2020 Vol. 11, No. 10

Everything Old Is New Again: Inhibitors targeting a host factor DHODH involved in de novo pyrimidine biosynthesis, like Leflunomide/Teriflunomide, that are known to treat autoimmune disease, exhibited antiviral activity at low efficacy. By developing novel and highly potent DHODH inhibitors with favorable drug-likeness and pharmacokinetic profiles, the old drug target DHODH is refreshed to be an attractive host target for developing broad-spectrum antivirals against many severe infectious viruses including newly-emerged coronavirus SARS-CoV-2 through a dual action of both antiviral and immuno-regulation.

Potential treatment of COVID-19 by inhibitors of human dihydroorotate dehydrogenase
Yechun Xu, Hualiang Jiang
2020, 11(10): 699-702. doi: 10.1007/s13238-020-00769-9
The impact of aging and COVID-19 on our immune system: a high-resolution map from single cell analysis
Jing Yang, Hao Li
2020, 11(10): 703-706. doi: 10.1007/s13238-020-00782-y
Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics
Hua Qin, Andong Zhao
2020, 11(10): 707-722. doi: 10.1007/s13238-020-00738-2
The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, antiapoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Research articles
Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
Rui Xiong, Leike Zhang, Shiliang Li, Yuan Sun, Minyi Ding, Yong Wang, Yongliang Zhao, Yan Wu, Weijuan Shang, Xiaming Jiang, Jiwei Shan, Zihao Shen, Yi Tong, Liuxin Xu, Yu Chen, Yingle Liu, Gang Zou, Dimitri Lavillete, Zhenjiang Zhao, Rui Wang, Lili Zhu, Gengfu Xiao, Ke Lan, Honglin Li, Ke Xu
2020, 11(10): 723-739. doi: 10.1007/s13238-020-00768-w
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broadspectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
A human circulating immune cell landscape in aging and COVID-19
Yingfeng Zheng, Xiuxing Liu, Wenqing Le, Lihui Xie, He Li, Wen Wen, Si Wang, Shuai Ma, Zhaohao Huang, Jinguo Ye, Wen Shi, Yanxia Ye, Zunpeng Liu, Moshi Song, Weiqi Zhang, Jing-Dong J. Han, Juan Carlos Izpisua Belmonte, Chuanle Xiao, Jing Qu, Hongyang Wang, Guang-Hui Liu, Wenru Su
2020, 11(10): 740-770. doi: 10.1007/s13238-020-00762-2
Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtypespecific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.
Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids
Bing Zhao, Chao Ni, Ran Gao, Yuyan Wang, Li Yang, Jinsong Wei, Ting Lv, Jianqing Liang, Qisheng Zhang, Wei Xu, Youhua Xie, Xiaoyue Wang, Zhenghong Yuan, Junbo Liang, Rong Zhang, Xinhua Lin
2020, 11(10): 771-775. doi: 10.1007/s13238-020-00718-6
Mouse-adapted SARS-CoV-2 replicates efficiently in the upper and lower respiratory tract of BALB/c and C57BL/6J mice
Jinliang Wang, Lei Shuai, Chong Wang, Renqiang Liu, Xijun He, Xianfeng Zhang, Ziruo Sun, Dan Shan, Jinying Ge, Xijun Wang, Ronghong Hua, Gongxun Zhong, Zhiyuan Wen, Zhigao Bu
2020, 11(10): 776-782. doi: 10.1007/s13238-020-00767-x