Topic: Differential modulation of TLR4 signalling as a paradigm for macrophage “desensitization”
Speaker: Dr. Subhra Biswas
Date: Tuesday, 2 September 2008 @ 11:00AM

Affiliation: Singapore Immunology Network (SIgN)
Biomedical Sciences Institutes (A*STAR), Singapore

Convenor: Assoc. Prof. Herbert Schwarz

Abstract:
“Desensitization” of Toll-Like Receptor (TLR) signaling in innate immune cells has been proposed as a basis for their immunosuppressive phenotype in various chronic pathologies. We are engaged in investigating the molecular mechanisms for desensitization of TLR4 signalling in macrophages under different pathological conditions.

Evidence for TLR4 desensitization will be presented from an in vitro model of repeated exposure to low doses of endotoxin that resulted in progressive hyporesponsiveness to subsequent endotoxin challenge, a phenomenon often encountered following sepsis. Lipid A-induced desensitization was linked to suppressed transcription of inflammatory genes like TNFa, CCL3 and a differential regulation of MyD88 vs TRIF signalling.

Use of genetic, biochemical and bioinformatics approaches pertaining to the TLR4 pathway, we will demonstrate that the desensitization-induced suppression of TNFa and CCL3 expression was mediated by the functional TRIF pathway and its downstream mediators. These observations constitute evidence for a role of TRIF/IFN pathway in the regulation of LipidA/TLR4-mediated endotoxin desensitization. Interestingly, studying the transcriptome and molecular phenotype of tumor associated macrophages (TAM) in chemically-induced murine fibrosarcoma, we also observed a strikingly similar basis for desensitization.

This was characterized by defective MyD88/NF-kB signaling, but constitutively upregulated TRIF pathway. Defective NF-kB signaling in both the above cases was attributed to overexpression of inhibitory NF-kB p50 homodimers. Indeed, targeting of p50 NF-kB could partially reverse TAM desensitization. These studies establish the differential modulation of MyD88 and TRIF pathway as an emerging paradigm for macrophage desensitization in different pathologies.

Topic: Immunomodulatory properties of polysaccharide-protein complex from Lycium barbarum L
Speaker: Mr. Chen Zhisong
Date: Friday, 5 September 2008 @ 2:00PM 

Affiliation: Department of Microbiology, NUS

Convenor: Prof. Chan Soh Ha

Topic: New insights into erythrocyte invasion by malaria merozoites
Speaker: Assoc. Prof. Peter R Preiser
Date: Tuesday, 9 September 2008 @ 11.00AM

Affiliation: School of Biological Sciences
Nanyang Technological University, Singapore

Convenor: Dr. Kevin Tan Shyong Wei

Abstract:
Malaria merozoites are able to invade erythrocytes using a range of different invasion pathways. Each invasion pathway is specified by the interaction of parasite ligands with their appropriate receptors on the erythrocyte surface. Only if all the appropriate interactions are formed will invasion occur. While significant insights have been gained from the studies of individual parasite ligand-host receptor interactions our overall understanding of what defines a parasite invasion pathway is still limited.

Recent work using the rodent malaria parasite P. yoelii has shown that variation in the amount of parasite ligands also make a significant contribution to erythrocyte invasion (Iyer et al., 2007).

To obtain a better understanding of the contribution of merozoite proteins to different invasion phenotypes we have combined microarray analysis with quantitative proteomics to investigate changes in the expression pattern of merozoite proteins in P. falciparum merozoites displaying different invasion pathways. This approach has led to a number of new and surprising insights about merozoite invasion.

Topic: Characterising of Helicobacter pylori biofilm as a survival strategy in the extragastric environment
Speaker: Miss Ng Chow Goon (MSc candidate)
Date: Friday, 12 September @ 11:00AM

Affiliation: Department of Microbiology, NUS

Convenor: Assoc. Prof. Ho Bow

Topic: uPAR induces shape changes in integrin CD11bCD18
Speaker: Dr. Tan Suet Mien (DPhil), Assistant Professor
Date: Tuesday, 16 September 2008 @ 11:00AM

Affiliation: School of Biological Sciences
Nanyang Technological University, Singapore

Convenor: Assoc. Prof. Herbert Schwarz

Abstract:
Integrins are type I membrane cell adhesion molecules form by two distinct subunits. In general, the transition of an integrin from a bent conformation to an extended conformation serves as a hallmark of its activation – a prerequisite for ligand-binding.

However, gaining evidence suggest important roles of integrins with bent conformations. A good example comes from the association of integrins with uPAR (urokinase-type plasminogen activator receptor; CD87) in the same cell. The marked difference in the dimensions of these molecules disfavors uPAR interacting with an extended integrin.

In this talk, I will discuss the interaction of uPAR with integrin CD11bCD18 (CR3), which are both important players in leukocyte functions, and suggest a possible mechanism of uPAR-integrin signaling.

Topic: Malaria Drug Discovery at the Novartis Institute for Tropical Diseases (NITD)
Speaker: Dr. Thierry Diagana
Date: Tuesday, 30 September 2008 @ 11:00AM

Affiliation: Novartis Institute for Tropical Diseases Singapore

Convenor: Dr. Kevin Tan Shyong Wei

Abstract:
Today, artemisinin is the last defense against drug resistant malaria and recent reports suggest that decades of continuous use of these potent antimalarials as monotherapies may have fostered artemisinin drug resistance in Plasmodium. Unfortunately there are few ongoing efforts to discover and develop novel and effective antimalarial drugs to fight this
ancient and resilient scourge.

To address this unmet global health need, NITD has led the formation of a research consortium to bring together Novartis' cutting-edge drug discovery with world-class malaria biology expertise. Armed with a grant from the Wellcome Trust, the Medicines for Malaria Venture and the Singapore Economic Development Board, the consortium has the ambitious
goals of identifying (1) new drugs with a potential for a single-dose cure for P. falciparum malaria and, (2) a curative modality for P. vivax malaria.

These two goals were set to address two weaknesses with the current antimalarials, namely the poor patient compliance with most P. falciparum malaria treatments and the inability to rapidly and safely eradicate the parasite liver stages following a P. vivax infection. An overview of our efforts to achieve these goals will be presented.