Congratulations to the four Microbiology and Immunology researchers who have made successful bids for 2017 Marsden funding. Dr Bruce Russell ($960,000), Associate Professor Peter Fineran ($945,000), Dr Rob Fagerlund (Fast-Start Grant, $300,000) and Professor Greg Cook (Associate Investigator, $920,000).
Unraveling the molecular basis for vivax malaria's unhealthy attraction to human reticulocytes
$960,000
Plasmodium vivax (Pv) is the most widely distributed and difficult to cure form of human malaria. Pv is certainly the most important cause of malaria in the Asia Pacific region. Difficulties in diagnosis, treating the dormant liver stage and the recent spread of drug resistant Pv have provided impetus for vaccine development against vivax malaria. The ability of Pv to cause disease is dependent on invasion of immature red blood cells (reticulocytes). How Pv identifies and invades reticulocytes remains unknown. We aim to identify the specific blood cell receptors and corresponding parasite proteins used to invade human reticulocytes. To do this, a proteomic shortlist of reticulocyte receptors will be targeted by neutralizing antibodies/knockdowns in Pv invasion assays. The identification of the reticulocyte specific receptors and corresponding ligands will aid in the development of vaccines against vivax malaria.
Uncovering regulatory networks controlling CRISPR-Cas adaptive immunity
$945,000
Bacteria are constantly exposed to invasive elements, such as viruses and plasmids, and these interactions are key factors in global nutrient cycles, the emergence of pathogens and spread of antibiotic resistance. To protect themselves from these invaders, bacteria have CRISPR-Cas adaptive immune systems, which provide sequence-specific heritable memory of past infections. Immunity relies on the acquisition of ‘memory’ sequences from the invader, which produce short guide RNAs that assist Cas proteins in recognition and destruction of complementary invader genomes. Despite the obvious immune benefits, carriage of these systems can be costly for bacteria. For example, errors in ‘memory’ generation can often result in autoimmunity against the host bacterial chromosome. We propose that extensive regulatory networks exist to maximise CRISPR-Cas immunity when bacteria would be most vulnerable to infection, while also limiting activity when least required – to mitigate autoimmunity. Regulation of CRISPR-Cas activity is poorly understood, and in general there is a paucity of high-throughput approaches to comprehensively identify mutations influencing bacterial gene expression. We will develop and utilise a state-of-the-art single-cell method of broad applicability that combines fluorescent reporters, transposon mutagenesis, fluorescence activated cell sorting and high-throughput sequencing to uncover the pathways involved in the regulation of CRISPR-Cas activity.
CRISPR-Cas immunity in cyanobacteria
Fast-Start Grant, $300,000
Cyanobacteria represent an ancient and diverse phylum with key roles in fresh and marine water ecosystems and global carbon cycles, and are emerging as a vehicle in solar-powered biotechnology. Cyanobacteria are under constant threat of phage infection and one mechanism used to counter these is the CRISPR-Cas defence system. CRISPR-Cas provide prokaryotes heritable and adaptive immunity by initially capturing a genetic memory of the invading element and then using that memory to produce short RNA molecules to specifically target and eliminate the invader. This ability of CRISPR-Cas systems to seek and destroy invading elements has led to a surge in novel genome editing tools. A poorly understood type of system from cyanobacteria appears to be a chimera of two other distinct systems and it is not clear how it functions, although it is very likely to utilise unique features in viral nucleic acid degradation. I will use a combination of genetic, structural and biochemical approaches to investigate the molecular mechanisms used by this system to orchestrate viral defence. In addition, there is potential for discovery of novel enzymes of biotechnical utility and their application in controlling phage infections during industrial cyanobacterial bioprocessing.
TB or not TB - examining the origin and evolution of tuberculosis in the pre-European Pacific
$920,000
The origin and antiquity of tuberculosis (TB) in the Pacific is controversial. TB-causing Mycobacterium tuberculosis complex (MTBC) bacteria are thought to have arrived with European sailors or settlers but TB-like lesions in pre-European skeletal remains from across the Pacific contradict this popular view. We will combine palaeogenetic and macroscopic analyses of pre-European human and animal remains to determine how TB arrived and evolved in the Pacific. This study has the potential to fundamentally alter our understanding of how TB spread around the world and to provide new insights into how MTBC bacteria adapt to human hosts and alter their potential for causing epidemics.
