Gee W. Lau
Assistant Professor, Pathobiology
Professional Interests: My research interests are concentrated at the interface of host-microbial interactions. There are two major ongoing projects in my laboratory:
1. The virulence of Pseudomonas aeruginosa redox active phenazine toxins in airway diseases. P. aeruginosa is a major pathogen that infects cystic fibrosis (CF), and immuno-compromised individuals. Among the reasons that it has been such a formidable adversary include its abilities to form impenetrable biofilms, develop resistance to antibiotics, and release a large arsenal of virulence factors. P. aeruginosa secrets 0.1 mM concentrations of redox active exotoxin pyocyanin (PCN) in the airways of CF patients that it determines the color of their expectorated sputum. PCN kills human cells and microorganisms. Most recently, we have demonstrated that PCN is required for acute and chronic pneumonia infections, and inhibits the expression and localization of CFTR by inactivating vacuolar ATPase. Current research efforts focus on whether:
(I) Inactivation of V-ATPase interferes with the ability of various small molecule therapeutic compounds aims at improving the trafficking of ?F508 CFTR, prevents phagosome-lysosome fusions, and contributes to the defects in antigen capture, processing and presentation in macrophages and dendritic cells.
(II) Chronic exposure to PCN polarizes the lung cytokines and immune cells towards a Th2 type response, resulting in airway fibrosis and goblet cell hyperplasia. Also, we are comparing whether the mouse lungs of various CFTR -/- models develop accelerated and exacerbated pulmonary destructions upon chronic exposure to PCN.
(III) Neutralizing the toxicity of phenazines by antioxidants or enzymatic degradation could improve the normal lung functions of CF and other P. aeruginosa infected patients.
2. Antimicrobial mechanisms of pulmonary surfactant
proteins. Pulmonary surfactants are complexes of phospholipids
and proteins that line the alveolar space. Surfactants are composed
of 90% phospholipids and 10% proteins, which include s urfactant p roteins
SP-A, B, C, D. SP-A and SP-D are hydrophilic mannose-binding protein-like
collectins with roles in pulmonary host defense. SP-A and SP-D opsonize
microorganisms and enhance their clearance. Recent studies also have
shown that SP-A and SP-D directly inhibit the proliferation of bacteria
and fungi in a macrophage- and aggregation-independent manner, by increasing
the permeability of the microbial cell membrane. Despite their antimicrobial
properties, the mechanisms by which SP-A and SP-D increase membrane
permeability and opsonization are poorly understood. By screening a
signature-tagged mutagenesis (STM) library, we have identified five
mutants with increased sensitivity to SP-A. Detailed characterizations
of these mutants indicate that they are preferentially susceptible
to membrane permeabilization by SP-A. We are currently deciphering
the mechanisms underlying the resistance and sensitivity to SP-A by
determining which of these pathways contribute to LPS structure, cell
wall and cytoplasmic membrane integrity and modification.
Selected Publications:
Zhang S, McCormack FX, Levesque RC, O'Toole GA, Lau GW. (2007). The flagellar protein, FlgE, is a molecular target for clearance of Pseudomonas aeruginosa by SP-A. In revision for Mol Microbiol (MMI-2006-05122).
Caldwell CC, Chen Y, Borchers MT, Goetzmann H, Zhang S, Mavrodi D, Thomashow L and Lau GW. (2007). Induction of pulmonary fibrosis by a Pseudomonas aeruginosa exotoxin: implication on cystic fibrosis airway pathogenesis. In revision for J Immunol (#06-2779 ).
Borchers MT, Harris NL, Wesselkamper SC, Chen Y, Zhang S, Young L, and Lau GW. (2006). The NKG2D activating receptor mediates pulmonary clearance of Pseudomonas aeruginosa. Infect Immun. 74:2578-86.
Kong FS, Young LE, Ran H, Meyers M, Chen Y, Joseph P, Hassett DJ and Lau GW. (2006). Pseudomonas aeruginosa pyocyanin inactivates lung epithelial vaculoar ATPase-dependent CFTR expression and localization. Cell Microbiol. 8:1121-113.
Zhang S, Chen Y, Potvin E, Sanschagrin F, Levesque RC, McCormack FX and Lau GW. (2005). Comparative signature-tagged mutagenesis identifies Pseudomonas aeruginosa factors conferring resistance to pulmonary collectin SP-A. PLoS Pathogens 1(3): e31.
Lau GW, Hassett DJ and Britigan BE. (2005). Modulation of lung epithelial functions by Pseudomonas aeruginosa . Trends Microbiol. 13: 389-397.
Lau GW, Britigan BE and Hassett DJ. (2005). Pseudomonas aeruginosa OxyR is required for full virulence in rodent and insect models of infection and for resistance to human neutrophils. Infect Immun. 73: 2550-2553.
Lau GW, H Ran H, Hassett DJ and Kong FS. (2004). The role of pyocyanin in Pseudomonas aeruginosa infection. Trends Mol Med. 10: 599-606.
Lau GW, H Ran, FS Kong, DJ Hassett and D Mavrodi. (2004). Pseudomonas aeruginosa pyocyanin is critical for lung infection in mice. Infect Immun. 72:4275-4278.
Potvin E, Lehoux D, Kukavica-Ibrujl I, Richard K, Sanschagrin F, Lau GW and Levesque RC. (2003). In vivo functional genomics of Pseudomonas aeruginosa for high throughput screening of novel virulence factors and antibacterial targets. Environmental Microbiol. 5: 1294-1308.
Ran H, Hassett DJ and Lau GW. (2003). Human Targets of Pseudomonas aeruginosa pyocyanin. Proc Natl Acad Sci USA. 100: 14315-14320 (Track II).
