Systems Immunology

Research Vision: 

To create a future for our children without immune mediated diseases

Research Focus Areas:

The current focus areas for the team are:

Development of cutting-edge tools to decipher the immune system.

Immune responses are governed by multiple layers of molecular regulation. The aim of this research program is to employ a series of cutting-edge tools to better understand the ground rules that control the regulation of the immune response. Multi-omic profiling will be employed to unveil the molecular networks that underpin immune activation. The contribution of different subpopulations of immune cells to the overall immune response will be dissected at single cell resolution. Network driver genes that function as master regulators of immune activation will be unmasked with pooled CRISPR screening technology. These studies will significantly advance our understanding of the functionality of the immune system and identify novel targets for therapeutic intervention.

Using systems biology to understand asthma exacerbations and develop better treatments.

Asthma exacerbations are usually brought on by rhinovirus infections and are one of the most common reasons for a child to miss school or require emergency care. Very few treatment options exist, and drug development programs in this area are currently stalled because the underlying biology is not well understood. We have discovered that children with severe asthma exacerbations can be divided into IRF7^Hi verses IRF7^Lo molecular subphenotypes. The aim of this research program is to better understand the molecular mechanisms that determine IRF7 phenotypes in children, and evaluate the capacity of new treatments to modulate IRF7 response patterns. Airway epithelial cells will be infected with rhinovirus, and the underlying gene networks will be identified through network analysis of molecular profiling data. Pooled CRISPR screening technology will be employed to identify the master regulators of IRF7 gene networks. In parallel, we have developed a unique rat model of asthma exacerbations, in two different strains of rats that mirror the IRF7^Hi verses IRF7^Lo molecular subphenotypes we observed in children. The rat model will be utilised to determine if IRF7 phenotypes can be rewired with immunomodulatory drugs. These studies will characterise the role of IRF7 gene networks in asthma and develop new treatments that are targeted to these networks. 

Understanding heightened susceptibility to acute viral bronchiolitis in infants through personalised transcriptome analysis.

Acute viral bronchiolitis is a frequent cause of hospitalisation amongst young children, and risk is inversely related to age. The aim of this study is to compare and contrast immune response patterns in infants versus older children who are hospitalised for acute viral bronchiolitis. Immune response patterns were profiled by multiplex analysis of plasma cytokines, flow cytometry, and transcriptomic studies in peripheral blood and nasal mucosal samples. Personalised analysis of the transcriptome data will be employed to identify molecular subphenotypes that underpin this disease and the heightened susceptibility observed among infants.

Understanding benign versus pathologic allergy.

Compelling data from human clinical trials and experimental animal models supports a causal role for Th2-associated effector mechanisms in the development of allergic diseases like asthma. However, only a subset of individuals who are sensitized to allergens manifest clinical signs of disease. The aim of this research program is to unlock the molecular mechanisms that determine expression of disease symptoms. House dust mite is the dominant asthma-associated allergen in the Perth region, and it is present in local households at high levels throughout the year, and therefore we reasoned that the presence or absence of asthma symptoms amongst house dust mite sensitised subjects will be reflected by variations in gene network patterns amongst cell populations accessible in sputum (i.e. mucus secretions from the lower airways). Employing this approach, we discovered that house dust mite sensitized atopics are characterized by upregulation of Th2 responses in sputum-derived cells, regardless of the presence or absence of asthma. However, in subjects with asthma, the Th2 networks were interlinked with airway epithelial-associated pathways. Our findings suggest that pathologic allergy is associated with the rewiring and interlinking of Th2 networks and airway epithelial networks.

Rewiring developmental pathways to shape phenotypic traits.

Environmental exposures in early life can have dramatic consequences for organismal development and physiological function in adulthood. We have developed a mouse model of respiratory viral infection, in which infected neonates have impaired lung function as adults, long after the infection has cleared. Conversely, when infection occurs in adulthood, there are no long-term functional impairments. The aim of this study is to identify virus-induced perturbations to pulmonary gene networks that are linked to developmental and physiological changes. We also want to determine if virus-induced perturbations can be reversed with repurposed drugs to restore normal lung development and function.

Harnessing the immune system to develop better treatments for cancer.

Immune checkpoint blockage therapy is a major breakthrough in the treatment of cancer, because it can “cure” the disease in a subset of patients. However, the majority of patients do not respond to this treatment. The aim of this project is to characterize the molecular networks that mediate the response to immune checkpoint blockage therapy, and identify synergistic drug combinations that increase the response rate. We employed a unique mouse model of mesothelioma, which was characterized by a dichotomous response to immune checkpoint blockade therapy. Molecular profiles were generated in whole tumours from responding and nonresponding mice, and network analysis was employed to identify gene network patterns underlying the therapeutic response. Targeted these networks via selective modulation of hub genes or alternatively with drugs identified through computational repurposing markedly enhanced the efficacy of checkpoint blockade therapy.