While host proteins incorporated into virions during viral budding from infected cell are known to play essential roles in multiple process of the life cycle of progeny virus, these characteristics have been largely neglected in studies on rabies virus (RABV). Here, we purified the RABV virions with good purity and integrity, and analyzed their proteome by nano LC-MS/MS, followed by the confirmation with immunoblot and immuno-electronic microscopy. In addition to the 5 viral proteins, 49 cellular proteins were reproducibly identified to be incorporated into matured RABV virions. Function annotation suggested that 24 of them were likely involved in virus replication. Furthermore, cryo-EM was employed to observe the purified RABV virions, generating high-resolution pictures of the bullet-shaped virion structure of RABV. This study has provided new insights into the host proteins composition in RABV virion and shed the light for further investigation on molecular mechanisms of RABV infection, as well as the discovery of new anti-RABV therapeutics.
Rabies is a severe zoonotic disease in China, but the circulation and distribution of rabies virus (RABV) within animal reservoirs is not well understood. We report the results of 15 years of surveillance of the first Chinese Rabies Surveillance Plan in animal populations, in which animal brain tissues collected during 2004–2018 were tested for RABV and phylogenetic and spatial–temporal evolutionary analyses performed using obtained RABV sequences. The results have provided the most comprehensive dataset to date on the infected animal species, geographic distribution, transmission sources, and genetic diversity of RABVs in China. In particular, the transboundary transmission of emerging RABV subclades between China and neighboring countries was confirmed. The study highlights the importance of continuous animal rabies surveillance in monitoring the transmission dynamics, and provides updated information for improving current control and prevention strategies at the source.
The compound 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG), a gallotannin present in various plants such as Rhus chinensis Mill and Paeonia suffruticosa, has a broad spectrum of antiviral effects. The present study investigated its potency against infection of mice with rabies virus (RABV). Results demonstrated that PGG strongly inhibited virus titers (50-fold), viral mRNA expression (up to 90%), and protein synthesis in vitro. Importantly, we found that PGG not only suppressed viral adsorption and entry, but also directly inactivated RABV through suppression of autophagy by mediating activation of the mTOR-dependent autophagy signaling pathway. In vivo, PGG (10 mg/kg) alleviated the clinical symptoms and reduced the mortality of infected mice by 27.3%. Collectively, our results indicate that PGG has potent anti-RABV effect, and merits further investigation as an anti-RABV drug.
Our previous study showed that pentagalloylglucose (PGG), a naturally occurring hydrolyzable phenolic tannin, possesses significant anti-rabies virus (RABV) activity. In BHK-21 cells, RABV induced the overactivation of signal transducer and activator of transcription 3 (STAT3) by suppressing the expression of suppressor of cytokine signaling 3 (SOCS3). Inhibition of STAT3 by niclosamide, small interfering RNA, or exogenous expression of SOCS3 all significantly suppressed the replication of RABV. Additionally, RABV-induced upregulation of microRNA 455-5p (miR-455-5p) downregulated SOCS3 by directly binding to the 3′ untranslated region (UTR) of SOCS3. Importantly, PGG effectively reversed the expression of miR-455-5p and its following SOCS3/STAT3 signaling pathway. Finally, activated STAT3 elicited the expression of interleukin-6 (IL-6), thereby contributing to RABV-associated encephalomyelitis; however, PGG restored the level of IL-6 in vitro and in vivo in a SOCS3/STAT3-dependent manner. Altogether, these data identify a new miR-455-5p/SOCS3/STAT3 signaling pathway that contributes to viral replication and IL-6 production in RABV-infected cells, with PGG exerting its antiviral effect by inhibiting the production of miR-455-5p and the activation of STAT3. IMPORTANCE Rabies virus causes lethal encephalitis in mammals and poses a serious public health threat in many parts of the world. Numerous strategies have been explored to combat rabies; however, their efficacy has always been unsatisfactory. We previously reported a new drug, PGG, which possesses a potent inhibitory activity on RABV replication. Herein, we describe the underlying mechanisms by which PGG exerts its anti-RABV activity. Our results show that RABV induces overactivation of STAT3 in BHK-21 cells, which facilitates viral replication. Importantly, PGG effectively inhibits the activity of STAT3 by disrupting the expression of miR-455-5p and increases the level of SOCS3 by directly targeting the 3′ UTR of SOCS3. Furthermore, the downregulated STAT3 inhibits the production of IL-6, thereby contributing to a reduction in the inflammatory response in vivo. Our study indicates that PGG effectively inhibits the replication of RABV by the miR-455-5p/SOCS3/STAT3/IL-6-dependent pathway.
Dogs play an important role in rabies transmission throughout the world. In addition to the severe human rabies situation in China, spillover of rabies virus from dogs in recent years has caused rabies outbreaks in sheep, cattle and pigs, showing that there is an increasing threat to other domestic animals. Two livestock rabies outbreaks were caused by dogs in Shanxi province, China from April to October in 2015, resulting in the deaths of 60 sheep, 10 cattle and one donkey. Brain samples from one infected bovine and the donkey were determined to be rabies virus (RABV) positive by fluorescent antibody test (FAT) and reverse transcription polymerase chain reaction (RT-PCR). The complete RABV N genes of the two field strains, together with those of two previously confirmed Shanxi dog strains, were amplified, sequenced and compared phylogenetically with published sequences of the N gene of RABV strains from Shanxi and surrounding provinces. All of the strains from Shanxi province grouped closely, sharing 99.6 %-100 % sequence identity, indicating the wide distribution and transmission of dog-mediated rabies in these areas. This is the first description of donkey rabies symptoms with phylogenetic analysis of RABVs in Shanxi province and surrounding regions. The result emphasizes the need for mandatory dog rabies vaccination and improved public education to eradicate dog rabies transmission.
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