No.18 NOV 2017 Spotlight Bat cave solves mystery of deadly SARS virus — and suggests new outbreak could occur fter a detective hunt across China, researchers chasing the origin of the deadly SARS virus have finally found their smoking gun. In a remote cave in Yunnan province, virologists have identified a single population of horseshoe bats that harbours virus strains with all the genetic building Science Tips | blocks of the one that jumped to humans in 2002, killing almost 800 people around the world. The killer strain could easily have arisen from such a bat population, the researchers Researchers analysed strains of SARS virus circulating in Express News News Express horseshoe bats, such as this one (Rhinolophus sinicus), i | report in PLoS Pathogens on 30 November. They warn that the ingredients are in place for n a cave in Yunnan province, China. Credit: Libiao Zhang a similar disease to emerge again. /Guangdong Institute of Applied Biological Resource In late 2002, cases of a mystery To clinch the case, a team led by Shi pneumonia-like illness began occurring in Zheng-Li and Cui Jie of the Wuhan Institute of Guangdong province, southeastern China. The Virology in China sampled thousands of disease, dubbed severe acute respiratory horseshoe bats in locations across the country. syndrome (SARS), triggered a global “The most challenging work is to locate the emergency as it spread around the world in caves, which usually are in remote areas,” says 2003, infecting thousands of people. Cui. After finding a particular cave in Yunnan, southwestern China, in which the strains of Scientists identified the culprit as a strain coronavirus looked similar to human versions, Research Progress | Cooperation | Progress Research of coronavirus and found genetically similar the researchers spent five years monitoring viruses in masked palm civets (Paguma larvata) the bats that lived there, collecting fresh sold in Guangdong’s animal markets. Later guano and taking anal swabs. surveys revealed large numbers of SARS- Spotlight| related coronaviruses circulating in China’s They sequenced the genomes of 15 viral horseshoe bats (Rhinolophus) — suggesting strains from the bats and found that, taken that the deadly strain probably originated in together, the strains contain all the genetic the bats, and later passed through civets pieces that make up the human version. before reaching humans. But crucial genes — Although no single bat had the exact strain of for a protein that allows the virus to latch SARS coronavirus that is found in humans, the onto and infect cells — were different in the analysis showed that the strains mix often. human and known bat versions of the virus, The human strain could have emerged from leaving room for doubt about this hypothesis. such mixing, says Kwok-Yung Yuen, a virologist http://english.whiov.cas.cn NEWSLETTER No.18 NOV 2017 Spotlight at the University of Hong Kong who co- sequences, most not yet published, with discovered the SARS virus: “The authors which they will continue to monitor the virus’s should be congratulated for confirming what evolution. has been suspected.” And they warn that a deadly outbreak But Changchun Tu, a virologist who directs could emerge again: the cave where the the OIE Reference Laboratory for Rabies in elements of SARS were found is just 1 Changchun, China, says the results are only kilometre from the nearest village, and “99%” persuasive. He would like to see genetic mixing among the viral strains is fast. scientists demonstrate in the lab that the “The risk of spillover into people and human SARS strain can jump from bats to emergence of a disease similar to SARS is another animal, such as a civet. "If this could possible,” the authors write in their paper. have been done, the evidence would be perfect,” he says. Although many markets selling animals in Science Tips China have already been closed or restricted | Another outstanding question is how a following outbreaks of SARS and other virus from bats in Yunnan could travel to infectious diseases, Yuen agrees that the .animals and humans around 1,000 kilometres latest results suggest the risk is still present away in Guangdong, without causing any “It reinforces the notion that we should not suspected cases in Yunnan itself. That “has disturb wildlife habitats and never put wild Express News News Express puzzled me a long time”, says Tu. animals into markets,” says Yuen. Respecting | nature, he argues, “is the way to stay away Cui and Shi are searching for other bat from the harm of emerging infections”. populations that could have produced strains capable of infecting humans. The researchers Source: Nature (https://www.nature.com/articles/d415 have now isolated some 300 bat coronavirus 86-017-07766-9?from=timeline&isappinstalled=0) Research Progress Scientists identify IE1 as the first potential HCMV-encoded E3 ubiquitin ligase Research Progress | Cooperation | Progress Research ongenital human cytomegalovirus Infection downregulates Hes1 protein at the (HCMV) infection is one of the most level in human NPCs through IE1 via a newly common causes of neurological identified function, which may be a key Spotlight| disabilities in children. However, the mechanism that contributes to fetal brain relationship between Hes1 regulation and maldevelopment caused by congenital HCMV virus infection, in particular whether and how infection. HCMV regulates Hes1, remained unknown. The scientists demonstrated that HCMV In the present study, the research group infection downregulates Hes1 protein levels in led by Prof. LUO Minhua from Wuhan Institute infected human NPCs. Importantly, IE1 leads of Virology of the Chinese Academy of to Hes1 depletion by mediating Hes1 Sciences report for the first time that HCMV ubiquitination and proteasomal degradation http://english.whiov.cas.cn NEWSLETTER No.18 NOV 2017 Research Progress by acting as a potential E3 ubiquitin ligase. IE1 physically interacts with Hes1 via amino acids (AA) 451–475, which are also essential for IE1- mediated Hes1 ubiquitination. In addition, Sp100A, an important component of PML nuclear bodies (PML-NBs), is identified as an additional ubiquitination substrate of IE1 ubiquitination. This study not only suggests an important mechanism for fetal brain development disorders induced by congenital HCMV infection, but also reveals a novel unanticipated function of HCMV IE1 as a Science Tips potential E3 ubiquitin ligase. | The results have been published in PloS Pathogens entitled "Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase". Express News News Express | This work was supported by the National Natural Science Foundation of China and the National Basic Research Program of China (973 Program). Link: http://journals.plos.org/plospathogens/article?id= 10.1371/journal.ppat.1006542#abstract1 Scientists provide therapeutic possibilities for combating infections caused by flavivirus Research Progress | Cooperation | Progress Research lavivirus pathogens are taxonomically In the present study, the research group classified in the genus Flavivirus and led by Prof. XIAO Gengfu from Wuhan family Flaviviridae. These viruses Institute of Virology of the Chinese Academy Spotlight| comprise over 70 different pathogens such as of Sciences screened an FDA-drugs library Japanese encephalitis virus (JEV), Zika virus with 1018 compounds and identified five hit (ZIKV), dengue virus (DENV), West Nile virus drugs, especially calcium inhibitors, exerting (WNV), and yellow fever virus (YFV). Most ant 41 i-flavivirus activity that blocked viral flaviviruses are arthropod-borne and cause replication. The in vivo efficacy and toxicity of public health problems worldwidely. However, manidipine were investigated with a JEV- flavivirus-induced diseases are still pandemic infected mouse model and the viral target was and few therapies beyond intensive identified by generating adaptive mutant. supportive care are currently available. http://english.whiov.cas.cn NEWSLETTER No.18 NOV 2017 Research Progress Five hit drugs were identified that replacement of Q130, located in inhibited JEV infection with a selective index > transmembrane domain 3 of the non- 10. Antiviral activities of these five hit drugs structural NS4B protein while relatively against other flavivirus, including Zika virus, conserved in flavivirus, with R or K conferred were also validated. As three of the five hit JEV resistance to manidipine, a voltage-gated drugs were calcium inhibitors, additional Ca2+ 30 channel (VGCC) inhibitor, without types of calcium inhibitors were utilized that apparent loss of the viral growth profile. confirmed calcium was essential for JEV infection, most likely during viral replication. Furthermore, manidipine was indicated to Adaptive mutant analysis uncovered that protect mice against JEV-induced lethality by decreasing viral load in brain, while abrogating histopathological changes associated with JEV infectionThe study provided novel insights into the molecular mechanisms underlying Science Tips flavivirus infection, and offer new and | promising therapeutic possibilities for combating infections caused by flavivirus. The results have been published in Journal of Virology entitled "Screening of FDA-1 Express News News Express Approved Drugs for Inhibitors against | Japanese Encephalitis Virus Infection". This work was supported by the National Natural Sciences Foundation of China. Link: http://jvi.asm.org/content/early/2017/08/10/JVI. 01055-17.abstract?sid%20=61e6a00f-55bb-49ad-ab65-