Resistance from pathogens to antibiotics or antiparasitic drugs is a growing concern and affects millions patients worldwide every year. There is an urgent need to find novel treatment to improve the care of people as bacteria or parasites are becoming resistant to all existing antibiotics and antiparasitic agents. Novel & innovative strategies are desperately needed for this problem. In the general population, there are individual differences between humans that give some people an advantage in their ability to resist severe disease caused by infections. Our group aims to understand why these people are resistant to pathogens using mouse as a model. We use cutting-edge technologies (next-generation sequencing, genome editing) to study the biology of the interaction between the host and the pathogens.
Our group use CRISPR/Cas9 genome editing technology as a tool to study diseases with a specific focus on parasitic and bacterial infections. Our group also develops the technology and aims to better understand the editing and repair mechanisms. We are particularly interested on the mechanisms of Cas9 binding and repair after double strand break. As part of the Australian Phenomics Network our group provides to the scientific community CRISPR/Cas9 edited mice, advices on the technology and expertise on the development of the technology for specific applications.
Genetic identification of the host response to malaria
Malaria infection is the third lethal disease worldwide and a treatment is desperately needed. Malarial parasites have led to selected mutations showing an increase in the gene pool of human population living in endemic regions and these mutations render the human population more resistant to malaria. We are interested in understanding the mechanisms of resistance from the malaria parasite. We have performed a large-scale N-Ethyl-N-Nitrosourea (ENU) mutagenesis and CRISPR/Cas9 experiment in mice and in red blood cells precursors by mutating genes that confer resistance to the malaria parasite. We have identified over 40 genes conferring resistance to the malaria parasite. We are also interested in a better understanding of the interactions between the parasite and the host. We have developed a system to interrogate simultaneously the changes in the parasite and the host during the course of the infection and to survey the rapid adaptation of the parasite to the host. From the bench to clinics, we have developed a series of assays and a pre-clinical pipeline for any potential antimalarial drugs.
Genetics of the host response to multiresistant drug bacteria or “superbugs”
Hospital acquired infections are caused by bacteria, viruses and fungi. These infections are strongly increasing in prevalence to 1 in 25 patients in Australia, Europe and USA. Over 700,000 patients in the US a year contract a hospital-acquired infection. Most of these hospital-acquired infections are caused by multi resistant bacteria to antibiotics “superbugs”. There are growing concerns due to the acquisition of multi resistance to antibiotics from the bacteria and the lack of novel antibiotics in the market. We are interested in understanding how the host can combat these multi-resistant bacteria and become resistant to these multidrug resistant bacteria and how the bacteria escape to the host immune system.
Genome editing as a novel way to study the interactions between the host and the pathogens
Novel precision genetic technologies such as CRISPR/Cas9 genome editing technology offer novel avenues to a better understanding of the interactions between the host and the pathogens. Using CRISPR/Cas9 we are able to precisely and efficiently target any modification of the mouse and the pathogens genomes. We are able to precisely modify the mouse genome by creating knockout or a specific single nucleotide change to enable the study of the function of the gene of interest. We also modify the genome of the pathogens to study this fascinating interplay between the host and the pathogens.
Development of CRISPR/Cas9 genome editing technology
We aim to better understand how the CRISPR/Cas9 system works and how to improve it. Using genetic and molecular biology techniques, we are trying to understand the effect of the cellular environment on Cas9 binding and cutting efficiency. We also develop the novel methods and novel approaches to improve the efficiency of the CRISPR/Cas9 system in mouse and cell lines. We finally develop genome editing technologies alternative to CRISPR/Cas9.
PloS Biology paper published 23 April 2015: