The innate immune responses are intricately linked with the immunometabolic state of myeloid cells. Since myeloid cells are the primary targets of flaviviral infection, we are interested to investigate how flaviviruses, particularly dengue virus, alter host responses and the microenvironment to promote viral propagation. To study and characterize the host responses to viral infections, we will employ mulit-omics approaches, including transcriptomics, proteomics and metabolomics. The contribution of these host responses to viral dissemination and pathogenesis of the disease will be evaluated at the molecular level.
1. Characterization of host responses following antibody-dependent dengue virus infection
Antibodies have been demonstrated clinically to be a critical risk factor for severe dengue disease. However, the precise mechanisms in which antibodies augment dengue virus infection remain poorly understood. This project aims to investigate how immune complexes alter myeloid cell host responses to promote viral propagation.
Collaborators: Prof Eng Eong Ooi (Duke-NUS), Dr Yie Hou Lee (KKH)
2. Yellow fever virus (YFV) vaccination as a model to study correlates of symptomaticity
The live-attenuated vaccine strain, YF17D, can either be asymptomatic or result in mild adverse events that resemble an acute febrile illness in humans. However, the baseline determinants and the molecular events that lead to symptomatic outcome remain poorly defined. In collaboration with Eng Eong Ooi and Jenny Low, using well-designed clinical trials, this project aims to identify the baseline characteristics and host responses that lead to symptomatic outcome.
Collaborators: Prof Eng Eong Ooi (Duke-NUS), Assoc Prof Jenny Low (Duke-NUS, SGH)
3. Impact of immunometabolism in flaviviral infection
The myeloid cell microenvironment in the inflammation sites (e.g. oxygen content, nutrient availability) differs from blood. This project aims to uncover the immunometabolic response to flaviviral infection, and how these responses impact viral infection.
Chan CYY, John JZH, Gan ES, Ong EZ, Zhang SL, Tan HC, Chai X, Ghosh S, Ooi EE, Chan KR (2019). Antibody-dependent dengue virus entry modulates cell intrinsic responses for enhanced infection. mSphere, 4, 5.
Chan KR, Gan ES, Chan CY, Liang C, Low JZ, Zhang SL, Ong EZ, Bhatta A, Wijaya L, Lee YH, Low JG, Ooi EEE (2019). Metabolic perturbations and cellular stress underpin susceptibility to symptomatic live attenuated yellow fever infection. Nature Medicine, 25, 8, 1218-1224.
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 design and characterisation of a Zika virus neutralising antibody that targets a quaternary epitope. Cell Host Microbe, 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 systemic approach to the development of a safe live attenuated Zika vaccine, Nat Commun, 9, 1, 1031.
Chan CY, Chan KR**, Chua CJ, Nur Hazirah S, Ghosh S, Ooi EE (2017). Early molecular correlates of adverse events following yellow fever vaccination. JCI Insight, 2, 19. **Co-first author.
Gan ES, Cheong WF, Chan KR, Ong EZ, Chai X, Tan HC, Ghosh S, Wenk MR, Ooi EE (2017). Hypoxia enhances antibody-dependent dengue virus infection. EMBO J, 36,10,1348-63.
Chan KR, Wang XH, Saron WAA, Gan ES, Tan HC, Mok DZ, Zhang SL, Lee YH, Liang C, Wijaya L, Ghosh S, Cheung YB, Tannenbaum SR, Abraham SN, St John AL, Low JG, Ooi EE (2016). Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity. Nat Microbiol, 1, 16164.
Robinson LN, Tharakaraman K, Rowley KJ, Costa VV, Chan KR, Wong YH, Ong LC, Tan HC, Koch T, Cain D, Kirloskar R, Viswanathan K, Liew CW, Tissire H, Ramakrishnan B, Myette JR, Babcock GJ, Sasisekharan V, Alonso S, Chen J, Lescar J, Shriver Z, Ooi EE, Sasisekharan R (2015). Structure-guided design of an anti-dengue antibody directed to a non-immunodominant epitope. Cell, 162, 493-504.
Chan KR, Ong EZ, Tan HC, Zhang SL, Zhang Q, Tang KF, Kaliaperumal N, Lim AP, Hibberd ML, Chan SH, Connolly JE, Krishnan M, Lok SM, Hanson BJ, Lin CN, Ooi EE (2014). Leukocyte immunoglobulin-like receptor B1 is critical for antibody-dependent dengue. Proc Natl Acad Sci USA, 111, 2722-7.