PhD Student, Monash University
My research focuses on how the immune system recognises superbugs. I am looking at a cell type called dendritic cells, which act as sentinels of the immune system- waiting for invading pathogens and directing an appropriate immune response. Dendritic cells are essential for the induction of the immune responses that allow us to recover from infections and also the immune responses to a vaccine that prevent infection.
Some pathogens, are able to avoid detection by dendritic cells, and thus avoid subsequent immune responses. I am working on Staphyloccus aureus (golden staph), investigating how the bacteria are able to persist in chronic blood stream infections without being detected by dendritic cells. In particular, I am focusing on strains of this bacteria that are resistant to antibiotics. Antibiotic resistance is now a serious issue, with resistance currently occurring faster than scientists can discover new antibiotics. Current modelling commissioned by the UK Department of Health suggests that the annual mortality rate of antibiotics resistant infections will supersede cancer by 2050.
I am working with clinical samples of bacteria, taken from real patients who have succumb to antibiotic resistant infections. My research provides a better understanding as to how these infections avoid immune detection, with the ultimate goal of being able to find ways to reinvigorate the immune response to eliminate these infections, thus circumventing the need for antibiotics.
Abstract: The spread of multidrug-resistant Staphylococcus aureus (MRSA) strains in the clinical environment has begun to pose serious limits to treatment options. Yet virtually nothing is known about how resistance traits are acquired in vivo. Here, we apply the power of whole-genome sequencing to identify steps in the evolution of multidrug resistance in isogenic S. aureus isolates recovered periodically from the bloodstream of a patient undergoing chemotherapy with vancomycin and other antibiotics. After extensive therapy, the bacterium developed resistance, and treatment failed. Sequencing the first vancomycin susceptible isolate and the last vancomycin nonsusceptible isolate identified genome wide only 35 point mutations in 31 loci. These mutations appeared in a sequential order in isolates that were recovered at intermittent times during chemotherapy in parallel with increasing levels of resistance. The vancomycin nonsusceptible isolates also showed a 100-fold decrease in susceptibility to daptomycin, although this antibiotic was not used in the therapy. One of the mutated loci associated with decreasing vancomycin susceptibility (the vraR operon) was found to also carry mutations in six additional vancomycin nonsusceptible S. aureus isolates belonging to different genetic backgrounds and recovered from different geographic sites. As costs drop, whole-genome sequencing will become a useful tool in elucidating complex pathways of in vivo evolution in bacterial pathogens.
Pub.: 23 May '07, Pinned: 26 Aug '17
Abstract: Daptomycin remains one of our last-line anti-staphylococcal agents. This study aims to characterize the genetic evolution to daptomycin resistance in S. aureus.Whole genome sequencing was performed on a unique collection of isogenic, clinical (21 strains) and laboratory (12 strains) derived strains that had been exposed to daptomycin and developed daptomycin-nonsusceptibility. Electron microscopy (EM) and lipid membrane studies were performed on selected isolates.On average, six coding region mutations were observed across the genome in the clinical daptomycin exposed strains, whereas only two mutations on average were seen in the laboratory exposed pairs. All daptomycin-nonsusceptible strains had a mutation in a phospholipid biosynthesis gene. This included mutations in the previously described mprF gene, but also in other phospholipid biosynthesis genes, including cardiolipin synthase (cls2) and CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase (pgsA). EM and lipid membrane composition analyses on two clinical pairs showed that the daptomycin-nonsusceptible strains had a thicker cell wall and an increase in membrane lysyl-phosphatidylglycerol.Point mutations in genes coding for membrane phospholipids are associated with the development of reduced susceptibility to daptomycin in S. aureus. Mutations in cls2 and pgsA appear to be new genetic mechanisms affecting daptomycin susceptibility in S. aureus.
Pub.: 13 Jan '12, Pinned: 26 Aug '17
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