Ph. D. in Virology Rutgers University
Areas of Specialty
Clinical Virology、Biotechnology、Molecular Biology、Biochemistry
Research Center for Emerging Viral Infections
Lab & Research Interest
Translational Research: from Basic Molecular Virology to Clinical Virology and Antiviral Research
(Enterovirus 71 and Influenza Virus Researches)
Our team has been studying the emerging RNA viruses in many aspects, including identification of unknown viruses using novel biotechnology, pathogenesis study of those RNA viruses and antiviral developments. Our study of EV71 began in 1998, in which a large EV71 outbreak in Taiwan led to 78 mortalities. Our participation contributed significantly to the laboratory diagnosis of this virus in the outbreak. Our subsequent efforts focused on viral-host interactions, in which molecular targets for drug discovery were identified. Two series of compounds were also developed that inhibit EV71 replication, pyridyl imidazolidinones and pyrazolo[3,4-d]pyrimidines (targeting capsid protein VP1 and 3D polymerase, respectively). I was bestowed the National Medal for Outstanding Youth in 2004 for contributing to EV71 research in Taiwan.
I received training in another RNA virus, influenza virus, and a Ph.D. in Molecular Virology at Rutgers University in the United States. Upon returning to Taiwan in 1996, I established the Molecular Virology Laboratory at Chang Gung University, having published more than 70 papers (nearly 50 over the past five years) on emerging RNA viruses, e.g., enteroviruses, SARS coronaviruses and influenza viruses. These papers have been cited at least 500 times over the past five years. Results of our study have also led to eight patents granted.
(I) EV71 research
Our research efforts involving EV71 over the past decade have received international recognition. Previously, I served as the Executive Editor of Current Pharmaceutical Design, responsible for editing review articles on antiviral research. Following recognition of our anti-EV71 research by the Journal of Antimicrobial Chemotherapy, the journal invited me to contribute a “Leading Article”. In addition to the international recognition of our antiviral research in EV71, our basic virology and pathogenesis studies of EV71 have yielded increasingly fruitful results in recent years. More recently, I served as the host convener of a session on RNA viruses (Positive Strand RNA Viruses and Host Proteins Interactions) at the annual meeting of the American Society for Virology. Another notable index is our publishing of a series of papers in renowned international journals such as Nucleic Acids Research and PLoS Pathogens. The latest article in PLoS Pathogens describes a novel finding that EV71 protease 3C cleaves CstF-64 and inhibits cellular polyadenylation. The significance and novelty of our finding extend the scope of the research field of viral host interactions in picornaviruses. This explains why this article appeared in PLoS Pathogens, a prestigious journal with a high impact factor [impact factor = 9.125; 5/91 in the field of microbiology (the first four are review journals)].
(II) Influenza virus research
Later on in 2004, with the emerging threat of avian influenza virus, our research group has devoted considerable efforts to influenza virus, including laboratory-based surveillance, viral-host interplay and antiviral development. I have conducted influenza virus research since my Ph.D. study, which allowed me to monitor the progress of this competitive research field. Over the past five years, we have published a series of articles in the Journal of Clinical Microbiology, Emerging Infectious Diseases, and Journal of Virology. The swine-origin influenza A H1N1 virus has spread rapidly worldwide recently. Based on our research capabilities cultivated in recent years, we have successfully established a rapid laboratory diagnostics procedure for this new N1N1 virus. We have also identified several molecular signatures that may serve as important virulence markers for the new H1N1 virus. The manuscript about this work has been accepted for publication by Emerging Infectious Diseases. The timely publication (several months after the new outbreak) of our research findings demonstrates our capability in actively researching emerging RNA viruses.
Our team is widely recognized as a friendly collaborator in virus research worldwide. We have provided many timely materials (e.g., virus isolates, plasmids harboring viral genes, diagnostic reagents and antibodies) and protocols to many researchers, as well as provided the training programs of several special techniques in RNA virus research (e.g., reverse genetics, and plaque reduction assay) to other groups. Given the above contributions, I have been invited numerous times to several institutes for scientific talks, leading to the establishment of several international collaborations (e.g., Pasteur Institutes in Paris and in Shanghai, University of Hong Kong, and University of Medicine and Dentistry in New Jersey, United States.).
Our laboratory over the past decade has actively researched on topics involving the EV71 outbreak, the SARS outbreak and several influenza endemics. I have published 30 first or corresponding author papers over the past five years. Those papers completed in Taiwan have been cited over 500 times over the past five years. These numbers reflect our contributions to emerging virus research. Our recently papers in the Journal of Virology, Journal of Infectious Diseases, Emerging Infectious Diseases, Nucleic Acids Research and PLoS Pathogens attest to our globally recognized contribution in the field of virus infection. Our efforts are underway to continue with translational research of emerging virus, i.e. from the basic virology to applied diagnostic virology and antiviral development. Hopefully, our efforts will provide valuable reagents, information and antivirals that are timely for a future outbreak of the RNA virus. As our long term study in the past has laid the foundation, our future efforts will build upon this knowledge to further elucidate the emerging RNA virus, as well as contribute to controlling and preventing viral infections.
1. Huang CG, Lee LA, Fang TJ, Li HY, Liao CT, Kang CJ, Yen TC, Tsao KC, Chen TC, Shih SR. Human papillomavirus infection is not associated with laryngeal squamous cell carcinoma in Taiwan. J Microbiol Immunol Infect. 2018 Feb 21. pii: S1684-1182(18)30047-1. doi: 10.1016/j.jmii.2018.02.002
2. Huang CG, Lee LA, Wu YC, Hsiao MJ, Horng JT, Kuo RL, Huang CH, Lin YC, Tsao KC, Chen MC, Chen TC, Shih SR. A pilot study on primary cultures of human respiratory tract epithelial cells to predict patients' responses to H7N9 infection. Oncotarget. 2018 Feb 20;9(18):14492-14508. doi: 10.18632/oncotarget.24537.
3. Lee KM, Gong YN, Hsieh TH, Woodman A, Dekker NH, Cameron CE, *Shih SR. Discovery of enterovirus A-like nonstructural genomes in recent circulating viruses of the enterovirus A species. Emerging Microbes and Infections, 2018 Jun 21;7(1):111. doi: 10.1038/s41426-018-0107-0.
4.Gong YN, RL Kuo, Chen GW, *Shih SR. Centennial review of influenza in Taiwan, Biomedical Journal, 2018 Aug;41(4):234-241. doi: 10.1016/j.bj.2018.08.002. Epub 2018 Sep 10. Review.
5. Yeung ML, Jia L, Yip CC, Chan JF, Teng JL, Chan KH, Cai JP, Zhang C, Zhang AJ, Wong WM, Kok KH, Lau SK, Woo PC, Lo JY, Jin DY, Shih SR, Yuen KY. Human tryptophanyl-tRNA synthetase is an IFN-γ-inducible entry factor for Enterovirus. J Clin Invest. 2018 Aug 28. pii: 99411. doi: 10.1172/JCI99411. [Epub ahead of print]
6. Woodman A, Lee KM, Janissen R, Gong YN, Dekker N, Shih SR, Cameron CE. Predicting intraserotypic recombination in enterovirus 71. J Virol. 2019 Feb 5;93(4). pii: e02057-18. doi: 10.1128/JVI.02057-18. Print 2019 Feb 15.
7. Kuo RL, Chen CJ, Wang RYL, Huang HI, Lin YH, Tam EH, Tu WJ, Wu SE, Shih SR. Role of enteroviral RNA-depedent RNA polymerase in regulation of MDA5-mdiated beta interferon activation. J Virol. 2019 May 1;93(10). pii: e00132-19. doi: 10.1128/JVI.00132-19. Print 2019 May 15.
8. Gong YN, Tsao KC, Chen GW, Wu CJ, Chen YH, Liu YC, Yang SL, Huang YC, *Shih SR. Population dynamics at neuraminidase position 151 of influenza A (H1N1)pdm09 virus in clinical specimens. J Gen Virol. 2019;100(5):752-759. doi: 10.1099/jgv.0.001258. Epub 2019 Apr 17.
9. Huang SY, Huang CH, Chen CJ, Chen TW, Lin CY, Lin YT, Kuo, SM, Huang CG, Lee LA, Chen YH, Chen MF, Kuo RL and *Shih SR. Novel role of miR-1290 in host species specificity of influenza A virus. Mol Ther Nucleic Acids. 2019 15;17:10-23. doi: 10.1016/j.omtn.2019.04.028. [Epub ahead of print]
10. Lin RW, Chen GW, Sung HH, Lin RJ, Yen LC, Tseng YL, Chang YK, Lien SP, Shih SR, Liao CL. Naturally occurring mutations in PB1 affect influenza A virus replication fidelity, virulence and adaptability. J Biomed Sci. 2019 Jul 31;26(1):55. doi: 10.1186/s12929-019-0547-4
11. Li ML, Lin JY, Chen BS, Weng KF, Shih SR, Calderon JD, Tolbert BS, Brewer G. EV71 3C protease induces apoptosis by cleavage of hnRNP A1 to promote apaf-1 translation. PLoS One. 2019 9;14(9):e0221048. doi: 10.1371/journal.pone.0221048.
12. Lin JY, Kung YA, *Shih SR. Antivirals and vaccines for enterovirus A71. J Biomed Sci. 2019 3;26(1):65. doi: 10.1186/s12929-019-0560-7. Review.
13. Huang CT, Hung CY, Hseih YC, Chang CS, Velu AB, He YC, Huang YL, Chen TA, Chen TC, Lin CY, Lin YC, Shih SR, Dutta A.Effect of aloin on viral neuraminidase and hemagglutinin-specific T cell immunity in acute influenza. Phytomedicine. 2019 ;64:152904. doi: 10.1016/j.phymed.2019.152904. Epub 2019 Apr 4.
14. Lee KM, Gong YN, *Shih SR. Methods for detection and study of virus-derived small RNAs produced from the intramolecular base-pairing region of the picornavirus genome. Methods. 2019. pii: S1046-2023(19)30192-6. doi: 10.1016/j.ymeth.2019.08.011. [Epub ahead of print] Review.
15. Liu YC , Kuo RL, *Shih SR. COVID-19: The first documented coronavirus pandemic in history. Biomedical Journal. 2020. https://doi.org/10.1016/j.bj.2020.04.007.
16. Huang CG, Lee KM, Hsiao MJ, Yang SL, Huang PN, Gong YN, Hsieh TH, Huang PW, Lin YJ, Liu YC, Tsao KC, *Shih SR. Culture-based virus isolation to evaluate potential infectivity of clinical specimens tested for COVID-19. Journal of Clinical Microbiology, 2020 Jul 23;58(8):e01068-20. doi: 10.1128/JCM.01068-20. Print 2020 Jul 23.PMID: 32518072
17. Nat Struct Mol Biol. 2020 Jul 31. doi: 10.1038/s41594-020-0480-y. Online ahead of print.PMID: 32737466
18. Gong YN, KC Tsao, Hsiao MJ, Huang CG, Huang PN, Huang PW, Lee KM, Liu YC, Yang SL, RL Kuo, Chen KF, Liu YC Huang SY, Huang HI, Liu MT, Yang JR, Chiu CH, Yang CT, Chen GW, *Shih SR. SARS-CoV-2 genomic surveillance in Taiwan revealed novel ORF-8 deletion mutant and clade associated with infections in Middle East. Emerging Microbes and Infections, 2020 Dec;9(1):1457-1466. doi: 10.1080/22221751.2020.1782271.
19. Huang KA, Huang PN, Huang YC, Yang SL, Tsao KC, Chiu CH, Shih SR, Lin TY. Emergence of genotype C1 Enterovirus A71 and its link with antigenic variation of virus in Taiwan. PLoS Pathog. 2020 Sep 16;16(9):e1008857. doi: 10.1371/journal.ppat.1008857. eCollection 2020 Sep.
20. Hung HC, Ke YY, Huang SY, Huang PN, Kung YA, Chang TY, Yen KJ, Peng TT, Chang SE, Huang CT, Tsai, YR, Wu SH, Lee SJ, Lin JH, Liu BS, Sung WC, *Shih SR, Chen CT, J, Hsu. Discovery of M protease inhibitors encoded by SARS-CoV-2. Antimicrob Agents Chemother. 2020 Aug 20;64(9):e00872-20. doi: 10.1128/AAC.00872-20. Print 2020 Aug 20.
21. Wang HC, Hung HC, Huang PN, Kung YA, Tseng SN, Wang YM, Shih SR, Tsu-An Hsu J. Engineering a novel IgG-like bispecific antibody against enterovirus A71. Biochem Biophys Rep. 2020 Dec 5;24:100860. doi: 10.1016/j.bbrep.2020.100860. eCollection 2020 Dec.
22. Wang HC, Huang PN, Hung HC, Tseng SN, Chang CC, Tsai YR, Wang YM, Shih SR, Hsu JT. Effect of a Neuropilin-1-Derived Virus Receptor Trap on Enterovirus A71 Infection In Vitro. Antimicrob Agents Chemother. 2020 Dec 16;65(1):e00695-20. doi: 10.1128/AAC.00695-20. Print 2020 Dec 16.
23. Li ML, Chen BS, Shih SR. Editorial: Viral Encephalitis. Front Microbiol. 11:599257. doi: 10.3389/fmicb.2020.599257. eCollection 2020.
24. Feb 26;17(2):e1009352. doi: 10.1371/journal.ppat.1009352. Online ahead of print.
25. Kiew LV, Chang CY, Huang SY, Wang PW, Heh CH, Liu CT, Cheng CH, Lu YX, Chen YC, Huang YX, Chang SY, Tsai HY, Jung YA, Huang PN, Hsu MH, Leo BF, Foo YY, Su CH, Hsu KC, Huang PH, Ng CJ, Kamarulzaman A, Yuan CJ, Shieh DB, * Shih SR, Chung LY, Chang CC. Development of flexible electrochemical impedance spectroscopy-based biosensing platform for rapid screening of SARS-CoV-2 inhibitors. Biosensor and Bioelectronics, 2021 Apr 3;183:113213. doi: 10.1016/j.bios.2021.113213. Online ahead of print.PMID: 33857754 .
26. Liu YC, Mok BW, Wang P, Kuo RL, Chen H, *Shih SR. Cellular 5’-3’ mRNA exoribonuclease XRN1 inhibits interferon beta activation and facilitates influenza A virus replication. mBio. 2021 Aug 31;12(4):e0094521. doi: 10.1128/mBio.00945-21. Epub 2021 Jul 27.
27. Janissen R, Woodman A, Shengjuler D, Vallet T, Lee KM, Kuijpers L, Moustafa IM, Fitzgerald F, Huang PN, Perkins AL, Harki DA, Arnold JJ, Solano B, Shih SR, Vignuzzi M, Cameron CE, Dekker NH. Induced intra- and intermolecular template switching as a therapeutic mechanism against RNA viruses Mol Cell. 2021 Nov4;81(21): 4467-4480.e7.doi:10.1016/ j.molcel. 2021.10.003. Epub 2021 Oct 22.PMID: 34687604.
28. Hsieh SM, Liu MC, Chen YH, Lee WS, Hwang SJ, Cheng SH, Ko WC, Hwang KP, Wang NC, Lee YL, Lin YL, Shih SR, Huang CG, Liao CC, Liang JJ, Chang CS, Chen C, Lien CE, Tai IC, Lin TY. Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan. Lancet Respir Med. 2021 Dec;9(12):1396-1406. doi: 10.1016/S2213-2600(21)00402-1. Epub 2021 Oct 13.PMID: 34655522.
29. Chen YC, Kung YA, Janapatla RP, Hsu MH, Lien R, Chen JC, Shih SR, Chiu CH. Neutralization antibody titers against SARS-CoV-2 in an infant born to a mother with COVID-19. Pediatr Neonatol. 2021 Nov;62(6):661-663. doi: 10.1016/j.pedneo.2021.07.007. Epub 2021 Sep 10.
30. Li ML, Shih SR, Tolbert BS, Brewer G. Enterovirus A71 Vaccines. Vaccines (Basel). 2021 Feb 27;9(3):199. doi: 10.3390/vaccines9030199.
31. Kuo RL, Chen YT, Li HA, Wu CC, Chiang HC, Lin JY, Huang HI, Shih SR, Chin-Ming Tan B. Molecular determinants and heterogeneity underlying host response to EV-A71 infection at single-cell resolution. RNA Biol. 2021 May;18(5):796-808. doi: 10.1080/15476286.2021.1872976. Epub 2021 Feb 23.
32. *mSphere. 2021 Mar 31;6(2):e00104-21. doi: 10.1128/mSphere.00104-21.
33. Mwale PF, Lee CH, Huang PN, Tseng SN, Shih SR, Huang HY, Leu SJ, Huang YJ, Chiang LC, Mao YC, Wang WC, Yang YY. In Vitro Characterization of Neutralizing Hen Antibodies to Coxsackievirus A16 . Int J Mol Sci. 2021 Apr 16;22(8):4146. doi: 10.3390/ijms22084146.
34. Lee KM, Wu CC, Wu SE, Lin YH, Wang LT, Chang CR, Huang PN, Shih SR, Kuo RL. The RNA-dependent RNA polymerase of enterovirus A71 associates with ribosomal proteins and positively regulates protein translation. RNA Biol.17(4):608-622. doi: 10.1080/15476286.2020.1722448. Epub 2020 Feb 6. PMID: 32009553
35.Huang CG, Dutta A, Huang CT, Chang PY, Hsiao MJ, Hsieh YC, Lin SM, Shih SR, Tsao KC, Yang CT. Relative COVID-19 Viral Persistence and Antibody Kinetics. Pathogens. 2021 Jun 13;10(6):752. doi: 10.3390/pathogens10060752.
36. Hsieh SM, Liu WD, Huang YS, Lin YJ, Hsieh EF, Lian WC, Chen C, Janssen R, Shih SR, Huang CG, Tai IC, Chang SC. Safety and immunogenicity of a Recombinant Stabilized Prefusion SARS-CoV-2 Spike Protein Vaccine (MVC-COV1901) Adjuvanted with CpG 1018 and Aluminum Hydroxide in healthy adults: A Phase 1, dose-escalation study. EClinicalMedicine. 100989. doi: 10.1016/j.eclinm.2021.100989. Online ahead of print. PMID: 34222848
37. Lin JY, Weng KF, Chang CK, Gong YN, Huang GJ, Lee HL, Chen YC, Huang CC, Lu JY, Huang PN, Chiang HJ, Chen CM, *Shih SR. Enterovirus A71 Induces Neurological Diseases and Dynamic Variants in Oral Infection of Human SCARB2-Transgenic Weaned Mice. J Virol. 2022. JVI0089721. doi: 10.1128/JVI.00897-21. Online ahead of print. PMID: 34379497
38. Kung YA, Chiang HJ, Li ML, Gong YN, Chiu HP, Hung CT, Huang PN, Huang SY, Wang PY, Hsu TA, Brewer G, *Shih SR. Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis. mBio. 2022. e0271721. doi: 10.1128/mbio.02717-21. Online ahead of print. PMID: 35038927
39. Chen CY, Liu KT, Shih SR, Ye JJ, Chen YT, Pan HC, Hsu HJ, Sun CY, Lee CC, Wu CY, Lai CC, Wu IW. Neutralization Assessments Reveal High Cardiothoracic Ratio and Old Age as Independent Predictors of Low Neutralizing Antibody Titers in Hemodialysis Patients Receiving a Single Dose of COVID-19 Vaccine. J Pers Med. 12(1):68. doi: 10.3390/jpm12010068. PMID: 35055386.
40. Liu KT, Gong YN, Huang CG, Huang PN, Yu KY, Lee HC, Lee SC, Chiang HJ, Kung YA, Lin YT, Hsiao MJ, Huang PW, Huang SY, Wu HT, Wu CC, Kuo RL, Chen KF, Hung CT, Oguntuyo KY, Stevens CS, Kowdle S, Chiu HP, Lee B, Chen GW, *Shih SR. Quantifying Neutralizing Antibodies in Patients with COVID-19 by a Two-Variable Generalized Additive Model. mSphere.e0088321. doi: 10.1128/msphere.00883-21. Online ahead of print. PMID: 35107336
41. Kung YA, Lee KM, Chiang HJ, Huang SY , Wu CJ, *Shih SR. Molecular Virology of SARS-CoV-2 and Related Coronaviruses. Microbiology and Molecular Reviews. 2022 Mar 28:e0002621. doi: 10.1128/mmbr.00026-21. Online ahead of print.PMID: 35343760
42. Nguyen TT, Chiu CH, Lin CY, Chiu NC, Chen PY, Le TTV, Le DN, Duong AH, Nguyen VL, Huynh TN, Truong HK, Phan TL, Nguyen TTT, Shih SR, Huang CG, Weng YJ, Hsieh EF, Chang S, Chen C, Tai IC, Huang LM. Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2022 Apr 12:S0140-6736(22)00313-0. doi: 10.1016/S0140-6736(22)00313-0. Epub ahead of print. PMID: 35427481.
Methods Mol Biol. 2022.PMID: 35554897.
44. Hsieh SM, Chang SC, Cheng HY, Shih SR, Lien CE Durability and Immunogenicity of Neutralizing Antibodies Response Against Omicron Variants After Three Doses of Subunit SARS-CoV-2 Vaccine MVC-COV1901: An Extension to an Open-Label, Dose-Escalation Phase 1 Study. Infect Dis Ther. 2022.PMID: 35579840.
45. Chen CP, Huang KA, Shih SR, Lin YC, Cheng CY, Huang YC, Lin TY, Cheng SH. Anti-Spike Antibody Response to Natural Infection with SARS-CoV-2 and Its Activity against Emerging Variants. Microbiol Spectr. 2022 Aug 31;10(4):e0074322. doi: 10.1128/spectrum.00743-22. Epub 2022 Jun 15.PMID: 35703556
46. Chiu YF, Huang YW, Chen CY, Chen YC, Gong YN, Kuo RL, Huang CG, Shih SR. Visualizing Influenza A Virus vRNA Replication. Front Microbiol. 2022 Jun 6;13:812711. doi: 10. 3389/ fmicb.2022.812711. eCollection 2022. PMID: 35733972
47. Chen CY, Liu KT, Shih SR, Ye JJ, Chen YT, Hsu CK, Pan HC, Hsu HJ, Sun CY, Lee CC, Wu CY, Lai CC, Wu IW. Adequacy of Hemodialysis Serves as an Independent Predictor of Humoral Response to ChAdOx1 Prime-Boost Vaccination in Hemodialysis Patients. Viruses. 2022 May 26;14(6):1149. doi: 10.3390/v14061149.PMID: 35746621
48. Wang PJ, Pang YH, Huang SY, Fang JT, Chang SY, Shih SR, Huang TW, Chen YJ, Sun CK. Microwave resonant absorption of SARS-CoV-2 viruses. Sci Rep. 2022 Jul 22;12(1):12596. doi: 10.1038/s41598-022-16845-5.PMID: 35869163
49. Kung YA, Huang SY, Huang CG, Liu KT, Huang PN, Yu KY, Yang SL, Chen CP, Cheng CY, Lee IK, Lin SM, Chang HP, Lin YT, Liu YC, Chen GW, *Shih SR. Factors influencing neutralizing antibody titers elicited by coronavirus disease 2019 vaccines. Microbes Infect. 2022 Sep 9:105044. doi: 10.1016/j.micinf.2022.105044. Online ahead of print.PMID: 36096357
50. Chen CJ, Yang LY, Chang WY, Huang YC, Chiu CH, Shih SR, Huang CG, Huang KA. A randomized controlled trial of heterologous ChAdOx1 nCoV-19 and recombinant subunit vaccine MVC-COV1901 against COVID-19. Nat Commun. 2022 Sep 17;13(1):5466. doi: 10.1038/s41467-022-33146-7.PMID: 3611585