Lethal murine infection model for human respiratory disease-associated Pteropine orthoreovirus

Kanai, Yuta; Okamoto, Minoru; Sakai, Yusuke; Matsuura, Yoshiharu; Kobayashi, Takeshi

doi:10.1016/j.virol.2017.10.021

Cited by 14 publications

(13 citation statements)

References 35 publications

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“…The infection displayed no signs and this observation was also not unexpected as it has been reported before that human infection can occur without clinical manifestations [3]. This was in contrast to experimental infection studies in mice, where 100% of infected animals exhibit disease signs and eventually succumb to the infection [5,33]. It is possible that certain risk factors absent in healthy individuals pre-dispose the development of clinical signs in monkeys and humans upon PRV exposure, and further epidemiological studies in patient cohorts would help clarify this.…”

Section: Discussionsupporting

confidence: 58%

Serological evidence and experimental infection of cynomolgus macaques with pteropine orthoreovirus reveal monkeys as potential hosts for transmission to humans

Tan

Wittwer

Lim

et al. 2019

Emerging Microbes & Infections

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Pteropine orthoreoviruses (PRV) are emerging bat-borne viruses with proven zoonotic transmission. We recently demonstrated human exposure to PRV in Singapore, which together with previous reports from Malaysia and Vietnam suggest that human infection of PRV may occur periodically in the region. This raises the question whether bats are the only sources of human infection. In this study, we screened 517 cynomolgus macaques caught in Singapore for evidence of exposure to PRV3M (also known as Melaka virus), which was first isolated from human patients in Melaka, Malaysia. We found that 67 serum samples were PRV3M positive by ELISA and 34 were also positive by virus neutralization assay. To investigate whether monkeys could act as hosts for PRV transmission, we experimentally infected cynomolgus macaques with PRV3M and housed these animals with uninfected monkeys. Although no clinical signs of infection were observed in infected animals, viral RNA was detected in nasal and rectal swabs and all infected macaques seroconverted. Additionally, one of the uninfected animals seroconverted, implying active shedding and transmission of PRV3M. We provide evidence that PRV exposure in the macaque population in Singapore occurs at a relatively high prevalence and this study suggests that cynomolgus macaques may be an intermediate or reservoir host for PRVs.

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Section: Discussionsupporting

confidence: 58%

Serological evidence and experimental infection of cynomolgus macaques with pteropine orthoreovirus reveal monkeys as potential hosts for transmission to humans

Tan

Wittwer

Lim

et al. 2019

Emerging Microbes & Infections

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“…To investigate the role of FAST-p10 protein in vivo , the pathogenicity of wild-type rsMB and rsMB-ΔFAST was compared in a mouse model for lethal PRV infection [38]. Intranasal infection with rsMB caused lethal lung infection (with progressive bodyweight loss in the early stages) in inbred C3H/HeNCrl mice, with 80% mortality within 14 days post infection (Fig 6A and 6B).…”

Section: Resultsmentioning

confidence: 99%

Cell–cell fusion induced by reovirus FAST proteins enhances replication and pathogenicity of non-enveloped dsRNA viruses

et al. 2019

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Fusogenic reoviruses encode fusion-associated small transmembrane (FAST) protein, which induces cell–cell fusion. FAST protein is the only known fusogenic protein in non-enveloped viruses, and its role in virus replication is not yet known. We generated replication-competent, FAST protein-deficient pteropine orthoreovirus and demonstrated that FAST protein was not essential for viral replication, but enhanced viral replication in the early phase of infection. Addition of recombinant FAST protein enhanced replication of FAST-deficient virus and other non-fusogenic viruses in a fusion-dependent and FAST-species-independent manner. In a mouse model, replication and pathogenicity of FAST-deficient virus were severely impaired relative to wild-type virus, indicating that FAST protein is a major determinant of the high pathogenicity of fusogenic reovirus. FAST-deficient virus also conferred effective protection against challenge with lethal homologous virus strains in mice. Our results demonstrate a novel role of a viral fusogenic protein and the existence of a cell–cell fusion-dependent replication system in non-enveloped viruses.

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“…The NBV-MB isolated from a patient with acute respiratory infection, can cause lethal outcomes with severe pneumonia in adult immunocompetent inbred mice when administered intranasally but not orally, indicating that NBV might cause respiratory diseases [34]. Hence, it is possible that NBV might be transmitted among humans, resulting in disease.…”

Section: Discussionmentioning

confidence: 99%

The effects of autophagy on the replication of Nelson Bay orthoreovirus

Tao

Zhao

Wei

et al. 2019

Virol J

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Background Nelson Bay orthoreovirus (NBV) was first isolated over 40 years ago from a fruit bat in Australia. Normally, NBV does not cause human diseases, but recently several NBV strains have been associated with human respiratory tract infections, thus attracting clinical attention. Autophagy, an evolutionarily conserved process in eukaryotic cells, degrades intracellular substrates, participates in multiple physiological processes, and maintains cellular homeostasis. In addition, autophagy is intimately involved in viral infection. Methods A new strain of NBV, isolated from a patient with a respiratory tract infection who returned to Japan from Bali, Indonesia, in 2007, was used in this study. NBV was rescued using a reverse genetics system involving cotransfection of BHK cells with 11 plasmids (pT7-L1 MB, pT7-L2 MB, pT7-L3 MB, pT7-M1 MB, pT7-M2 MB, pT7-M3 MB, pT7-S1 MB, pT7-S2 MB, pT7-S3 MB, pT7-S4 MB, and pcDNA3.1-T7), yielding NBV-MB. Recovered viruses were confirmed by immunofluorescence. The effect of NBV-MB on autophagy was evaluated by measuring the LC3-I/II proteins by immunoblot analysis after infection of BHK cells. Furthermore, after treatment with rapamycin (RAPA), 3-methyladenine (3-MA), chloroquine (CQ), or plasmid (GFP-LC3) transfection, the changes in expression of the LC3 gene and the amount of LC3-I/II protein were examined. In addition, variations in viral titer were assayed after treatment of BHK cells with drugs or after transfection with plasmids pCAGM3 and pCAGS3, which encode virus nonstructural proteins μNS and σNS, respectively. Results NBV-MB infection induced autophagy in host cells; however, the level of induction was dependent on viral replication. Induction of autophagy increased viral replication. By contrast, inhibiting autophagy suppressed NBV replication, albeit not significantly. The NBV-MB nonstructural protein μNS was involved in the induction of autophagy with viral infection. Conclusions NBV-MB infection triggered autophagy. Also, the NBV nonstructural protein μNS may contribute to augmentation of autophagy upon viral infection.

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Lethal murine infection model for human respiratory disease-associated Pteropine orthoreovirus

Cited by 14 publications

References 35 publications

Serological evidence and experimental infection of cynomolgus macaques with pteropine orthoreovirus reveal monkeys as potential hosts for transmission to humans

Serological evidence and experimental infection of cynomolgus macaques with pteropine orthoreovirus reveal monkeys as potential hosts for transmission to humans

Cell–cell fusion induced by reovirus FAST proteins enhances replication and pathogenicity of non-enveloped dsRNA viruses

The effects of autophagy on the replication of Nelson Bay orthoreovirus

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