Associate Professor Kevin SW Tan

Kevin SW Tan

BSc (Hons), PhD, CBiol, FRSB

Associate Professor, Head of Department

Department of Microbiology and Immunology

Affliations:

  • Vice-Dean (Graduate Studies), Yong Loo Lin School of Medicine, NUS
  • Member, NUS Graduate School Integrative Sciences and Engineering Programme (ISEP)

Email: mictank@nus.edu.sg

Tel: 6516 6780

Research Interest

Plasmodium falciparum – Exploiting unique features of cell death for the discovery of novel anti-malarials

Malaria is a potentially fatal infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent species, Plasmodium falciparum, infects approximately 200 million people and claims 0.5 million lives annually. The parasite infects red blood cells (RBC) of all ages, multiplies within them, before rupturing the host cell to release parasite progeny. Despite the importance of malaria, evidenced by overwhelming number of deaths, there are numerous gaps in our knowledge of P. falciparum biology. Our laboratory has developed numerous assays for the characterization of drug-induced programmed cell death (PCD) pathways in P. falciparum. We have shown that a new mode of action of chloroquine and other lysosomotropic drugs is the disruption of the parasite digestive vacuole (DV), resulting in PCD-like features post DV rupture. We observed that DV rupture can occur in vivo and is a physiologically relevant alternative mode of drug-mediated parasite death. Recent studies from our team have implicated a calcium/ calpain pathway that is universally activated upon drug-induced DV rupture.

Leveraging on newer technologies such as imaging flow cytometry, we have developed a platform for the discovery of novel DV disruption molecules. This platform has resulted in a collaboration with industry (GSK) with the objective of identifying DV disruption molecules among a focused compound library. Screening the MMV Malaria Box and Pathogen Box have also resulted in the identification of potent DV disruptors. Together with partners at the Department of Chemistry and Pharmacy, we have developed fluorescent- and chemosensitizer-tagged chloroquine hybrid molecules that have been validated to be excellent reporter molecules and potent chemoreversal drugs respectively. Our research on malaria has implicated the parasite digestive vacuole as an attractive and tractable drug target. With the development of an imaging-based platform, a robust and rapid method for the identification and DV disruption compounds is available to the scientific community.

Blastocystis – Parasite-host interactions and microbiomes to understand pathogenesis

Our laboratory has contributed extensively to the current understanding of Blastocystis biology. Our research on this protist focuses on host-pathogen interactions, which aims to clarify its controversial role in intestinal disease. We have shown that the parasite exhibits IgA, IgM and IgG protease activity and induces contact-independent apoptosis, F-actin rearrangement, and barrier function disruption in IEC-6 cells. We have also observed that parasite cysteine proteases mediate IL-8 production in human colonic epithelial T-84 cells in a NF-kB dependent manner. We subsequently report that Blastocystis-induced tight junction compromise is mediated by host cell rho-ROCK pathway. More recent studies shed new light on the interaction between Blastocystis and host antimicrobial peptides.

Humans can be infected by numerous genotypically distinct subtypes of Blastocystis. We have contributed to new knowledge that such a complex nature of the parasite can lead to significant inter- and intra-subtype variation in cell biology, drug sensitivity and cytopathic effects including variations in adhesion, host cell death, barrier compromise and host pathology. A mouse model of acute Blastocystis infection was recently developed and will provide the scientific community with a means to better define the pathogenesis of Blastocystis.

Our laboratory is currently investigating the roles of Blastocystis in the context of parasite-microbiota interactions using in vitro and in vivo (acute mouse model) approaches. Our preliminary data suggest that Blastocystis modulates host microbiota populations leading to dysbiosis and intestinal disease.

Current Projects

  • Pathogenesis of malaria and Blastocystis
  • Identification of PCD modulators in malaria and Blastocystis
  • Novel cell death pathways in Protozoa
  • Microbiome-host interactions
  • High-content imaging for biological insights and drug screening

Recent Publications

  1. Deng L, Wojciech L, Png CW, Kioh DYQ, Gu YX, Aung TT, Malleret B, Chan ECY, Peng G, Zhang YL, Gascoigne NRJ, Tan KSW (2023) Colonization with two different Blastocystis subtypes in DSS-induced colitis mice is associated with strikingly different microbiome and pathological features. Theranostics doi:10.7150/thno.81583 (In Press).
  2. Deng L, Wojciech L, Png CW, Koh EYL, Aung TT, Kioh DYQ, Chan ECY, Malleret B, Zhang YL, Peng G, Gascoigne NRJ, Tan KSW (2022) Experimental colonization with Blastocystis ST4 is associated with protective immune responses and modulation of gut microbiome in a DSS-induced colitis model. Cell Mol Life Science 79: 245.
  3. Chia W, Gomez-Lorenzo MG, Castellote I, Tong JX, Chandramohanadas R, Thu Chu TT, Shen W, Go ML, de Cozar C, Crespo B, Almela MJ, Neria-Serrano F, Franco V, Gamo FJ, Tan KSW (2021) High-Content Phenotypic Screen of a Focused TCAMS Drug Library Identifies Novel Disruptors of the Malaria Parasite Calcium Dynamics. ACS Chem Biol 16:2348-2372. (Cover Issue)
  4. Deng L, Wojciech L, Gascoigne NRJ, Peng G, Tan KSW (2021) New insights into the interactions between Blastocystis, the gut microbiota, and host immunity. PLoS Pathog 17(2): e1009253.
  5. Yason JA, Liang YR, Png CW, Zhang YL, Tan KSW (2019) Interactions between a pathogenic Blastocystis subtype and gut microbiota: in vitro and in vivo studies. Microbiome 7:30.
  6. Tong JX, Ang SEL, Tan EHN, Tan KSW (2019) Viability screen of LOPAC1280 reveals tyrosine kinase inhibitor tyrphostin A9 as a novel partner drug for artesunate combinations to target the Plasmodium falciparum ring stage. Antimicrob. Agents Chemother 63(4): e02389-18.
  7. Yason JA, Koh KARP, Tan KSW (2018) Viability screen of LOPAC®1280 reveals phosphorylation inhibitor auranofin as potent inhibitor of Blastocystis ST1, ST4 and ST7 isolates. Antimicrob. Agents Chemother 62(8):e00208-18.
  8. Tong JX, Chandramohanadas R, Tan KSW (2018) High-content screening of MMV Pathogen Box for Plasmodium falciparum digestive vacuole disrupting molecules reveals valuable starting points for drug discovery. Antimicrob. Agents Chemother 62(3): e02031-17.
  9. Kosaisavee V, Suwanarusk R, Chua ACY, Kyle DE, Malleret B, Zhang R, Imwong M, Imerbsin R, Ubalee R, Sámano-Sánchez H, Yeung BKS, Ong JJY, Lombardini E, Nosten F, Tan KSW, Bifani P, Snounou G, Rénia L, Russell B (2017) Strict tropism for CD71+/CD234+ human reticulocytes limits the zoonotic potential of Plasmodium cynomolgi. Blood 130:1357-1363.
  10. Wang JG, Zhang CJ, Chia WN, Loh CCY, Li ZJ, Lee YM, He YK, Yuan LX, Lim TK, Liu M, Liew CX, Lee YQ, Zhang JB, Lu NC, Lim CT, Hua ZC, Liu B, Shen HM, Tan KSW*, Lin QS* (2015) Heme-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat. Commun 6:10111. (* co-corresponding authors).
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Lab Members

Recent Lab Alumni

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