Department of Biological Science
National University of Singapore
14 Science Drive 4
Ph.D.(Royal Postgraduate Medical School,University of London, UK
Innate Immunity & Pathogen surveillance strategies
Our lab studies host-pathogen interaction and innate immune response during the acute phase of infection. We examine the mechanisms of action of pattern recognition receptors (PRRs) and their interaction partners in response to pathogen-associated molecular patterns (PAMPs). We have discovered new and important functions of immune-responsive proteins (eg: lectins, complements, proteases, protease inhibitors and natural antibodies), which are evolutionarily conserved ~500 million years. We focus on elucidating the ensemble of immune-responsive PRRs and what regulates their immediate action during acute infection-inflammation, which boosts pathogen surveillance and immune response. We use cell lines, primary human cells and knockout mice to ascertain the physiological relevance.
Some research projects in our lab include investigations on: (a) how polymicrobial infections drive crosstalk between TLR pathways, and how immune responsive transcription factors and gene promoters are regulated; (b) how the redox-reactive cell-free haemoglobin released during haemolytic infection induces innate immune response; (c) how macrophages live or die during acute phase infection- the interphase between immune response and apoptosis or immune-overactivation and cancer; (d) how the host downregulates immune-overactivation through SARM and its interaction with other pro- and anti- apoptotic factors.
Besides unravelling fundamental mechanisms of innate immunity, we characterize and delineate the bioactive domains of the PRR-PRR and PRR-PAMP. Recombinant proteins and peptides derived from LPS-binding proteins are developed into potential probes for LPS-sensors and prototypes for antimicrobials and immunomodulators.
Wai Hoe Lau, Xiphias Ge Zhu, Shamaine Wei Ting Ho, Shu Chun Chang, Jeak Ling Ding (2017).
Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells. Oncotarget DOI: 10.18632/oncotarget.15862 pdf
Zhiwei Ang, Jun Zhi Er, Nguan Soon Tan, Jinhua Lu, Yih-Cherng Liou, Johannes Grosse & Jeak Ling Ding, Human and mouse monocytes display distinct signalling and cytokine profiles upon stimulation with FFAR2/FFAR3 short-chain fatty acid receptor agonists. Scientific Reports | 6:34145 | DOI: 10.1038/srep34145 pdf
Bing Liu, Qian Liu, Lei Yang, Sucheendra K. Palaniappan, Ivet Bahar, P. S. Thiagarajan,* Jeak Ling Ding* , Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathway, Published 12 July 2016, Sci. Signal. 9, ra70 (2016) pdf
Bing Liu, Qian Liu, Lei Yang, Sucheendra K. Palaniappan, Ivet Bahar, P. S. Thiagarajan, Jeak Ling Ding, Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways. SCIENCE SIGNALING.org 12 July 2016 Vol 9 Issue 436 ra70 pdf
Qian Liu and Jeak Ling Ding, The molecular mechanisms of TLR-signaling cooperation in cytokine regulation. Immunology and Cell Biology (2016), 1–5 pdf
Zhiwei Ang and Jeak Ling Ding, GPR41 and GPR43 in Obesity and inflammation – Protective or Causative? Frontiers in immunology, Mini Review, (2016) pdf
Carlsson E, Ding JL, Byrne B. SARM modulates MyD88-mediated TLR activation through BB-loop
dependent TIR-TIR interactions. Biochimica et Biohysica Acta (Molecular Cell Research) 1863 (2016) 244-253 pdf
Chang SC, Ding JL. SAG-UPS regulates malignant transformation – from chronic inflammation to protumorigenesis to liver cancer. Cell Death and Diseases (2015) 6, e1941; doi:10.1038/cddis.2015.312
Chang SC, Choo WQW, Toh HC, Ding JL. SAG-UPS attenuates proapoptotic SARM and Noxa to confer survival advantage to early hepatocellular carcinoma. Cell Death Discovery (2015) 1, 15032; doi:10.1038/cddiscovery.2015.32
Liu Q, Zhu Y, Yong WK, Sze NSK, Tan NS, Ding JL. Synchronisation of IRF1, JunB & C/EBPb activities during TLR3-TLR7 crosstalk orchestrates timely cytokine synergy in the proinflammatory response J. Immunol. Cutting Edge (2015) 195: 801-805
Panneerselvam P, Ding JL. Beyond TLR signalling – the role of SARM in antiviral immune defense, apoptosis and development. Intl. Revs. Immunol. (2015) 34: 432-444. doi:10.3109/08830185.2015.1065826
Ang ZW, Er JZ, Ding JL. The short-chain fatty acid receptor GPR43 is transcriptionally regulated by XBP1 in human monocytes. Scientific Reports (2015) 5: 8134 doi:10.1038/srep08134
Lee SK, Goh SY, Wong YQ, Ding JL. Response of neutrophils to extracellular haemoglobin and LTA in human blood system. EBioMedicine (2015) http://dx.doi.org/10.1016/j.ebiom.2015.01.003
Panda S, Ding JL. Natural antibodies bridge innate and adaptive immunity. J. Immunol. (2015) 194: 13-20
Leong KW, Ding JL. The unexplored roles of human serum IgA. DNA Cell Biol. (2014) 33(12): 823-829
Chang SC, Ding JL. Ubiquitination by SAG regulates macrophage survival/death and immune response during infection. Cell Death Differentiation (2014) 21: 1388-1398 pdf
Tan ST, Ho B, Leung BPL, Ding JL. TLR crosstalk confers specificity to innate immunity. Intl Reviews of Immunol. (2014) 33:443–453
Bahl N, Winarsih I, Tucker-Kellogg L, Ding JL. Extracellular haemoglobin upregulates and binds to tissue factor on macrophages: implications for coagulation and oxidative stress. Thrombosis and Haemostasis (2014) 111: 67-78
Panda S, Zhang J, Yang LF, Anand GS, Ding JL. Molecular interaction between natural IgG and ficolin – mechanistic insights on adaptive-innate immune crosstalk. Scientific Reports 4: 3675 DOI: 10.1038/srep03675
Panda, S., Zhang, J., Tan, N.S., Ho, B. and Ding, J.L. Natural IgG antibodies provide innate protection against ficolin-opsonized bacteria. EMBO J. Advance online publication, 3 September 2013; doi:10.1038/emboj.2013.199
Rebecca Suet Ting Tan, Bin Lin, Qian Liu, Lisa Tucker-Kellogg, Bow Ho, Bernard PL Leung and Jeak Ling Ding. The synergy in cytokine production through MyD88-TRIF pathways is co-ordinated with ERK phosphorylation in macrophages. Immunol. Cell Biol. (2013) doi:org/10.1038/icb.2013.13
Karthik Subramanian, Ruijuan Du, Nguan Soon Tan, Bow Ho and Jeak Ling Ding. CD163 and IgG Codefend against Cytotoxic Hemoglobin via Autocrine and Paracrine Mechanisms. J. Immunol. (2013) doi:10.4049/jimmunol.1202648
Panneerselvam P, Laishram PKS, Selvarajoo V, Chng WJ, Ng SB, Tan NS, Ho B, Chen JZ and Ding JL. T cell death following immune activation is mediated by mitochondria-localized SARM. Cell Death and Differentiation (2013) 20, 478–489
Panneerselvam P, Laishram PKS, Ho B, Chen JZ and Ding JL. Targeting of pro-apoptotic TLR adaptor, SARM, to mitochondria: definition of critical region and residues in the signal sequence. Biochem. J. (2012) 442: 263-271.
Du R, Winarsih I, Ho B and Ding JL. Lipid-free apolipoprotein AI exerts an antioxidative role against cell-free hemoglobin. Am. J. Clin. Exp. Immunol. (2012) 1: 33-48.
Bahl N, Du R, Winarsih I, Ho B, Tucker-Kellogg L, Tidor B and Ding JL. Delineation of LPS-binding sites on hemoglobin – from in silico predictions to biophysical characterization. J. Biol. Chem. (2011) 286: 37793-37803.
Zhu PC, Tan MJ, Huang R-L, Tan CK, Chong HC, Pal M, Lam CRI, Boukamp P, Pan JY, Tan SH, Kersten S, Li HY, Ding JL and Tan NS. Angiopoietin-like 4 Protein Elevates the Prosurvival Intracellular O2– : H2O2 Ratio and Confers Anoikis Resistance to Tumors. Cancer Cell (2011) 19: 401-415.
Bing Liu, Jing Zhang, Pei Yi Tan, David Hsu, Anna M. Blom, Benjamin Leong, Sunil Sethi, Bow Ho, Jeak Ling Ding*, P. S. Thiagarajan* A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System
PLoS Comput Biol (2011) 7(1): e1001059. doi:10.1371/journal.pcbi.1001059
Low DHP, Frecer F, Le Saux A, Srinivasan GA, Ho B, Chen J, and Ding JL. Molecular Interfaces of the Galactose-binding Protein Tectonin Domains in Host-Pathogen Interaction. J. Biol. Chem. (2010) 285 (13): 9898–9907
Zhang J, Yang L, Ang ZW, Yoong SL, Tran TTTT, Ganesh SA, Tan NS, Ho B and Ding JL. Secreted M-ficolin anchors onto monocyte transmembrane GPCR43 and crosstalks with plasma CRP to mediate immune signaling and regulate host defense. J. Immunol. (2010): 6899-6910.
SARM inhibits both TRIF- and MyD88-mediated AP-1 activation Jun Peng, Quan Yuan, Bin Lin, Porkodi Panneerselvam, Xiaowei Wang, Xiao Lei Luan, Soon Kok Lim, Bernard P Leung, Eur. J. Immunol.(2010). 40: 1738-1747
Du RJ, Ho B & Ding JL. Rapid reprogramming of haemoglobin structure-function exposes multiple dual-antimicrobial potencies. EMBO J. (2010) doi:10.1038/emboj.2009.380
Zhang J, Koh JY, Lu JH, Thiel S, Leong BSH, Sethi S, He CYX, Ho B & Ding JL. Local inflammation induces complement crosstalk which amplifies the antimicrobial response. PLoS Pathogens (2009) 5 (1): 1-15.
Low DHP, Ang ZW, Yuan Q, Frecer V, Ho B, Chen J & Ding JL. A novel human Tectonin protein with multivalent b-propeller folds interacts with ficolin and binds bacterial LPS. PLoS One (2009) 4 (7):e6260, doi:10.1371/journal.pone.006260.
Leptihn S, Har JY, Chen J, Ho B, Wohland T & Ding JL. Single molecule resolution of the antimicrobial action of quantum dot-labeled sushi peptide on live bacteria. BMC Biol. (2009) 7:22, doi:10.1186/1741-7007-7-22.
Jiang N, Thangamani S, Chor CF, Wang SY, Winarsih I, Du RJ, Sivaraman J, Ho B & Ding JL. A novel serine protease inhibitor acts as an immunomodulatory switch while maintaining homeostasis. J Innate Immunity(2009) 1 (5): 465-479.
Ding JL, Gan ST & Ho B (2009) ssDNA oligoaptamers: molecular recognition and LPS-antagonism are length- and secondary structure-dependent. J Innate Immunity 1 (2009):46-58
Le Saux A, Ng MLP, Koh JJY, Low DHP, Leong GEL, Ho B & Ding JL. The macromol assembly of PRRs is impelled by serine proteases via their CCP modules. J Mol Biol 377 (2008): 902-913.
Loh WCB, Wang XW, Bui THH, Luan XL, Ho B, Ding JL, SARM: a novel Toll-like receptor adaptor, is functionally conserved from arthropod to human Mol. Immunol. (2008): 45 (2008) 1732–1742
Wang XW, Tan BZ, Sun M, Ho, B and Ding JL. TXNL6 protects retinal cell line from photooxidative damage by upregulating NF-kB activity. Free Rad Biol Med. 45 (2008): 336-344.
Fan ZH, Wang XW, Lu JH, Ho B & Ding JL. Elucidating the function of an ancient NF-kB p100 homologue, CrRelish, in antibacterial defense. Infection & Immunity 76 (2008): 664-670
Li Y, Ng MLP, Ho B & Ding JL. CrOctin is a femal-specific pentraxin that binds microbial phosphoethanolamine and bridges PRRs to the invading bacteria. Eur. J. Immunol. 37 (2007): 3477-3488.
Jiang N, Tan NS, Ho B & Ding JL. Respiratory proteins generate ROS as an antimicrobial strategy. Nature Immunology, doi. 10.1038/ni1501 (Sept 2007)
Ng PML, Le Saux A, Lee CM, Tan NS, Lu JH, Thiel S, Ho B & Ding JL. C-reactive protein collaborates with plasma lectins to boost immune response against bacteria. EMBO J. (2007) (online publication doi: 10.1038/sj.emboj.7601762).
Wang XW, Tan NS, Ho B & Ding JL. Evidence for the ancient origin of the NFkB/IkB cascade - its archaic role in infection and immunity. Proc. Natl. Acad. Sci (USA). 103 (2006): 4204-4209.
Li P, Sun M, Ho B & Ding JL. The specificity of sushi peptides for endotoxin and anionic phospholipids: potential application of POPG as an adjuvant for anti-LPS strategies. Biochem. Soc. Trans. (London) 34 (2006):270-272. (pdf of paper- Mounted on the Internet with the permission of The Biochemical Society, 2006)
Ding JL, Tan KC, Thangamani S, Kusuma N, Seow WK, Hanh BTH, Wang J & Ho B. Spatial and temporal co-ordination of expression of immune response during Pseudomonas infection of horseshoe crab, Carcinoscorpius rotundicauda. Genes & Immunity 6 (2005): 557-574.
Ong ST, Wang LH, Zhu Y, Ho B & Ding JL. The response of ferritin to LPS and acute phase of Pseudomonas infection. J. Endotoxin Res. 11 (2005): 268-280.
Tan SSH, Ng PML, Ho B & Ding JL. The antimicrobial properties of C-reactive protein (CRP). J. Endotoxin Res. 11 (2005):249-256.
Yong Zhu, Saravanan Thangamani, Bow Ho and Jeak Ling Ding, The ancient origin of the complement system. The EMBO Journal (2005) 24, 382-394
Li, P., Wohland, T, Ho, B. and Ding JL. Perturbation of LPS micelles by Sushi3 (S3) antimicrobial peptide: the importance of intermolecular disulfide-bond in S3 dimer for binding, disruption and neutralisation of LPS. J. Biol. Chem. 279 (2004): 50150-50156.
Ng, MLP., Tan, SH., Ho, B. and Ding JL. The C-reactive protein: a predominant LPS-binding acute phase protein responsive to Pseudomonas infection. J. Endotoxin Res. 10 (2004): 163-174.
Ding, JL, Wang, LH. And Ho, B. Current genome-wide analysis on serine proteases in innnate immunity. Current Genomics 5 (2004): 147-155.
Frecer, V. Ho, B. and Ding, JHL. Denovo design of potent antimicrobial peptides. Antimicrobial Agents and Chemotherapy, 48 (2004): 3349-3357.
Wang LH, Ho B & Ding J L, Transcriptional regulation of a limulus Factor C: repression of an NF?B motif modulates its responsiveness to bacterial lipopolysaccharide. J. Biol. Chem. 278 (2003): 49428-49437
Li AK, Sadasivam M & Ding J L, Receptor-ligand interaction: Vtg receptor and Vtg, implications on LDLR and Apo B/E. The first three ligand binding repeats of Vtg receptor interact with the N-terminal region of Vtg. J. Biol. Chem. 278 (2003): 2799-2806
Zhu Y, Ho B & Ding J L, Sequence and structural diversity in endotoxin-binding dodecapeptides. Biochim. Biophys. Acta 1611 (2003): 234-242
Li CG, Ng P M L, Zhu Y, Ho B & Ding J L, Tandem repeats of sushi peptide with enhanced LPS-binding and –neutralising activities. Protein Engineering 16 (2003): 629-635
Wang J, Tan N S, Ho B & Ding J L, Modular arrangement and secretion of a multidomain serine protease: evidence for involvement of proline-rich region and N-glycans in the secretion pathway. J. Biol. Chem. 277 (2002): 36363-36372
Goh YY, Ho B & Ding J L, A novel fluorescent protein-based biosensor for gram-negative bacteria. Appl. Environ. Microbiol. 68 (2002): 6343-6352
Goh YY, Frecer V, Ho B & Ding J L, Rational design of green fluorescent protein mutants as biosensor for bacterial endotoxin. Protein Engineering 15 (2002): 493-502
Tan N S, Ding J L & Ho B, Engineering a novel secretion signal for cross-host rcombinant protein expression. Protein Engineering 15 (2002): 337-345
Ding J L & Ho B, New era in pyrogen testing. Trends in Biotechnology, 19 (2001): 277-281
Yau YH, Ho B, Tan N S, Ng P M L & Ding J L, The high therapeutic index of Factor C sushi peptides: potent antimicrobials against Pseudomonas aeruginosa. Antimicrobial Agents Chemotherapy, 45 (2001): 2820-2825
Ding J L, Zhu Y & Ho B, High performance affinity capture/removal of bacteiral pyrogen from solutions. J. Chromatography, 795 (2001): 237-246.
Tan NS, Ho B & Ding JL (2000) High affinity LPS-binding domain(s) in recombinant Factor C of a horseshoe crab neutralizes LPS-induced lethality. FASEB Journal 14: 859-870.
Frecer V, Ho B & Ding JL (2000) Interpretation of biological activity data of bacterial endotoxins by simple molecular models of mechanism of action. Eur. J. Biochem. 267: 837-852
Tan NS, Ho B & Ding JL (2000) Definition of endotoxin-binding sites in horseshoe crab Factor C recombinant sushi proteins and neutralisation of endotoxin by sushi peptides. FASEB Journal 14: 1801-1813
Frecer V, Ho B & Ding JL (2000) Molecular dynamics study of lipid A from E. coli and its monophospho and dephospho analogues. Biochim. Biophys. Acta 1466: 87-104.
1998, 1999, 2001, 2002 -Cloning and expression of horseshoe crab Factor C for detection, removal of endotoxin & endotoxin therapeutics (US Patents granted)
1998 - 2009 Isolated nucleic acids encoding a secretory signal for expression and secretion of heterologous recombinant proteins (US Patent filed).
last updated November 2012
Leong Ka Wai and Saswati Panda, Ding Jeak Ling (2014) Elucidating the role of serum IgA . UROPS Report. pdf
last updated Nov 2016