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Molecular Immunity

The Molecular Immunity 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.

Vision: To understand the early cellular and molecular origins of childhood health and complex disease

Aim: Our goal is 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 (i) understand aetiology and (ii) 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.

Group Leaders: 
Team Leaders: 
Thomas Aitken
Dr Toby Mansell
Prof Terry Dwyer
Prof Anne-Louise Ponsonby
Prof Jeffrey Craig
Ms Line Hjort
Role: 
PhD Student
Dr Peter Rzehak
Role: 
Honorary Research Fellow (off campus)
Dr Nick Wong
Role: 
Honorary Research Fellow (off campus)
Dr Louise Ludlow
Role: 
Honorary Research Officer
Ms Alex Sexton-Oates
Role: 
PhD Student

1. Early life molecular programming 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 timepoints 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.
     
  • Early molecular and cellular determinants of health in humans
    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 the field of 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 the mechanistic (cellular and molecular) processes by which environmental risk becomes ‘biologically embedded’. The Barwon Infant Study (BIS) of 1074 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 the transfer of 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.  

2. 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 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.

3. 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.

4. 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 ultimate goal of informing strategies to improve clinical care and respiratory health throughout life.

5. 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 over time. 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, Aust
  • Medical Research Future Fund, Aust
  • National Institutes of Health (NIH), USA
  • Chan Zuckerburg Initiative
  • Thrasher Research Fund
  • Isabel and Josh Gilbertson Charitable Trust
  • CASS foundation
  • MCRI Lifecourse
  • MCRI 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
  • University of Queensland
  • University of South Australia
  • Telethon Kids Institute
  • Menzies Institute, Charles Darwin University, Darwin
  • Peter Doherty Institute
  • Florey Institute of Neurosciences
Publications: 

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