Man Lung Yeung

Chinese University of Hong Kong

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Kwok‐Yung Yuen

University of Hong Kong

Kuan‐Teh Jeang

National Institute of Allergy and Infectious Diseases

Yamina Bennasser

Institut de Génétique Humaine

Jasper Fuk‐Woo Chan

University of Hong Kong

Kelvin Kai‐Wang To

Queen Mary Hospital

Jian‐Piao Cai

South China Sea Institute Of Oceanology

Patrick C. Y. Woo

University of Hong Kong

Hin Chu

HKU-Pasteur Research Pole

Nelson Dusetti

Centre de Recherche en Cancérologie de Marseille

Jun‐ichirou Yasunaga

Kumamoto University

Cooperative Institutions

University of Hong Kong

195

Chinese University of Hong Kong

118

Queen Mary Hospital

Hong Kong Science and Technology Parks Corporation

Chinese Academy of Sciences

National Institutes of Health

Chinese Academy of Medical Sciences & Peking Union Medical College

National Institute of Allergy and Infectious Diseases

HKU-Pasteur Research Pole

University of Hong Kong - Shenzhen Hospital

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Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development

Proceedings of the National Academy of Sciences (2007)

Meritxell Gironella Mylène Seux Min-Jue Xie Carla E. Cano Richard Tomasini

Pancreatic cancer is a disease with an extremely poor prognosis. Tumor protein 53-induced nuclear protein 1 ( TP53INP1 ) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinoma (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1 −/− mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras V12 oncoproteins developed bigger tumors than TP53INP1 +/+ transformed MEFs or TP53INP1 −/− transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity.

miR-155

10.1073/pnas.0703942104

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Citations (550)

Middle East Respiratory Syndrome Coronavirus ORF8b Accessory Protein Suppresses Type I IFN Expression by Impeding HSP70-Dependent Activation of IRF3 Kinase IKKε

The Journal of Immunology (2020)

Lok-Yin Roy Wong Zi‐Wei Ye Pak‐Yin Lui Xuyang Zheng Shuofeng Yuan

Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic human coronavirus causing severe disease and mortality. MERS-CoV infection failed to elicit robust IFN response, suggesting that the virus might have evolved strategies to evade host innate immune surveillance. In this study, we identified and characterized type I IFN antagonism of MERS-CoV open reading frame (ORF) 8b accessory protein. ORF8b was abundantly expressed in MERS-CoV–infected Huh-7 cells. When ectopically expressed, ORF8b inhibited IRF3-mediated IFN-β expression induced by Sendai virus and poly(I:C). ORF8b was found to act at a step upstream of IRF3 to impede the interaction between IRF3 kinase IKKε and chaperone protein HSP70, which is required for the activation of IKKε and IRF3. An infection study using recombinant wild-type and ORF8b-deficient MERS-CoV further confirmed the suppressive role of ORF8b in type I IFN induction and its disruption of the colocalization of HSP70 with IKKε. Ectopic expression of HSP70 relieved suppression of IFN-β expression by ORF8b in an IKKε-dependent manner. Enhancement of IFN-β induction in cells infected with ORF8b-deficient virus was erased when HSP70 was depleted. Taken together, HSP70 chaperone is important for IKKε activation, and MERS-CoV ORF8b suppresses type I IFN expression by competing with IKKε for interaction with HSP70.

IRF3

IκB kinase

Ectopic expression

Coronavirus

10.4049/jimmunol.1901489

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Citations (37)

Development and Evaluation of Novel Real-Time Reverse Transcription-PCR Assays with Locked Nucleic Acid Probes Targeting Leader Sequences of Human-Pathogenic Coronaviruses

Journal of Clinical Microbiology (2015)

Jasper Fuk‐Woo Chan Garnet Kwan-Yue Choi Alan Ka-Lun Tsang Kah‐Meng Tee Hoyin Lam

Based on findings in small RNA-sequencing (Seq) data analysis, we developed highly sensitive and specific real-time reverse transcription (RT)-PCR assays with locked nucleic acid probes targeting the abundantly expressed leader sequences of Middle East respiratory syndrome coronavirus (MERS-CoV) and other human coronaviruses. Analytical and clinical evaluations showed their noninferiority to a commercial multiplex PCR test for the detection of these coronaviruses.

Multiplex

Coronavirus

10.1128/jcm.01224-15

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Citations (87)

Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system

Cell (2021)

Man Lung Yeung Jade L. L. Teng Lilong Jia Chaoyu Zhang Chengxi Huang

Peptidyl-Dipeptidase A

Angiotensin-converting enzyme 2

2019-20 coronavirus outbreak

10.1016/j.cell.2021.02.053

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Citations (254)

MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes

Hepatology (2010)

Krishna Banaudha Michael Kaliszewski Tamara Korolnek Liliana Florea Man Lung Yeung

MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection is considered a major cause of chronic liver disease and HCC, although the mechanism of virus infection–associated hepatocarcinogenesis remains unclear. We report a direct role of miRNAs induced in HCV-infected primary human hepatocytes that target the tumor suppressor gene DLC-1 (a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. MicroRNA miR-141 that targets DLC-1 was accentuated in cells infected with HCV genotypes 1a, 1b, and 2a. We present several lines of evidence that efficient HCV replication requires miR-141–mediated suppression of DLC-1. An increase in miR-141 correlated with the inhibition of DLC-1 protein in HCV-infected cells. Depletion of miR-141 with oligonucleotides complementary to the miRNAs inhibited virus replication, whereas artificially increased levels of intracellular miR-141 enhanced HCV replication. HCV-infected hepatocytes showed enhanced cell proliferation that can be countered by overexpression of DLC-1. Conclusion: The collective results of this study suggest a novel mechanism of HCV infection–associated miRNA-mediated regulation of a tumor suppressor protein that has the ability to influence cell proliferation and HCV infection–mediated liver cancer. (Hepatology 2011)

Replication

10.1002/hep.24016

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Citations (84)

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses

Biomedicines (2021)

Jessica Oi‐Ling Tsang Jie Zhou Xiaoyu Zhao Cun Li Zijiao Zou

Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses.

Coxsackievirus

Organoid

Cytopathic effect

10.3390/biomedicines9010088

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Citations (21)

Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset

The Journal of Infectious Diseases (2015)

Jasper Fuk‐Woo Chan Yanfeng Yao Man Lung Yeung Wei Deng Linlin Bao

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe disease in human with an overall case-fatality rate of >35%. Effective antivirals are crucial for improving the clinical outcome of MERS. Although a number of repurposed drugs, convalescent-phase plasma, antiviral peptides, and neutralizing antibodies exhibit anti-MERS-CoV activity in vitro, most are not readily available or have not been evaluated in nonhuman primates. We assessed 3 repurposed drugs with potent in vitro anti-MERS-CoV activity (mycophenolate mofetil [MMF], lopinavir/ritonavir, and interferon-β1b) in common marmosets with severe disease resembling MERS in humans. The lopinavir/ritonavir-treated and interferon-β1b-treated animals had better outcome than the untreated animals, with improved clinical (mean clinical scores ↓50.9%–95.0% and ↓weight loss than the untreated animals), radiological (minimal pulmonary infiltrates), and pathological (mild bronchointerstitial pneumonia) findings, and lower mean viral loads in necropsied lung (↓0.59–1.06 log10 copies/glyceraldehyde 3-phosphate dehydrogenase [GAPDH]; P < .050) and extrapulmonary (↓0.11–1.29 log10 copies/GAPDH; P < .050 in kidney) tissues. In contrast, all MMF-treated animals developed severe and/or fatal disease with higher mean viral loads (↑0.15–0.54 log10 copies/GAPDH) than the untreated animals. The mortality rate at 36 hours postinoculation was 67% (untreated and MMF-treated) versus 0–33% (lopinavir/ritonavir-treated and interferon-β1b-treated). Lopinavir/ritonavir and interferon-β1b alone or in combination should be evaluated in clinical trials. MMF alone may worsen MERS and should not be used.

Lopinavir

Ritonavir

Lopinavir/ritonavir

10.1093/infdis/jiv392

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Citations (615)

Modulation of Nuclear Factor-κB by Human T Cell Leukemia Virus Type 1 Tax Protein: Implications for Oncogenesis and Inflammation

Immunologic Research (2006)

Jean‐Marie Péloponèse Man Lung Yeung Kuan‐Teh Jeang

Tropical spastic paraparesis

10.1385/ir:34:1:1

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