Molecular Immunity
To understand the early cellular and molecular origins of childhood health and complex disease.
Our group applies genetic, environmental cellular and molecular analyses to understand how genes and environment interact in early life to modify the risk of developing a range of non-communicable diseases in children and adults. We aim to understand disease mechanisms and identify biomarkers for improved diagnosis and risk stratification of childhood complex disorders.
Our goal is to understand how exposures interact with underlying genetic variation to ‘program’ later health and complex disease risk via cellular and molecular mediators, including epigenetics. We do this by integrating environmental, genetic, other ‘omic and phenotypic data to:
- Understand aetiology and,
- Identify biomarkers with clinical utility for predicting outcome, effective targeting and monitoring of interventions.
Our focus is on immune and inflammatory conditions, and we are applying a state-of-the-art analysis pipeline to a series of unique, mostly longitudinal, cohorts with extensive exposure and outcome data, plus deep biospecimens.
Our projects
Early molecular and cellular determinants of health in humans
Epigenetic variation following conception via Assisted Reproductive Technologies (ART)
The periconceptional period (around the time of fertilization) is a time of dynamic epigenetic reprogramming. By studying a unique cohort of ART conceived individuals (CHART cohort) we identified patterns of DNA methylation levels at birth associated with ART conception (since widely replicated). We are now testing epigenetic signatures across multiple cell types and time points to determine if specific cell lineages are more sensitive to perturbation by specific ART exposures and also to test stability of this ART-induced variation over time.
Peri/Postnatal Epigenetic Twins Study (PETS)
In collaboration with Prof Jeffrey Craig (Deakin University), we established the first longitudinal twin pregnancy cohort internationally with a deep biospecimen collection. The Peri/Postnatal Epigenetic Twin Study (PETS) has yielded some groundbreaking discoveries in early life programming, including the first definitive demonstration that both genetic and environmental factors contribute to the neonatal epigenome in humans. More recently, we have established a similar cohort in China, The Chongqing Longitudinal Twin Study (LoTiS).
Early life inflammation, and cardiovascular and metabolic outcomes
Despite compelling evidence that cardiometabolic conditions of adulthood begin early in life, little is known about the mechanistic (cellular and molecular) processes by which environmental risk becomes ‘biologically embedded’. The Barwon Infant Study (BIS) of 1,074 pregnancies was designed to fill this gap. We previously published the first evidence linking in utero and early postnatal factors with CV and metabolic markers in infancy and have confirmed the link between specific epigenetic variants in genes of the hypoxia and leptin pathways to infant adiposity and maternal BMI.
Intergenerational transmission of poor metabolic control
As part of national and international consortia, we are investigating the molecular processes (including epigenetic variation) involved in transferring metabolic risk across generations. This follows our earlier work in the Danish National Birth Cohort that showed exposure to Gestational Diabetes (GDM) impacts offspring metabolic health in childhood (age 9-16), in association with epigenetic variation and reduced telomere length in blood.
Molecular origins of childhood immune-related health
Childhood Food Allergy
Rates of food allergy are increasing globally, with Melbourne often referred to as the food allergy capital of the world. Childhood peanut, tree-nut and multi-food allergies often persist into adulthood and are associated with increased risk of severe reaction and poor quality of life. Using samples collected from the world’s largest cohorts of food allergy (HealthNuts, SchoolNuts, Vitality), we aim to extensively characterise immunity across childhood and food allergy phenotype, with the potential to identify markers for intervention.
Juvenille Idiopathic Arthritis
Juvenile idiopathic arthritis (JIA) is an autoimmune rheumatic disease affecting around 6000 Australian children per year. It is one of the leading causes of childhood disability, typically associated with joint pain and inflammation in the hands, knees, ankles, elbows and/or wrists. The CLARITY (Childhood Arthritis Risk factor Identification Study) biobank is one of the largest, most biospecimen and information-dense collections in the world, amenable to understanding the cellular and molecular changes associated with JIA. By combining longitudinal data and samples from this cohort with state-of-the-art transcriptome and epigenetic profiling, we aim to identify early life predictors of outcome and potential targets for the development of novel treatments in children living with JIA.
Molecular basis of trained immunity in children
Innate immune memory - monocyte studies
Monocytes, an innate immune cell type, can internalize inflammatory signals to form a non-specific memory, termed Trained Immunity. We apply epigenetic techniques to understand how trained immunity is established in monocytes in response to a range of exogenous stimuli, such as vaccines, hormones, and lifestyle factors.
Trained immunity and endothelial cell function
Trained Immunity has been reported in a range of non-immune cells, including epithelial stem cells and endothelial cells. In this project, we study how fetal and adult endothelial cells establish epigenetic memory, and how certain conditions, such as obesity, gestational diabetes, preeclampsia and other pregnancy complications affect endothelial cell responses to inflammatory stimuli.
Systems immunology of childhood respiratory disease
Early life inflammation is a hallmark of common childhood lung diseases, including cystic fibrosis, preschool wheeze and asthma, and acute lower respiratory tract infections. These childhood lung diseases cause significant morbidity in children, often involve pathological remodelling of the airway epithelium, and can inhibit pulmonary development, leading to lung impairment in adult life. In this project, we apply multi-omic approaches to define the immune response in the upper and lower airway, as well as the peripheral blood, in children with chronic pulmonary diseases with the goal of informing strategies to improve clinical care and respiratory health throughout life.
Hormonal influence on immune molecular and cellular profiles
Gender affirming hormone therapy
Sex-specific DNA methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise. How much of this sex-specific pattern is specified by genetics and how much by hormones? In this study, we profile blood cells from transgender individuals that undergo Gender Affirming Hormone Therapy to understand how hormones affect epigenetic marks and immune function.
Immune profile and function across pregnancy
Alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, and menopause. This project studies how pregnancy-associated hormones drive epigenetic change, and how this may affect how maternal immune cells respond to vaccines and infections.
Funding
- National Health and Medical Research Council, Australia
- Medical Research Future Fund, Australia
- National Institutes of Health (NIH), USA
- Chan Zuckerburg Initiative
- Thrasher Research Fund
- Isabel and Josh Gilbertson Charitable Trust
- CASS foundation
- Murdoch Children's Research Institute Lifecourse
- Murdoch Children's Research Institute Infection and Immunity Theme
Collaborations
- Chongqing Medical University, China
- Cincinnati Children’s Hospital, USA
- Medical University of Graz, Austria
- Radbound UMC, Netherlands
- Stanford University, USA
- University of British Columbia, Canada
- University of California, Santa Cruz, USA
- University of North Carolina, USA
- University of Granada
- King’s College London
- The University of Queensland
- The University of South Australia
- Telethon Kids Institute
- Menzies Institute, Charles Darwin University, Darwin
- Peter Doherty Institute
- Florey Institute of Neurosciences
Featured publications
- Altered immune cell profiles and impaired CD4 T cell activation in single and multi-food allergic adolescents. 2021
- Importance of accounting for sibling age when examining the association between family size and early childhood cognition, language and emotional behaviour: a birth cohort study. 2021
- Maternal and Cord Blood 25-Hydroxyvitamin D3 Are Associated with Increased Cord Blood and Naive and Activated Regulatory T Cells: The Barwon Infant Study. 2021
- Maternal prenatal gut microbiota composition predicts child behaviour. 2021
- The maternal gut microbiome during pregnancy and offspring allergy and asthma. 2021