Summary: According to a PNAS study, the RNAs of tick borne encephalitis virus (TBEV) are transported from the cell body to dendrites. The viral RNAs then reproduce the viruses within the dendrites, disturbing neural activity.
Source: Hokkaido University.
A deadly tick-borne virus uses the host neuron’s transportation system to move their RNA, resulting in the local reproduction of the virus and severe neurological symptoms.
Flaviviruses are a significant threat to public health worldwide, and some infected patients develop severe — potentially fatal — neurological diseases. Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, causes encephalic diseases resulting in photophobia, irritability and sleep disorders. However, little is known about their pathogenic mechanisms and no effective treatment is available at present.
A research team at Hokkaido University has previously showed that, in mouse neurons, genomic RNAs of TBEV are transported from the cell body to dendrites, the neuron’s wire-like protrusions. Viral RNAs then reproduce viruses locally in dendrites disturbing normal neuronal activities.
In the new study published in PNAS, the team looked into the transportation mechanism of viral RNAs in neurons, and discovered they make use of the cell’s transportation system, which is normally used to move neuronal RNAs in dendrites. A specific non-coding sequence near the terminal of viral RNAs was found pivotal in interacting with the transportation system. When the sequence was mutated, the infected mouse showed reduced neurological symptoms. In their biochemical experiments, viral RNAs could bind to a protein that forms a neuronal granule, which is part of the neuron’s transportation system.
Furthermore, their data shows that normal transportation of neuronal RNAs become affected by viral RNAs as a result of competition to use the transportation network.
Associate Professor Kentaro Yoshii, who led the research team, commented “It is unprecedented for a neuropathogenic virus to hijack the neuronal granule system to transport their genomic RNA, which results in severe neurological diseases. The disruption of the neuronal granule system is also known to be involved in non-viral diseases such as Alzheimer’s disease. So the unique virus-host interaction we revealed should help us understand their pathogenesis and develop treatments in the future.”
Funding: Funding provided by Ministry of Education, Culture, Sports, Science and Technology of Japan, and others.
Source: Naoki Namba – Hokkaido University
Image Source: NeuroscienceNews.com image is credited to Hirano M. et al., Proceedings of the National Academy of Sciences of the United States of America, Aug. 28, 2017.
Original Research: Abstract for “Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease” by Minato Hirano, Memi Muto, Mizuki Sakai, Hirofumi Kondo, Shintaro Kobayashi, Hiroaki Kariwa, and Kentaro Yoshii in PNAS. Published online August 28 2017 doi:10.1073/pnas.1704454114
Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease
Neurological diseases caused by encephalitic flaviviruses are severe and associated with high levels of mortality. However, little is known about the detailed mechanisms of viral replication and pathogenicity in the brain. Previously, we reported that the genomic RNA of tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is transported and replicated in the dendrites of neurons. In the present study, we analyzed the transport mechanism of the viral genome to dendrites. We identified specific sequences of the 5′ untranslated region of TBEV genomic RNA that act as a cis-acting element for RNA transport. Mutated TBEV with impaired RNA transport in dendrites caused a reduction in neurological symptoms in infected mice. We show that neuronal granules, which regulate the transport and local translation of dendritic mRNAs, are involved in TBEV genomic RNA transport. TBEV genomic RNA bound an RNA-binding protein of neuronal granules and disturbed the transport of dendritic mRNAs. These results demonstrated a neuropathogenic virus hijacking the neuronal granule system for the transport of viral genomic RNA in dendrites, resulting in severe neurological disease.
“Dendritic transport of tick-borne flavivirus RNA by neuronal granules affects development of neurological disease” by Minato Hirano, Memi Muto, Mizuki Sakai, Hirofumi Kondo, Shintaro Kobayashi, Hiroaki Kariwa, and Kentaro Yoshii in PNAS. Published online August 28 2017 doi:10.1073/pnas.1704454114