Molecular Immunity

Our vision is to understand the early cellular and molecular origins of childhood health and disease, with a focus on immune and inflammatory conditions.

To do this, we are integrating environmental, genetic, other ‘omics and phenotypic data to:

• Understand aetiology of complex childhood inflammatory diseases’
• Identify biomarkers with clinical utility for improved prediction, diagnosis, effective treatment targeting and monitoring of interventions.

Our collective work has generated highly influential papers that contributed to an explosion of interest in understanding the molecular processes that mediate the effects of the early life programming of human non-communicable disease.

We played a key role in the establishment of several internationally unique cohorts with detailed environmental and phenotype data, plus biospecimens amenable to state-of-the-art molecular and cellular profiling.

Together, these have attracted more than $50M in research funding. We have more than 300 publications and 20,000 citations of our work in the last 10 years, with over 100 invitations to present at both local and international meetings (including several plenary and keynote presentations).

We have authored many book chapters and an Epigenetics training course (Early Nutrition eAcademy) and have developed advanced experimental pipelines, including high dimensional flow cytometry, DNA methylation, chromatin immunoprecipitation, and single-cell sequencing.

Our research aims to understand the early cellular and molecular origins of childhood immune-related health and disease.

Our aim is to understand disease mechanisms and identify clinically relevant biomarkers for improved diagnosis and risk stratification.

We focus on understanding how early life exposures interact with underlying genetic variation to ‘program’ later health, via cellular and molecular mediators, including epigenetics.

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 biospecimens amenable to a range of biological measures

Our projects

Childhood food allergy

Rates of food allergy are increasing globally, with Melbourne often referred to as the food allergy capital of the world. Childhood food allergies often persist into adulthood and are associated with an increased risk of severe reactions and poor quality of life.

There are currently no robust, unambiguous approaches to accurately distinguish children according to their risk of food allergy. This makes it difficult to create effective and safe interventions for the children who need them most. Our research is geared towards filling this gap. We are in the process of establishing a pipeline to translation for other childhood immune-related conditions.

Using samples collected from the world’s largest cohorts of food allergy (HealthNuts, SchoolNuts, Vitality), we are using integrated ‘omics analysis to develop improved clinical approaches for:

1. Prediction: identifying those most at risk
2. Prevention: appropriately targeting early interventions
3. Diagnosis: improved accuracy/reliability and safety of diagnostic approaches
4. Monitoring: accurate and safe assessment of food allergy status without potentially harmful food challenges.

These approaches can then be further developed in Generation Victoria (GenV)

• Centre for Food and Allergy Research

Molecular basis of trained immunity in children

Monocytes, an innate immune cell type, can internalise inflammatory signals to form a non-specific memory, termed ‘trained immunity’.

We apply epigenetic techniques to understand how trained immunity is established in monocytes and endothelial cells in response to a range of exogenous stimuli, such as vaccines, hormones, and lifestyle factors. We also study how certain conditions, such as obesity, gestational diabetes, preeclampsia and other pregnancy complications affect trained immune responses to inflammatory stimuli.

As part of the International Trained Immunity (INTRIM) Consortium, we contribute to a range of human proof-of-principle clinical studies and therapeutic development of compounds that induce trained immunity.

Systems immunology of childhood respiratory disease

Early life inflammation is a hallmark of childhood lung diseases, including cystic fibrosis, preschool wheeze, asthma, as well as 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.

We have recently established the earlyAIR study which aims to develop a reference atlas of cells in the healthy paediatric airway in order to understand the changes caused by childhood lung disease. earlyAIR is a paediatric component of the global Human Cell Atlas consortium that aims to create comprehensive reference maps of all human cells as a basis for understanding human health and diagnosing, monitoring, and treating disease.

Juvenile Idiopathic Arthritis (JIA)

JIA is an autoimmune rheumatic disease that affects around 6,000 Australian children per year. JIA 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.

• Australian and New Zealand Childhood Arthritis Risk factor Identification Study (ANZ CLARITY)
  
  

Hormonal influence on immune molecular and cellular profiles

Sex-specific epigenetic patterns and sexual dimorphism in immune disease are widespread. Some sex-specific DNA methylation signatures are present from birth, while some arise during the life course. How much of this sex-specific pattern is specified by genetics and how much by hormones?

In this study, we profile blood cells from adult transgender individuals who undergo Gender Affirming Hormone Therapy to understand how hormones affect epigenetic marks and immune function.

Other projects

• Molecular profiling of Childhood Inflammatory Bowel Disease
• Epigenetic variation following conception via Assisted Reproductive Technologies (ART)
• Early life inflammation, and cardiovascular and metabolic outcomes
• Intergenerational transmission of poor metabolic health
• Barwon Infant Study (BIS)
• Generation Victoria (GenV)Generation Victoria (GenV)

Funding

• National Health and Medical Research Council, Australia
• European Commission Framework (FP7)
• Medical Research Future Fund, Australia
• National Institutes of Health (NIH), USA
• Chan Zuckerberg 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

1. Bannister et al. … Novakovic, Science Advances 2022
   This paper showed that BCG vaccine-induced epigenetic memory lasts more than one year in circulating monocytes. A role for interferon gamma signalling for the establishment of BCG-induced trained immunity was identified.
   
   
2. Neeland et al…. Saffery, Nature Comms 2021.
   This study was aimed at investigating why children seemed to be refractory to COVID-19 infection. We applied our state-of-the-art immune cell profiling to a series of blood cell samples collected from the few families in the local population with clear evidence of familial SARS-CoV-2 infection. We found evidence of a heightened innate immune response in SARS-CoV-2 infected children relative to adults, the first time this had been reported internationally. We speculated that this most likely played a role in their mild symptoms relative to adults.
   
   
3. Neeland et al., Nature Comms 2020
   This work was the result of an international collaboration between Molecular Immunity and HealthNuts cohort (PI Koplin) based at Murdoch Children’s Research Institute, with Professor Kari Nadeau at Stanford University. Using state-of-the-art high-dimensional mass cytometry, we defined the circulating immune cell signatures associated tolerance and clinical peanut allergy at one year of age. This was the first demonstration that children with peanut allergies have increased activated B cells, overproduction of TNFα and increased peanut-specific memory CD4 T cells. It also reaffirmed our previous findings that food allergy is characterised by the disruption of multiple immune cell types. The utility and power of high-dimensional flow cytometry revealed here is now a core platform in Molecular Immunity at Murdoch Children’s.
   
   
4. Novakovic et al. Saffery, Nature Comms 2019.
   This study was part of a series exploring the potential for epigenetic variation in offspring conception via Assisted Reproduction. We studied a unique cohort of individuals in Victoria, with longitudinal blood samples collected around birth and in adulthood. We found conclusive evidence for ART-associated variation in DNA methylation in the blood of newborns, which became less pronounced by adulthood. The ART epigenetic signature we identified at birth has since been independently replicated time times. It was included in a meta-analysis of ART and DNA methylation and was the focus of a piece in ‘The Conversation’ that has been viewed >24,800 times. 
   
   
5. Fleming, T.P., … Saffery, et al., The Lancet, 2018.
   This highly cited paper brought together key international leaders in the field of Developmental Origins of Health and Development (DOHaD) to examine the evidence for transgenerational inheritance of non-genetic effects, with a focus on pre and peri conception. It was the culmination of several international meetings and associated discussions. We presented animal findings that strongly supported such effects, including for conception via assisted reproduction, and discussed the likely role of epigenetic and other processes in mediating these effects.

 

 

 

 

 

 

 

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M. R. Neeland et al., Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children. Nat Commun 12, 1084 (2021).

M. R. Neeland et al., Mass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life. Nat Commun 11, 1091 (2020).

B. Novakovic et al., Assisted reproductive technologies are associated with limited epigenetic variation at birth that largely resolves by adulthood. Nat Commun 10, 3922 (2019).

T. P. Fleming et al., Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 1842-1852 (2018).

L. Hjort et al., Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children. JCI Insight 3,  (2018).

D. Martino et al., Epigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy. Nat Commun 9, 3308 (2018).

D. Martino et al., Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants. J Allergy Clin Immunol 135, 1319-1328.e1311-1312 (2015).

D. Martino et al., Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 14, R42 (2013).

S. Imran et al., Epigenomic variability is associated with age-specific naive CD4 T cell response to activation in infants and adolescents. Immunol Cell Biol,  (2023).

T. Mansell et al., Early life infection and proinflammatory, atherogenic metabolomic and lipidomic profiles in infancy: a population-based cohort study. Elife 11,  (2022).

S. Bannister et al., Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes. Sci Adv 8, eabn4002 (2022).

R. Shepherd et al., Gender-affirming hormone therapy induces specific DNA methylation changes in blood. Clin Epigenetics14, 24 (2022).

S. Imran et al., Epigenetic programming underpins B-cell dysfunction in peanut and multi-food allergy. Clin Transl Immunology 10, e1324 (2021).

E. Jentho et al., Trained innate immunity, long-lasting epigenetic modulation, and skewed myelopoiesis by heme. Proc Natl Acad Sci U S A 118,  (2021).

 S. Moorlag et al., beta-Glucan Induces Protective Trained Immunity against Mycobacterium tuberculosis Infection: A Key Role for IL-1. Cell Rep 31, 107634 (2020).

M. R. Neeland et al., B-cell phenotype and function in infants with egg allergy. Allergy 74, 1022-1025 (2019).

L. Hjort et al., Diabetes in pregnancy and epigenetic mechanisms-how the first 9 months from conception might affect the child's epigenome and later risk of disease. Lancet Diabetes Endocrinol 7, 796-806 (2019).

M. R. Neeland et al., Early life innate immune signatures of persistent food allergy. J Allergy Clin Immunol 142, 857-864.e853 (2018).

S. Bekkering et al., Metabolic Induction of Trained Immunity through the Mevalonate Pathway. Cell 172, 135-146 e139 (2018).

S. Cvitic et al., Human fetoplacental arterial and venous endothelial cells are differentially programmed by gestational diabetes mellitus, resulting in cell-specific barrier function changes. Diabetologia 61, 2398-2411 (2018).

R. J. Arts et al., Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity. Cell Metab 24, 807-819 (2016).

B. Novakovic et al., beta-Glucan Reverses the Epigenetic State of LPS-Induced Immunological Tolerance. Cell 167, 1354-1368 e1314 (2016).

B. Novakovic et al., Postnatal stability and tissue- and time-specific effects of methylation change in response to maternal smoking throughout pregnancy. Epigenetics : official journal of the DNA Methylation Society 9,  (2013).

L. Gordon et al., Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res 22, 1395-1406 (2012).