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Satoru Watanabe

Assistant Professor

Assistant Professor 

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Bio Research Publications

Satoru Watanabe is an Assistant Professor in the Programme in Emerging Infectious Diseases at Duke-NUS Medical School. He received his B.S and M.S from University of Tsukuba (Japan) in the field of biology (phycology). He obtained his PhD in the field of medical science (virology) from Tokyo Medical and Dental University (Japan). He was engaged in pathogenesis study for several viruses such as HIV, EBV, influenza and SIV using mouse models as well as monkey models before coming to Singapore. He joined Prof Subhash Vasudevan’s lab at Duke-NUS Medical School in 2010 and has been engaged in the study of dengue virus (DENV) as well as Zika virus (ZIKV)

We are interested in the pathogenesis of flavivirus infection, in particular to dengue virus (DENV) and Zika virus (ZIKV). We use mouse models of DENV and ZIKV infection to understand the mechanism of disease onset and develop therapeutics.

 

1. Investigate the pathological mechanisms that lead to severe dengue diseases in mice

Severe dengue diseases (DHF/DSS) are usually associated with secondary heterotypic infections due to a phenomenon termed as antibody-dependent enhancement of infection (ADE). We found that DENV infection in the presence antibodies increases vascular permeability specifically in the small intestine accompanied with massive production of pro-inflammatory cytokines in mice (Watanabe et al., 2015; Chacko et al., 2017), suggesting that dengue disease severity is regulated in a tissue-dependent manner. This project aims to identify the transcriptional and immunological factors that leads severe small intestinal pathology caused by DENV infection in mice.

2. Discover the factors that permit maternal-fetal transmission of ZIKV through the placental barrier

Viruses rarely cross the placental barrier, with particular exceptions such as ZIKV that is known to infect the fetus, resulting in severe birth defects such as microcephaly. We recently established a mouse model of ZIKV infection that allows vertical transmission of virus in 40-60% of fetuses when the dams acquire ZIKV infection during pregnancy (Watanabe et al. 2019). Using this model, we examine the placental pathology that permits vertical transmission of ZIKV by the gene expression profiling and cellular/histopathological approaches.

3. Develop the therapeutics against DENV and ZIKV infection.

We have been engaged in drug discovery research to find novel antivirals, especially against DENV, which can be applied to clinical settings (Low et al., 2014). This includes repurposing drugs, nucleotide analogs and other type of inhibitors targeting viral/host proteins (Watanabe et al. 2018). In addition, our mouse model of ZIKV infection was shown to be highly suited for testing small molecule inhibitors (Watanabe et al. 2019). Using our various mouse models of DENV and ZIKV infection, we continuously develop antivirals that can be translated into clinical settings.

Watanabe S, Tan NWW, Chan KWK, Vasudevan SG. (2019) Assessing the utility of antivirals for preventing maternal-fetal transmission of zika virus in pregnant mice. Antiviral Research, 167:104-109.

Watanabe S, Tan NWW, Chan KWK, Vasudevan SG. (2019) Dengue and Zika Virus Serological Cross-reactivity and their Impact on Pathogenesis in Mice. Journal of Infectious Diseases, 219(2):223-233.

Watanabe S, Low JG, Vasudevan SG. (2018) Preclinical Antiviral Testing for Dengue Virus Infection in Mouse Models and Its Association with Clinical Studies. ACS Infectious Diseases, 4(7):1048-1057.

Tharakaraman K, Watanabe S*, Chan KR, Huan J, Subramanian V, Chionh YH, Raguram A, Quinlan D, McBee M, Ong EZ, Gan ES, Tan HC, Tyagi A, Bhushan S, Lescar J, Vasudevan SG, Ooi EE, Sasisekharan R. (2018) Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope. Cell Host & Microbes, 23(5):618-627.

Kwek SS, Watanabe S*, Chan KR, Ong EZ, Tan HC, Ng WC, Nguyen MTX, Gan ES, Zhang SL, Chan KWK, Tan JH, Sessions OM, Manuel M, Pompon J, Chua C, Hazirah S, Tryggvason K, Vasudevan SG, Ooi EE. (2018) A systematic approach to the development of a safe live attenuated Zika vaccine. Nature Communications, 9(1):1031.

Chacko AM, Watanabe S*, Herr KJ, Kalimuddin S, Tham JY, Ong J, Reolo M, Serrano RMF, Cheung YB, Low JGH, Vasudevan SG. (2017) 18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response. JCI Insight, 2(9).

Watanabe S, Chan KW, Dow G, Ooi EE, Low JG, and Vasudevan SG. (2016) Optimizing celgosivir therapy in mouse models of dengue virus infection of serotypes 1 and 2: the search for a window for potential therapeutic efficacy. Antiviral Research, 127:10-9.

Chan KW, Watanabe S, Kavishna R, Alonso S, Vasudevan SG. (2015) Animal models for studying dengue pathogenesis and therapy. Antiviral Research, 123:5-14.

Watanabe S, Chan KW, Wang J, Rivino L, Lok SM, Vasudevan SG. (2015) Dengue virus infection with highly-neutralizing levels of cross-reactive antibodies cause acute lethal small intestinal pathology without high level of viremia in mice. Journal of Virology, 89(11):5847-61.

Fraser JE, Watanabe S, Wang C, Chan WK, Maher B, Lopez-Denman A, Hick C, Wagstaff KM, Mackenzie JM, Sexton PM, Vasudevan SG, Jans DA. (2014) A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection. Journal of Infectious Diseases, 210(11):1780-91.

Low JG, Sung C, Wijaya L, Wei Y, Rathore AP, Watanabe S, Tan BH, Toh L, Chua LT, Hou Y, Chow A, Howe S, Chan WK, Tan KH, Chung JS, Cherng BP, Lye DC, Tambayah PA, Ng LC, Connolly J, Hibberd ML, Leo YS, Cheung YB, Ooi EE, Vasudevan SG. (2014) Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet Infectious Diseases, 14:706-15.

Watanabe S, Rathore AP, Sung C, Lu F, Khoo YM, Connolly J, Low J, Ooi EE, Lee HS, Vasudevan SG. (2012) Dose- and schedule-dependent protective efficacy of celgosivir in a lethal mouse model for dengue virus infection informs dosing regimen for a proof of concept clinical trial. Antiviral Research, 96(1): 32-5.

Watanabe S, Tan KH, Rathore AP, Rozen-Gagnon K, Shuai W, Ruedl C, Vasudevan SG. (2012) The magnitude of dengue virus NS1 protein secretion is strain dependent and does not correlate with severe pathologies in the mouse infection model. Journal of Virology, 86(10):5508-14.

Rathore AP, Paradkar PN, Watanabe S, Tan KH, Sung C, Connolly JE, Low J, Ooi EE, Vasudevan SG. (2011) Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Research, 92(3):453-60.

Sugimoto C, Watanabe S, Naruse T, Kajiwara E, Shiino T, Umano N, Ueda K, Sato H, Ohgimoto S, Hirsch V, Villinger F, Ansari AA, Kimura A, Miyazawa M, Suzuki Y, Yamamoto N, Nagai Y, Mori K. (2010) Protection of macaques with diverse MHC genotypes against a heterologous SIV by vaccination with a deglycosylated live-attenuated SIV. PLoS One. 5(7):e11678.

Yajima M, Imadome K, Nakagawa A, Watanabe S, Terashima K, Nakamura H, Ito M, Shimizu N, Yamamoto N, Fujiwara S. (2009) T cell-mediated control of Epstein-Barr virus infection in humanized mice. Journal of Infectious Diseases, 200(10):1611-5.

Yajima M, Imadome K, Nakagawa A, Watanabe S, Terashima K, Nakamura H, Ito M, Shimizu N, Honda M, Yamamoto N, Fujiwara S. (2008) A new humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, lymphoproliferative disorder, and cell-mediated and humoral immune responses. Journal of Infectious Diseases, 198(5):673-82.

Watanabe S, Ohta S, Yajima M, Terashima K, Ito M, Mugishima H, Fujiwara S, Shimizu K, Honda M, Shimizu N, Yamamoto N. (2007) Humanized NOD/SCID/IL2Rgamma(null) mice transplanted with hematopoietic stem cells under nonmyeloablative conditions show prolonged life spans and allow detailed analysis of human immunodeficiency virus type 1 pathogenesis. Journal of Virology, 81(23):13259-64.

Watanabe S, Terashima K, Ohta S, Horibata S, Yajima M, Shiozawa Y, Dewan MZ, Yu Z, Ito M, Morio T, Shimizu N, Honda M, Yamamoto N. (2007) Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood, 109(1):212-8.

*Denotes equal contribution