Innate Immune Responses to Infection

Director’s Research Group

The subversion of host cell processes by microbial pathogens is an intrinsic part of the host-pathogen interaction. Many bacterial pathogens have the ability to transport virulence proteins, called effector proteins, into host cells via specialised protein secretion systems. We work on a range of virulence effectors from pathogenic E. coli, Shigella and Salmonella that interfere with host innate immune signalling pathways and block inflammation and cell death. The aim of this work is to investigate the manipulation of host cell signalling by effector protein families to understand their influence on host cell function, inflammatory signalling and the innate immune response. In this way effector proteins can be used as tools to understand the innate responses important for control of the pathogen.

Many bacterial pathogens have acquired the capacity to replicate inside human cells by avoiding cell intrinsic innate immune pathways. Pathogens such as Legionella and Burkholderia are environmental organisms that cause the life threatening opportunistic infections known as Legionnaire’s Disease and Melioidosis respectively. A feature of both pathogens is the capacity of the bacteria to replicate within human cells through the manipulation of host cell biology. This depends on the ability of the pathogens to inject multiple virulence effector proteins into the host cell during infection. Our goal is to identify and characterise effectors that interact with cell intrinsic innate immune pathways. Ultimately this will allow us to understand the molecular mechanisms by which intracellular bacteria cause disease.

 

Cancer Genetics and Functional Genomics

The work of the Cancer Genetics and Functional genomics research group directed by A/Professor Ron Firestein is focused on using functional and integrated genomic approaches to understanding the basic underpinnings of cancer.  Major themes in the lab are listed below:

    1. Integrative genomic approaches to identify new oncogenic drivers in cancer. Our lab has undertaken sophisticated integrative genomic analyses of colorectal, lung and breast cancers. Using innovative functional genomic screens (CRISPR, shRNA/siRNA) we have uncovered a number of novel oncogenic drivers and dissected their mechanistic input into cancer signalling pathways.  Importantly, two of these targets have led to novel small molecule programs that are currently in drug development (CDK8 and LDHB).
    2. Identification and characterisation of Wnt pathway regulators in colon cancer. While a post-doc at Dana Farber Cancer Institute, we identified CDK8 as a colon cancer oncogene that regulates the Wnt/b-catenin pathway (Firestein R. et al Nature 2008). Since then, my group has developed mouse models and in vivo systems to characterise the function of CDK8 and its paralog, CDK19, in normal homeostasis, development and cancer progression.  We have also collaborated with other groups to develop targeted therapies to upstream regulators of the Wnt pathway.
    3. Elucidation of novel cancer therapeutic biomarkers in preclinical models and clinical samples. Our recent work has identified an important role for enhancer mediated transcripts, i.e. eRNAs, as biomarkers for distinct cancer states and predicting therapeutic response. We are now working to systematically characterise eRNA function and expression in tumours using state of the art genomic editing technologies.

Epidemiology and Clinical Trials

Our group provides research expertise and capability to Monash Health and the State of Victoria via the Consultative Council for Obstetric and Paediatric Mortality and Morbidity. Our group is also an integral part of the Monash University, Department of Obstetrics and Gynaecology.

Our unique co-location within the hospital and Hudson Institute affords us the opportunity to undertake our own research and to support both scientists and clinicians in the translation of research findings from the laboratory bench to the hospital bedside. Through collaborations with other Hudson Institute researchers, we are also able to combine biological samples with clinical and epidemiological data.

We utilise epidemiological design principles, biostatistics and clinical trial expertise to improve the health of pregnant women and their babies/children. Current research areas include

  • Stillbirth
  • Maternal and perinatal outcomes among migrant and refugee women
  • Reducing perinatal mortality and morbidity in Victoria
  • Assessing the impacts of interventions and procedures related to pregnancy and labour care.
  • Randomised Controlled Trials to assess the efficacy of interventions in pregnancy and birth.
  • Implementation and health policy research
  • Homebirth

We also offer study design, human ethics advice and statistical support to Monash Health staff and the wider Ritchie Centre.

 

Perinatal Transition

This group undertakes research focusing on how events prior to, during, and after birth can adversely alter respiratory, cardiovascular and neurological outcomes, with specific focus on the transition from a fetus to a newborn. The unique strength of the group is the close collaboration between scientists and clinicians, incorporating respiratory and cardiovascular physiologists, neurologists, obstetricians and neonatologists, which focus the research on major clinical issues with rapid translation into improving the health and wellbeing of infants. We aim to understand how events around the time of birth can lead to lung, heart and brain inflammation, and injury leading to life-long consequences such as bronchopulmonary dysplasia pulmonary and systemic hypertension and cerebral palsy. With a focus on infants born preterm, with an increased risk of morbidity and mortality, we are investigating the impacts of events in three key periods around the time of birth, which increases susceptibility to organ injury:

  1. The preterm fetus is commonly exposed to a number of insults while in the womb, including inflammation/infection, antenatal corticosteroids and growth restriction. All of these may have adverse or beneficial effect on the developing lung, heart and brain.
  2. The period around the time of birth is a time of significant instability within the cardiopulmonary-cerebral circulation, and as such, is a critical period for the development of acute inflammation and injury. Our research focuses on improving the haemodynamic transition by investigating the influence of delayed cord clamping, physiological cord clamping and he influence of obstetric management on the circulatory transition at birth.
  3. Preterm infants often require respiratory support in the form of mechanical ventilation at birth. While life saving, our research has shown that it increases the risk of respiratory, cardiovascular and cerebral inflammation and injury. Our research focuses on improving respiratory support for preterm infants, which reduces lung and brain inflammation and injury, while improving the circulatory transition at birth. We utilise state of the art imaging techniques, including MRI, for early detection of injury, and test new therapies including Stem Cells and Erythropoietin, to protect the preterm brain.

Research Projects

  • Effect of intrauterine inflammation on preterm lung, heart and brain injury
  • Effect of intrauterine growth restriction on preterm lung, heart and brain injury
  • Physiological based cord clamping for improving the cardiopulmonary-cerebral circulation at birth.
  • Erythropoietin for protection of preterm lung and brain injury
  • Human amnion epithelial cells for protection of preterm lung and brain injury
  • Early detection of ventilation induced brain injury
  • Influence of resuscitation strategy on preterm lung, heart and brain injury
  • Long-term cardiovascular consequences of preterm birth.

Neurodevelopment and Neuroprotection

The Neurodevelopment and Neuroprotection research group is embedded within the Fetal and Neonatal Health Neurodevelopment and Brain Injury Theme of The Ritchie Centre, and is closely affiliated with the Cell Therapy and Regenerative Medicine Theme led by Professor Graham Jenkin. The group provides a focus for experimental and clinical studies directed towards understanding, and inhibiting, the mechanisms that contribute to perinatal brain injury and functional deficits associated with cerebral palsy. We strive towards the implementation of treatments to decrease neonatal brain injury and that can be effectively administered either during pregnancy or in the neonatal period. Such treatments include antioxidants, anti-inflammatory agents, and stem cells obtained from the cord blood and placenta.

Associate Professor Suzie Miller’s group comprises more than 20 members with experts in fetal physiology, neuroscience, stem cells, cardiovascular physiology, clinical obstetrics, neonatology and paediatrics. This group provides a highly-regarded training platform for biomedical and clinical students.

Research Projects

  • Stem cells to reduce perinatal brain injury – fact or fiction?
  • Protecting the intrauterine growth restricted (IUGR) fetal brain with natural neurosteroids.
  • Treating neonatal seizures with ganaxolone
  • Can we modify neurovascular development in the IUGR brain with endothelial progenitor stem cells derived from cord blood?
  • Umbilical cord blood stem cells to improve brain structure and function after severe birth asphyxia, when to administer and how many?
  • Improving newborn wellbeing in a rural Indian community with a simple transdermal patch.

Maternal and Perinatal Medicine

Professor Euan Wallace established the Maternal-Fetal Medicine Group (now Maternal and Perinatal Medicine) in 1996 after joining Monash University’s Department of Obstetrics and Gynaecology. The group’s original research focus on pregnancy and the fetus has expanded to include life after birth, leading to the inclusion of perinatal in its name. Improvement of maternal, fetal, and neonatal health remains the focus of the group’s work. As leaders in their field, the team continues to combine fundamental and clinical research to shape best clinical practice and improve patient care. Their impressive record for delivery of translational outcomes includes several world firsts.

Despite embracing fetal and neonatal research, the team’s central focus on the pregnant woman continues to align them with The Ritchie Centre’s Women’s Health Theme. With several other research groups evolving from the Maternal and Perinatal Medicine research group, they remain tightly embedded in the Centre’s broader research portfolios. These established independent groups have maintained active collaborations within the Centre.

Embryology and Placental Biology sub-research group

This Ritchie Centre research group studies development of the placenta and its role in the aetiology of major obstetric complications including, intrauterine growth restriction and stillbirth. A major focus of the group is understanding how creatine in the maternal diet, and its production by the placenta, influences pregnancy outcomes.

By studying the embryo and using micro-manipulation this group investigate the intricate relationship between the fetus and placenta. Differential development of the placenta in males and females is investigated, to understand the vulnerability of males to complications of pregnancy and birth.

How early life events, such as intrauterine growth restriction and birth asphyxia, impact on development of the fetus, affecting adult health and fertility is a research strength of this team.

A recent discovery of the only known menstruating rodent, the spiny mouse, provides an unprecedented opportunity to improve research into menstrual disorders, such as endometriosis and PMS. This team have sequenced and assembled the transcriptome of the spiny mouse and are characterising the genetics of this species.

Collaborators
Dr Kirsten Palmer – Monash Health
Professor Peter Temple-Smith – Dept Obstetrics and Gynaecology, Monash University
Professor Tony Papenfuss – WEHI
Professor Beverley Vollenhoven – Monash Health
A/Professor Ashley Siefert – University of Kentucky
Professor Rod Snow – Deakin University
Professor Karen Moritz – University of Queensland
Professor David Walker -RMIT

Lung Development

Many events during fetal and early postnatal life can affect lung development with life-long consequences. Our aim is to determine the mechanisms that regulate normal lung development and that lead to perturbed lung development.

The lung undergoes an incredible transition at birth because the placenta exchanges gases during fetal life, but the moment the umbilical cord is cut, the lung must take on the role of gas exchange, a role that it has never performed before. If the lung does not exchange gases adequately, the infant may die or suffer significant damage to the lungs, brain and other organs.

Babies that are born prematurely, or that have failed to reach their growth potential (fetal growth restriction) are born before the lungs are adequately developed. As a result, they often require assisted ventilation, which is necessary for their survival but it can injure the lungs and cause them to develop abnormally. This abnormal lung development is called Bronchopulmonary Dysplasia (BPD).

Research Projects

  • Identifying the mechanisms that regulate normal lung development, so that we can manipulate those mechanisms to accelerate lung development
  • Identifying the mechanisms by which lung injury leads to BPD, so that we can develop new therapeutic strategies to interfere with those mechanisms, preventing BPD
  • Identifying biomarkers to determine which babies sustain lung injury at birth and are at most risk of developing BPD; these are the babies that will require the treatments identified in (2)
  • Identifying more gentle strategies for respiratory support that reduce lung injury at birth, which should reduce the incidence of BPD.

Interventional Immunology in Early Life Diseases

The Nold Laboratory follows the innovation value chain from basic science to product development; with our main focus in harnessing our expertise in immunology to explore the molecular mechanisms of several poorly understood and currently largely untreatable diseases that affect our tiniest patients, namely babies born prematurely. These diseases include bronchopulmonary dysplasia (BPD) that severely compromises lung function and entails pulmonary arterial hypertension (PAH), which in turn often causes right heart failure; intracranial haemorrhage (ICH) whose survivors commonly require extensive special education; and necrotising enterocolitis (NEC), a disease of the intestine that carries up to 70 per cent mortality (see review #8). Our aim is rapid translation of our findings into clinical medicine, as best exemplified by a planned clinical trial that is based on one of our discoveries (see paper #1 & 2 below) and that may establish the first safe and effective treatment for BPD.

Our laboratory’s second major focus lies on the new interleukin (IL-)1 family cytokines IL-37 and IL 38. Our revelation of the powerful anti-inflammatory properties of IL-37 (see paper #3 below), its signalling mechanisms, cell surface receptor (see paper #4 below) and discovery that homodimerization limits the anti-inflammatory effect of IL-37 (see paper # 5 below) has led to a surge of international interest in these previously largely obscure cytokines and revealed IL-37’s translational potential. Examples of our current work include exploration of the therapeutic potential of IL-37 in NEC (see paper #6 below), and the characterisation of IL-38 in health and disease, including in systemic lupus erythematosus (SLE) (see paper #7 below), an incurable autoimmune disease that affects women during their childbearing age and their unborn children.

Research Projects

  • Exploring a new frontier: The immune and coagulation systems of the premature infant and their relevance for the risk of the major diseases of prematurity.
    Direct clinical relevance: high. Hands-on learning opportunities: Multi-color flow cytometry, protein arrays, cell culture of primary human blood cells.
  • Molecular tracking of the cytokine IL-37 in anti-inflammatory signalling.
    Direct clinical relevance: medium/low. Hands-on learning opportunities: Confocal microscopy, molecular engineering (cloning), cell culture of primary human blood cells and cell lines.
  • Novel anti-inflammatory approaches for currently untreatable diseases of the preterm baby: IL-1Ra and IL-37 in animal models of bronchopulmonary dysplasia and necrotising enterocolitis.
    Direct clinical relevance: high. Hands-on learning opportunities: Various aspects of work with mice, workup of tissues for various downstream applications, flow cytometry, histology, immunohistochemistry, protein detection by ELISA, synchrotron X-ray imaging.
  • Molecular characterisation of regulation and mechanism of action of the anti-inflammatory cytokine interleukin 37.
    Direct clinical relevance: medium/low. Hands-on learning opportunities: Culture of primary human blood cells and cell lines, protein detection by ELISA, RNA detection by real-time PCR, flow cytometry, immunohistochemistry.
  • The first in vivo exploration of IL-38.
    Direct clinical relevance: medium/low. Hands-on learning opportunities: Various aspects of work with mice, workup of tissues for various downstream applications, flow cytometry, histology, immunohistochemistry, protein detection by ELISA, RNA detection by real-time PCR.

Infant and Child Health

The work of the Ritchie Centre in this theme is focussed on early childhood development, particularly in relation to the at risk baby such as the preterm or growth restricted infant and children with sleep disorders.

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