus monkey model may be used to study not only the basic pathogenesis of EV71 viral infections, but also to examine clinical features, such as neurological lesions, in the CNS and pathological changes in associated organs.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Clinical Manifestations Of Ev71 Infection In Rhesus Monkeys mentioning

confidence: 99%

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Pathogenesis study of enterovirus 71 infection in rhesus monkeys

Zhang

Cui

Liu

et al. 2011

Laboratory Investigation

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“…In a cynomologus monkey model (12,13), EV71 showed a wider-spread distribution pattern in the CNS than PV following both intracranial (i.c.) and intravenous inoculations, and monkeys exhibited extrapyramidal signs, including tremor and ataxia.…”

mentioning

confidence: 99%

Retrograde Axonal Transport: a Major Transmission Route of Enterovirus 71 in Mice

Chen¹,

Yao²,

Lin³

et al. 2007

J Virol

151

126

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Enterovirus 71 (EV71), a single-positive-stranded RNA virus that belongs to the Enterovirus genus of the Picornaviridae family, is a highly neurotropic virus and has been regarded as the most important neurotropic EV after the eradication of the poliovirus (11). The brain stem is most likely the major target of EV71 infection (2, 8). However, neither the host cell receptor nor the neurotransmission route of EV71 is fully defined.As for poliovirus (PV), two possible routes by which the virus reaches the central nervous system (CNS) have been suggested: the virus either enters the CNS from the blood across the blood-brain barrier (BBB) or is transmitted to the CNS through peripheral nerves via retrograde axonal transport (1,3,14,23). Expression of certain gene segments would be responsible for determining the capacity of PV to spread to the CNS through bloodstream or neuronal pathways (18).In a cynomologus monkey model (12, 13), EV71 showed a wider-spread distribution pattern in the CNS than PV following both intracranial (i.c.) and intravenous inoculations, and monkeys exhibited extrapyramidal signs, including tremor and ataxia. However, after intraspinal inoculation, monkeys developed flaccid paralysis, a pyramidal sign suggesting direct virus invasion in the inoculation site. EV infection and persistence have been implicated in the pathogenesis of certain chronic muscle diseases (17). Furthermore, PV replicated in muscle cells that maintained constant viremia and spread to CNS from peripheral nerves (23). We previously showed that EV71 propagated more effectively in RD (human rhabdomyosarcoma) cells than in SK-N-SH (neuroblastoma) cells and Caco-2 (colorectal adenocarcinoma) cells. Furthermore, after oral (p.o.) inoculation of a mouse-adapted EV71 strain, EV71/MP4, 7-day-old ICR mice developed paralysis, with a mortality rate of 80%. Virus was first seen in the intestine. The virus then spread to muscle and CNS. A vast amount of virus was detected in the CNS and muscle, which led to neuronal loss and rhabdomyolysis of the mice with severe paralysis (21). In this study, we demonstrated that EV71 possesses strong neurotropism and that retrograde axonal transport in neuron cells might represent the major transmission route of EV71 in mice. MATERIALS AND METHODSCells and virus. RD cells (American Type Culture Collection, Manassas, VA) were maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum plus 2 mM L-glutamine, 100 IU penicillin, and 100 g of streptomycin per ml. EV71/MP4 strain, a mouse-adapted strain derived from parental virus EV71/Tainan/4643/98 (GenBank accession number AF304458) (22), was grown in RD cells. Working stocks contained 2 ϫ 10 7 PFU/ml. Experimental infection. Specific-pathogen-free, 7-day-old ICR mice

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Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children

et al. 2016

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IMPORTANCE Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines. OBJECTIVE To further characterize EV71-related neurological disease and neurological outcome in children. DESIGN, SETTING, AND PARTICIPANTS Prospective 2-hospital (The Sydney Children's Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013. MAIN OUTCOMES AND MEASURES Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. RESULTS Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P < .001). CONCLUSIONS AND RELEVANCE Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.

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Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation

Cited by 97 publications

References 33 publications

Pathogenesis study of enterovirus 71 infection in rhesus monkeys

Pathogenesis study of enterovirus 71 infection in rhesus monkeys

Retrograde Axonal Transport: a Major Transmission Route of Enterovirus 71 in Mice

Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children

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