Zika virus directly infects peripheral neurons and induces cell death

Oh, Yohan; Zhang, Feiran; Wang, Yaqing; Lee, Emily M.; Choi, In Young; Lim, Hotae; Mirakhori, Fahimeh; Li, Ronghua; Huang, Luoxiu; Xu, Tianlei; Wu, Hao; Li, Cui; Cheng, Qi; Wen, Zhexing; Wu, Qing; Tang, Hengli; Xu, Zhiheng; Jin, Peng; Song, Hongjun; Ming, Guo Li; Lee, Gabsang

doi:10.1038/nn.4612

Cited by 90 publications

(77 citation statements)

References 31 publications

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“…Other host proteins interacting with ZIKV sfRNA which has role embryonic development are SCML2, TBX2, PROX1, RTF1, ELAVL1, ATF6, SETDB2, PUM3 and ZBTB16. Further, ZIKV affect the differentiation, proliferation and death of neuronal cells (20)(21)(22)(23)(24). This study, provided indication proteins has role in the ZIKV pathogenesis in neuronal differentiation; proliferation and death are TCF4, TCF3, POU6F2, TCF12, FOXO3, REB3L2 and MEF2D.…”

Section: Discussionmentioning

confidence: 64%

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

Desingu

2019

Preprint

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Zika virus (ZIKV), circulating in more than 70 countries since 2014, is causing severe developmental abnormality to compare to pre-epidemic infection. ZIKV related flaviviruses as the ability to produce subgenomic flaviviral RNAs (sfRNAs) which are associated with pathogenicity in foetal mice. This study, delineate the increased virulence of ZIKV through sfRNA mediated host protein interaction. Phylogenetically ZIKV sfRNA formed three distinct clades of African, Asian and American strains. Compare with preepidemic, the epidemic ZIKV sfRNA has genetic, RNA secondary structure and host protein interacting profile diversity. Interestingly this study found that ZIKV sfRNA interacting proteins involved in the neuronal development, differentiation, proliferation, and apoptosis along with spermatogenesis, host immunity and viral pathogenesis. The difference in the interaction profile and interaction strength between pre-epidemic and epidemic virus could be the reason for the increased virulence of the recent epidemic viruses. Targeting this protein will be the potent choice for antiviral drug designing.

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Section: Discussionmentioning

confidence: 64%

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

Desingu

2019

Preprint

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“…During infection, viruses hijack the inward transport machinery of the cell [42][43][44][45]. While some viruses are able to fuse with the cell membrane and initiate infection almost immediately after entry, others need to be ferried long distances, e.g., during infection of neural cells [46][47][48][49]. This study focused on events that occur after the initial interaction between ZIKV and its cellular receptor.…”

Section: Discussionmentioning

confidence: 99%

Zika virus: mapping and reprogramming the entry

Owczarek

Chykunova

Jassoy³

et al. 2019

Cell Commun Signal

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Background The flaviviridae family comprises single-stranded RNA viruses that enter cells via clathrin-mediated pH-dependent endocytosis. Although the initial events of the virus entry have been already identified, data regarding intracellular virus trafficking and delivery to the replication site are limited. The purpose of this study was to map the transport route of Zika virus and to identify the fusion site within the endosomal compartment. Methods Tracking of viral particles in the cell was carried out with confocal microscopy. Immunostaining of two structural proteins of Zika virus enabled precise mapping of the route of the ribonucleocapsid and the envelope and, consequently, mapping the fusion site in the endosomal compartment. The results were verified using RNAi silencing and chemical inhibitors. Results After endocytic internalization, Zika virus is trafficked through the endosomal compartment to fuse in late endosomes. Inhibition of endosome acidification using bafilomycin A1 hampers the infection, as the fusion is inhibited; instead, the virus is transported to late compartments where it undergoes proteolytic degradation. The degradation products are ejected from the cell via slow recycling vesicles. Surprisingly, NH 4 Cl, which is also believed to block endosome acidification, shows a very different mode of action. In the presence of this basic compound, the endocytic hub is reprogrammed. Zika virus-containing vesicles never reach the late stage, but are rapidly trafficked to the plasma membrane via a fast recycling pathway after the clathrin-mediated endocytosis. Further, we also noted that, similarly as other members of the flaviviridae family, Zika virus undergoes furin- or furin-like-dependent activation during late steps of infection, while serine or cysteine proteases are not required for Zika virus maturation or entry. Conclusions Zika virus fusion occurs in late endosomes and is pH-dependent. These results broaden our understanding of Zika virus intracellular trafficking and may in future allow for development of novel treatment strategies. Further, we identified a novel mode of action for agents commonly used in studies of virus entry. Schematic representation of differences in ZIKV trafficking in the presence of Baf A1 and NH 4 Cl Electronic supplementary material The online version of this article (10.1186/s12964-019-0349-z) contains supplementary material, which is available to authorized users.

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“…ZIKV has been shown to replicate and cross the endothelial barrier without significantly affect its permeability (14, 15). Additionally, it was demonstrated that ZIKV replicates in human peripheral neurons in vitro (16). Thus, replication in motors and sensory tissues, in addition to contributes to viral load, could be a route used by ZIKV to access the peripheral nerves and reaches by retrograde axonal-transport some immuno privileged sites such as the brain (17).…”

Section: Introductionmentioning

confidence: 99%

Zika virus replicates in skeletal muscle contributing to peripheral viral amplification prior to reach neural tissue

Gavino-Leopoldino

et al. 2020

Preprint

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Zika virus (ZIKV) infections are still a worldwide concern due to the severity of neurological outcomes. ZIKV neurotropism is well characterized, but peripheral tissue could be sites of viral amplification, contributing to endothelial-barrier crossing and access to peripheral nerves. During acute and late phases of infection, ZIKV can be detected in several body fluids, eyes, testis and vagina. However, the importance of initial replication sites for the establishment of infection and viral spread remain unknown. Here we demonstrated that ZIKV replicates primarily in human muscle precursor cells, resulting in cell death and inhibition of myogenesis. ZIKV also replicates in fetal muscle after maternal transmission and in infected neonate mice, inducing lesions and inflammation. Muscle was an important site of viral amplification, sustaining higher peripheral viral loads than liver and spleen. In addition, ZIKV showed rapid and sustained replication kinetics in muscle even before replication in the neural tissues, persisting until 16 days post infection. Our results highlight the importance of muscle in ZIKV pathogenesis as a peripheral site of viral amplification which may contribute to ZIKV reaching neural structures.Author SummaryZika Virus (ZIKV) neurotropism and its deleterious effects on central nervous system have been well characterized. But, investigations of the initial replication sites for the establishment of infection and viral spread to neural tissues remain under explored. Here we demonstrated that ZIKV replicates primarily in human skeletal muscle precursor cells, resulting in cell death and disrupted myogenesis. ZIKV also replicates in muscle of fetus and neonate mice inducing muscle damage and inflammation. Muscle replication occurs before amplification in peripheral nerves and brain, contributing to the increase of peripheral ZIKV load and dissemination. In addition, ZIKV RNA still been detected in skeletal muscle at late stages of infection. Overall, our findings showed that skeletal muscle is involved in ZIKV pathogenesis, contributing to a broader understanding of ZIKV infection. Thus, opens new aspects in the investigation of the long-term consequence of early infection.

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Zika virus directly infects peripheral neurons and induces cell death

Cited by 90 publications

References 31 publications

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

Comparative analysis of sfRNA in the genome of pre-epidemic and epidemic Zika viruses for host interacting proteins potentially related to the recent epidemic

Zika virus: mapping and reprogramming the entry

Zika virus replicates in skeletal muscle contributing to peripheral viral amplification prior to reach neural tissue

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