Wei Kay Joanne Ku
Email Address
bchkwkj@nus.edu.sg
Organizational Units
YONG LOO LIN SCH OF MEDICINE
faculty
BIOCHEMISTRY
dept
6 results
Publication Search Results
Now showing 1 - 6 of 6
Publication Modulation of bacterial virulence and fitness by host glutathione(CURRENT BIOLOGY LTD, 2019-02) Ku, Joanne WK; Gan, Yunn-Hwen; Assoc Prof Yunn Hwen Gan; BIOCHEMISTRYGlutathione is a low molecular weight thiol that is important for maintaining intracellular redox homeostasis. Some bacteria are able to import exogenous glutathione as a nutritional source and to counter oxidative stress. In cytosolic pathogens Burkholderia pseudomallei and Listeria monocytogenes, host glutathione regulates bacterial virulence. In B. pseudomallei, glutathione activates the membrane-bound histidine kinase sensor VirA that leads to activation of the Type VI Secretion System. In L. monocytogenes, host glutathione leads to the binding of bacterial glutathione to the master virulence regulator PrfA as an allosteric activator. Glutathione can also modulate virulence factors to control their activity by S-glutathionylation. Thus, host glutathione acts as a spacio-temporal cue for some pathogens to switch on their virulence programs at the right time and place.Publication Skin models for cutaneous melioidosis reveal Burkholderia infection dynamics at wound's edge with inflammasome activation, keratinocyte extrusion and epidermal detachment(Taylor & Francis, 2021-12-06) Joanne Ku; Supatra Marsh; Mui Hoon Nai; Kim Robinson; Daniel Teo; Franklin Zhong; Katherine Brown; Thiam Chye Lim; Chwee Lim; Yunn-Hwen Gan; BIOMEDICAL ENGINEERING; MECHANOBIOLOGY INSTITUTE; BIOCHEMISTRYPublication The proteobacterial species Burkholderia pseudomallei produces ergothioneine, which enhances virulence in mammalian infection(FEDERATION AMER SOC EXP BIOL, 2018-12-01) Gamage, Akshamal M; Liao, Cangsong; Cheah, Irwin K; Chen, Yahua; Lim, Daniel RX; Ku, Joanne WK; Chee, Rhonda Sin Ling; Gengenbacher, Martin; Seebeck, Florian P; Halliwell, Barry; Gan, Yunn-Hwen; Assoc Prof Yunn Hwen Gan; SURGERY; DUKE-NUS MEDICAL SCHOOL; BIOCHEMISTRYBacteria use various endogenous antioxidants for protection against oxidative stress associated with environmental survival or host infection. Although glutathione (GSH) is the most abundant and widely used antioxidant in Proteobacteria, ergothioneine (EGT) is another microbial antioxidant, mainly produced by fungi and Actinobacteria. The Burkholderia genus is found in diverse environmental niches. We observed that gene homologs required for the synthesis of EGT are widely distributed throughout the genus. By generating gene-deletion mutants and monitoring production with isotope-labeled substrates, we show that pathogenic Burkholderia pseudomallei and environmental B. thailandensis are able to synthesize EGT de novo. Unlike most other bacterial EGT synthesis pathways described, Burkholderia spp. use cysteine rather than g-glutamyl cysteine as the thiol donor. Analysis of recombinant EgtB indicated that it is a proficient sulfoxide synthase, despite divergence in the active site architecture from that of mycobacteria. The absence of GSH, but not EGT, increased bacterial susceptibility to oxidative stresses in vitro. However, deletion of EGT synthesis conferred a reduced fitness to B. pseudomallei, with a delay in organ colonization and time to death during mouse infection. Therefore, despite the lack of an apparent antioxidant role in vitro, EGT is important for optimal bacterial pathogenesis in the mammalian host.Publication New roles for glutathione: Modulators of bacterial virulence and pathogenesis(Elsevier BV, 2021-08-01) Ku, JWK; Gan, YH; Assoc Prof Yunn Hwen Gan; BIOCHEMISTRYLow molecular weight (LMW) thiols contain reducing sulfhydryl groups that are important for maintaining antioxidant defense in the cell. Aside from the traditional roles of LMW thiols as redox regulators in bacteria, glutathione (GSH) has been reported to affect virulence and bacterial pathogenesis. The role of GSH in virulence is diverse, including the activation of virulence gene expression and contributing to optimal biofilm formation. GSH can also be converted to hydrogen sulfide (H2S) which is important for the pathogenesis of certain bacteria. Besides GSH, some bacteria produce other LMW thiols such as mycothiol and bacillithiol that affect bacterial virulence. We discuss these newer reported functions of LMW thiols modulating bacterial pathogenesis either directly or indirectly and via modulation of the host immune system.Publication Bacterial-induced cell fusion is a danger signal triggering cGAS-STING pathway via micronuclei formation(NATL ACAD SCIENCES, 2020-07-07) Ku, Joanne Wei Kay; Chen, Yahua; Lim, Bryan Jian Wei; Gasser, Stephan; Crasta, Karen Carmelina; Gan, Yunn-Hwen; Assoc Prof Yunn Hwen Gan; PHYSIOLOGY; BIOCHEMISTRYBurkholderia pseudomallei is the causative agent of melioidosis, an infectious disease in the tropics and subtropics with high morbidity and mortality. The facultative intracellular bacterium induces host cell fusion through its type VI secretion system 5 (T6SS5) as an important part of its pathogenesis in mammalian hosts. This allows it to spread intercellularly without encountering extracellular host defenses. We report that bacterial T6SS5- dependent cell fusion triggers type I IFN gene expression in the host and leads to activation of the cGAMP synthase-stimulator of IFN genes (cGAS-STING) pathway, independent of bacterial ligands. Aberrant and abortive mitotic events result in the formation of micronuclei colocalizing with cGAS, which is activated by double-stranded DNA. Surprisingly, cGAS-STING activation leads to type I IFN transcription but not its production. Instead, the activation of cGAS and STING results in autophagic cell death. We also observed type I IFN gene expression, micronuclei formation, and death of chemically induced cell fusions. Therefore, we propose that the cGAS-STING pathway senses unnatural cell fusion through micronuclei formation as a danger signal, and consequently limits aberrant cell division and potential cellular transformation through autophagic death induction.Publication Copper-Nanoparticle-Coated Fabrics for Rapid and Sustained Antibacterial Activity Applications(AMER CHEMICAL SOC, 2022-09-23) Goncalves, Rui A; Ku, Joanne WK; Zhang, Hao; Salim, Teddy; Oo, Guodong; Zinn, Alfred A; Boothroyd, Chris; Tang, Richard MY; Gan, Chee Lip; Gan, Yunn-Hwen; Lam, Yeng Ming; Assoc Prof Yunn Hwen Gan; BIOCHEMISTRYThe scientific community has recognized that copper can kill bacteria; however, the effect of the particle size, concentration, and oxidation state on antibacterial activity remains unclear for copper and its nanoparticles (NPs), in particular. In this study, copper NP coatings with extremely fast and sustained antibacterial activity are reported. It is found that coating with cuprous oxide (Cu2O) NPs (150 nm) and coating with metallic copper NPs (50 nm) on commonly used fabrics for cleaning and masks can kill bacteria within 45 s. Our bacterial study was conducted using Staphylococcus aureus as a Gram-positive bacterium and Klebsiella pneumoniae and Pseudomonas aeruginosa as Gram-negative bacteria. Scanning electron micrographs suggest bacterial damage, and bacterial DNA harvested after interaction with copper-coated fabrics indicates DNA fragmentation. On top of this, significantly higher levels of 8-hydroxy-2′-deoxyguanosine are also detected in DNA after interaction with coated fabrics, signifying that both copper and Cu2O NPs rapidly induce oxidative stress. Furthermore, cumulative inoculations with K. pneumoniae for 144 h show excellent sustained bacterial killing in the presence of Cu2O NPs. Using a combination of detailed physical and chemical analysis of the NPs and a study of how bacteria interact with the coated substrate, it is possible to establish the parameters that resulted in speedy and robust antibacterial properties in Cu2O-coated fabrics. This study offers a rational strategy on how to slow down or even halt the transmission of infectious pathogens.