Directory

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.

Assessing the utility of antivirals for preventing maternal-fetal transmission of zika virus in pregnant mice.

Antiviral Research – Watanabe S, Tan NWW, Chan KWK, Vasudevan SG. (2019)

167 104-109

Dengue Virus and Zika Virus Serological Cross-reactivity and Their Impact on Pathogenesis in Mice.

Journal of Infectious Diseases – Watanabe S, Tan NWW, Chan KWK, Vasudevan SG. (2019)

219 (2); 223-233

Preclinical Antiviral Testing for Dengue Virus Infection in Mouse Models and Its Association with Clinical Studies.

ACS infectious diseases – Watanabe Satoru; Low Jenny Guek-Hong; Vasudevan Subhash G (2018)

4 (7); 1048-1057

Rational Engineering and Characterization of an mAb that Neutralizes Zika Virus by Targeting a Mutationally Constrained Quaternary Epitope.

Cell Host & Microbe – 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)

23 (5); 618-627

A systematic approach to the development of a safe live attenuated Zika vaccine.

Nature Communications – 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)

12 (9);

18F-FDG as an inflammation biomarker for imaging dengue virus infection and treatment response

JCI Insight – Chacko AM, Watanabe S (equal contribution), Herr KJ, Kalimuddin S, Tham JY, Ong J, Reolo M, Serrano RMF, Cheung YB, Low JGH, Vasudevan SG (2017)

2 (9);

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 – Watanabe S, Chan KW, Dow G, Ooi EE, Low JG, Vasudevan SG (2016)

127 10-19

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 – Watanabe S, Chan KW, Wang J, Rivino L, Lok SM, Vasudevan SG (2015)

89 (11); 5847-5861

A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection

Journal of Infectious Diseases – 14. 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)

210 (11); 1780-1791

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 – 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)

14 (8); 706-715