CENTRE FOR INNATE IMMUNITY AND INFECTIOUS DISEASES 2022 Student Research Projects 2023 Student Research Projects
Contents
Welcome to Hudson Institute
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Centre for Innate Immunity and Infectious Diseases
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Cancer and Immune Signalling
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Cell Death and Inflammatory Signalling
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Gastrointestinal Infection and Inflammation
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Host-Pathogen Interactions
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Innate Immune Responses to Infection
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Microbiota and Systems Biology
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Nucleic Acids and Innate Immunity
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Pattern Recognition Receptors and Inflammation
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Regulation of Interferon and Innate Signalling 16 Synergy Program
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Respiratory and Lung Disease
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Structural Biology of Inflammation and Cancer Research 22 Viral Immunity and Immunopathology
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Contact our supervisors
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The Translational Research Facility is connected via a link bridge to Monash Health and provides a crucial link between our scientific discoveries and medical treatments. The facility houses six worldleading technology platforms and an eight-bed, 21-chair Clinical Trials Centre that support the transition of discoveries from initial Phase I testing through to Phase IV primary health trials. 2 Centre for Innate Immunity and Infectious Diseases | Student Research Projects 2023
Welcome to Hudson Institute Hudson Institute specialises in discoveries in five areas of medical need • Inflammation • Reproductive health and pregnancy • Infant and child health
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Join regular networking and learning and development programs, including the off-site Institute student retreat
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Learn a range of dynamic and transferable skills for careers in the biomedical and clinical research sectors including commercialisation
All work and no play … Our students can join in a range of student networking and social events organised by Hudson Institute Student Society (HISS), including being part of the management committee.
Our precinct
• Cancer • Hormones and health Our 443 scientists and students focus on laboratory discovery science and translational research – taking discoveries to patients and industry for real-world impact.
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STAFF
STUDENTS
RESEARCH GROUPS
RESEARCH PUBLICATIONS
Hudson Institute is a leading Australian medical research institute recognised internationally for discovery science and translational research into inflammation, reproductive health and pregnancy, infant and child health, cancer, hormones and health. Our Institute is home to 443 world-class scientists, who push the boundaries of scientific knowledge to answer complex questions about human disease, including prevention and treatment. We are a founding member of the Monash Health Translation Precinct (MHTP) with partners Monash Health and Monash University. Our close ties with clinicians and industry enable us to translate our discoveries into new preventative approaches, therapies and devices for patients. Our location at Monash Medical Centre means our research is informed by patient need and our discoveries are transitioned into practical treatments.
Students at a glance 2021
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POSTGRADUATE AND HONOURS STUDENTS COMPLETED
STUDENTS 125 PhD 1 MASTERS 50 HONOURS
STUDENTS WITH MEDICAL TRAINING
Working alongside clinicians in Melbourne hospitals for more than 50 years, our scientists pioneered IVF and stem cell discoveries and are now leading developments in cell therapies, paediatric cancer and the human microbiome. Our worldwide scientific and medical collaborations provide a foundation for transformative healthcare programs across the globe.
We educate and train more than 170 students through our academic affiliation with Monash University. Our postgraduate training is predominantly through the School of Clinical Sciences at Monash Health, part of the Faculty of Medicine, Nursing and Health Sciences at Monash University.
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Are exposed to university, institute, and hospital research
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Attend national and international conferences
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Publish their research in high impact journals
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Are mentored by leading supervisors and their teams
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Win prestigious prizes and awards
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Centre for Innate Immunity and Infectious Diseases Location: Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash Medical Centre, Clayton t: +61 3 85722738 e: amber.crowley@hudson.org.au w: https://hudson.org.au/research-centre/centrefor-innate-immunity-infectious-diseases/ Centre Head: Prof Brendan Jenkins
in practical and theoretical aspects and career development. Staff and students working in CiiiD have collective multidisciplinary expertise in molecular biology, signal transduction, protein interactions, cell biology, immunology, cancer, bacteriology, infectious disease, functional genomics and bioinformatics, as well as clinical research and transgenic techniques for generating and characterising gene knockout and transgenic mouse preclinical models of human disease. CiiiD students are first authors on scientific papers in prestigious journals Students were first authors on 37 of Hudson Institute's 257 research publications in 2021. Some examples from our Centre are: ●
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At the Centre for Innate Immunity and Infectious Diseases (CiiiD) we discover and model how the innate immune response regulates disease. We translate our findings into practical outcomes that impact on our health. The immune response is important in every disease you’ll study as a scientist or doctor. A successful early, innate immune response can resolve infectious diseases and eliminate cancer. A poorly regulated immune response causes chronic inflammatory diseases, with multi-organ impact. We:
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Are world-leaders in research on the innate, or first, immune response Perform high quality discovery research using the latest technologies Translate our research into preventions, diagnostics and treatments Publish in the world's top impact journals
Chonwerawong M, et al., Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue. Gastroenterology. 2020 Jul;159(1):169-182.e8. Mohamed Saad et al., ADAM17 selectively activates the IL-6 trans-signalling/ERK MAPK axis in KRAS-addicted lung cancer. EMBO Mol Med. 2019;11:e9976. Jesse Balic, et al., STAT3 serine phosphorylation is required for TLR4 metabolic reprogramming and IL-1β expression, Nature Comm. 2020; 11(1); 3816
CiiiD students win prestigious prizes and awards ● ● ● ●
Winner Faculty of Medicine, Nursing and Health Sciences ‘3 Minute Thesis’ Competition – Zoe Marks Milstein Travel Award for the International Cytokine and Interferon Society – Mohamed Saad Travel grant from the Science Mobilisation Program of the Embassy of France in Australia – Kimberley D’Costa Winner, PhD Student Prize, Victorian Infection and Immunity Network Young Investigator Symposium – Charlotte Nejad
What we study Infectious diseases (influenza, HIV, Helicobacter pylori, diarrhoeal diseases, Legionnaire’s disease, Shigella, Respiratory syncytial virus and others) Cancer (stomach, lung, pancreas, ovary, breast and others) Inflammatory diseases (inflammatory bowel disease, sepsis, lupus, gastritis, diabetes, COPD)
CiiiD houses the largest group of inflammation researchers in Australia, bringing in approx. $7.2M in grant funding per annum and publishing approx. 300 peer-reviewed publications in the past five years, including works in prestigious journals such as Nat Rev Cancer, Nat Rev Immunol, Nat Rev Biotechnol, Lancet Respir Med, Gut, Gastroenterol, Nat Commun, EMBO Mol Med and Clin Cancer Res. CiiiD values its students. We offer world-class training in biomedical research and carefully help students find appropriate projects and supervisors. Students receive one-on-one training and mentoring
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Research Groups Heads Cancer and Immune Signalling Professor Brendan Jenkins brendan.jenkins@hudson.org.au
Pattern Recognition Receptors and Inflammation Associate Professor Ashley Mansell Ashley.mansell@hudson.org.au
Cell Death and Inflammatory Signalling Dr Kate Lawlor kate.lawlor@hudson.org.au
Nucleic Acids and Innate Immunity Associate Professor Michael Gantier michael.gantier@hudson.org.au
Gastrointestinal Infection and Inflammation Professor Richard Ferrero richard.ferrero@hudson.org.au
Regulation of Interferon and Innate Signalling Professor Paul Hertzog paul.hertzog@hudson.org.au
Host-Pathogen Interactions Dr Jaclyn Pearson
Respiratory and Lung Disease Professor Phil Bardin
jaclyn.pearson@hudson.org.au
philip.bardin@monash.edu
Innate Immune Responses to Infection Professor Elizabeth Hartland
Structural Biology of Inflammation and Cancer Research Dr Wilson Wong
elizabeth.hartland@hudson.org.au
Microbiota and Systems Biology Dr Sam Forster sam.forster@hudson.org.au
Wilson.wong@hudson.org.au
Viral Immunity and Immunopathology Associate Professor Michelle Tate michelle.tate@hudson.org.au
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Cancer and Immune Signalling
biological and genetic approaches (including CRISPR/Cas9).
Identification of immune system regulators as therapeutic targets in lung cancer
Precision medicine for innate immune pattern recognition receptors in pancreatic cancer
Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSci (Hons)
Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSci (Hons)
Project leader: Prof Brendan Jenkins
Project leader: Prof Brendan Jenkins
e: brendan.jenkins@hudson.org.au
e: brendan.jenkins@hudson.org.au
Project description: The cytokine Interleukin-6 (IL-6) has been implicated as a causative factor in lung cancer, the most lethal cancer worldwide, albeit by unknown mechanisms. Since IL-6 is also important for immune system homeostasis, the development of anti-IL-6 therapies requires an intimate knowledge of pathological versus physiological IL-6 signalling pathways. To address this, we are studying the role of the ADAM family of proteases as key upstream oncogenic regulators of pathological IL-6 signalling in the lung. This project aims for the first time to fully elucidate the mechanistic basis by which ADAM family proteases can influence lung carcinogenesis, and in doing so also identify how they potentially impact on innate immune responses triggered by pattern recognition receptors. This project employs a combination of in vivo lung cancer mouse models (genetically engineered, xenograft - including patientderived), CRISPR gene editing and clinical biopsies to foster translation, as well as a vast range of molecular and cellular biological techniques.
Project description: Pattern recognition receptors (PRRs) are key molecules of the innate immune system that recognise microbial- and/or host-derived products to trigger the inflammatory response. Recently, however, we and others have identified that PRRs, such as toll-like receptors (TLRs) can be involved in non-immune responses, such as driving tumour cell survival and proliferation. In this regard, this project aims to understand the molecular basis by which specific PRRs promote pancreatic cancer, which is one of the most lethal and aggressive cancers in the world that is strongly linked with a dysregulated immune response (albeit ill defined). This research is intimately linked with the use of preclinical genetically engineered and xenograft (including patient-derived) mouse models, as well as translational studies using our large collection of biobanked pancreatic cancer patient samples. Such research will ultimately assist in identifying genes that could be used as biomarkers for screening/early detection of pancreatic cancer, and also targets for the design of therapeutic treatment strategies in the context of precision medicine/targeted therapy.
Keywords: cancer, lung cancer, ADAM proteases, innate immunity, pattern recognition receptors, cytokines, signal transduction
Keywords: cancer, pancreatic cancer, innate immunity, patient samples, mouse models, translational studies, biomarkers
Keywords: cancer, gastric carcinogenesis, pattern recognition receptors, cytokines, signal transduction, innate immunity
Identification of novel immune regulators in stomach (gastric) cancer Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSci (Hons) Project leader: Prof Brendan Jenkins e: brendan.jenkins@hudson.org.au Project description: Stomach (gastric) cancer is among the most common cancers worldwide, and is strongly linked with a deregulated immune response, leading to chronic inflammation. However, the identity of regulators of the immune system, in particular those of innate immunity, with oncogenic potential in the stomach remains largely unknown. Using preclinical genetically engineered and xenograft mouse models for gastric cancer, our aim is to identify and understand how novel immune regulators (e.g. pattern recognition receptors, inflammasomes, cytokine signal transducers such as STAT3) in the stomach trigger chronic inflammatory and oncogenic responses that lead to gastric cancer. This project encompasses a wide range of molecular and cell 6 Centre for Innate Immunity and Infectious Diseases | Student Research Projects 2023
Cell Death and Inflammatory Signalling
Mitochondrial apoptosis and inflammasome activation Suitability: Honours, PhD/Doctorate Project leader: Dr Kate Lawlor e: kate.lawlor@hudson.org.au
Defining regulators of cell death and inflammasome activation Suitability: PhD/Doctorate, Honours Project leader: Dr Kate Lawlor e: kate.lawlor@hudson.org.au Project description: Pattern recognition receptors, including Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are key components of the innate immune response. They sense microbial, host derived and environmental danger molecules, and induce inflammatory signalling responses, via inflammasomes and other molecular complexes. We recently defined how deficiency in the cell death inhibitory protein XIAP sensitises innate immune cells to TLR-induced NLRP3 inflammasome activation (Lawlor KE et al. Nature Comms 2015, Lawlor KE* et al. Cell Reports 2017). The aim of this project is to further define molecules, like XIAP, that regulate this alternative inflammasome pathway. This project offers the opportunity to be trained in a variety of techniques, including cell culture, Western blotting/immunoprecipitation, proteomics, overexpression/CRISPR Cas9 gene editing, flow cytometry, ELISA and qPCR. Keywords: Cell death, Inflammasomes, Innate immunity, infection, type I IFN, signal transduction
Identifying mitochondrial factors that activate inflammatory signalling Suitability: PhD/Doctorate, Honours Project leader: Dr Kate Lawlor e: kate.lawlor@hudson.org.au Project description: Mitochondrial (“intrinsic” BCL-2 family regulated) apoptosis has long been thought to be immunologically silent. However, using small molecule inhibitors of pro-survival BCL-2 family members, we have recently discovered that mitochondrial apoptosis can induce a cascade of events that culminate in activation of the NOD-like receptor 3 (NLRP3) inflammasome and proinflammatory cytokine, IL-1beta (Cell Reports 2018). In this project we will further characterise this pathway and test whether its activation alters cancer progression in vivo. This project will use our novel gene knockout macrophages and specific targeted drugs, plus a range of cell biology, biochemical and molecular approaches (e.g. inflammasome/cell death assays, ELISA, Western blotting, CRISPR Cas9 gene editing screens, proteomics). Keywords: Cell death, Cell signalling pathways, Inflammasomes, Innate immunity, Cancer
Project description: Macrophages are innate immune cells that detect environmental, pathogen or host cellular danger molecules, and initiate appropriate immune responses. We have recently discovered that targeting pro-survival proteins BCL-XL and MCL-1 in macrophages induces apoptosis to clear microbial infection (Speir M et al. Nature Microbiology 2016) and also triggers inflammation via activation of the NOD-like receptor 3 (NLRP3) inflammasome and Interleukin-1beta (Cell Reports 2018). This project aims to define novel regulators of this pathway and investigate how these proteins alter pathogen clearance. This project will use our novel gene knockout macrophages and specific targeted drugs, as well as a range of cell biology and biochemical/molecular approaches (e.g. inflammasome/cell death assays, ELISA, Western blotting, Q-PDR, over-expression systems, CRISPR Cas9 gene editing, infectious preclinical models). Keywords: Cell death, Cell signalling pathways, Inflammasomes, Innate immunity, Infectious Diseases
Role of pore forming proteins in Type 2 Diabetes Suitability: PhD/Doctorate Project leaders: Dr Kate Lawlor, Dr Hazel Tye e: kate.lawlor@hudson.org.au Project description: Dietary danger molecules, such as the saturated fatty acid palmitate, trigger the activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β), via NLRP3 inflammasome activation. Based on our past work (Lawlor KE Nature Commun 2015 6:282) we recently discovered that extrinsic apoptotic caspase-8 activity in myeloid cells may drive this pathogenic NLRP3 inflammasome activation in a model of Type 2 Diabetes. Gasdermins (GSDMs) are a family of membrane pore-forming proteins that have recently been defined as proteolytic caspase substrates that induce a lytic form of cell death called pyroptosis. Specifically, inflammasome-associated caspase-1 and apoptotic caspase-8 have been shown to cleave GSDMD (Kayagaki N Nature 2015 526:666; Orning P Science 2018 362:1064), and apoptotic effector caspase-3 cleaves GSDME (Wang Y Nature 2017 547:99) to allow the release of inflammatory damage associated molecular patterns (DAMPS). The aim of this project is to define, using our GSDMD-, GSDME- and GSDMD/E-deficient mice, whether GSDM-dependent pyroptotic cell death contributes to NLRP3 inflammasome activation and/or DAMP release to worsen obesity-induced Type 2 Diabetes. This project offers the opportunity to be trained in a variety of techniques, including cell culture, Western blotting, inflammasome/cell death assays, ELISA, qPCR, tissue analysis-histology, flow cytometry, serum/liver/adipose metabolic assays, Type 2 diabetes preclinical models. Keywords: Type 2 Diabetes, Inflammation, IL-1, inflammasomes, immunometabolism, Gasdermins 7
Centre for Innate Immunity and Infectious Diseases | Student Research Projects 2023
Gastrointestinal Infection and Inflammation Defining the immunomodulatory and oncogenic properties of bacterial extracellular vesicles Suitability: Honours Project leaders: Prof Richard Ferrero, Dr Le Ying e: richard.ferrero@hudson.org.au, le.ying@hudson.org.au Project description: The release of extracellular vesicles (EVs) is a property that has been conserved by both multi- and unicellular organisms during evolution. One of the major functions of these EVs is to facilitate intercellular communication and transport of molecules. The release of EVs by prokaryotes was first described over 50 years ago, yet the biological significance of these structures is only beginning to be appreciated. We have shown that bacterial EVs are potent modulators of host immune responses. The overall aim of the project is to investigate the immunomodulatory and oncogenic properties of bacterial-derived EVs. For this, we will use cell culture and mouse models to elucidate EV interactions with host cells and to characterise the responses induced by these EVs. This project will involve a variety of techniques, including cell culture, mouse models, proteomics, molecular biology, fluorescence imaging, flow cytometry, cytokine ELISA and qPCR.
These questions will be addressed in both in vitro and in vivo models, including conditional knockout mice. The project will involve various techniques, such as primary cell culture, mouse infection, immunohistochemistry, flow cytometry, cytokine ELISA and qPCR. Keywords: Innate immunity, infection, signal transduction, gastric disease, cancer, MALT lymphoma
The role of the innate immune system in preventing stomach cancer during chronic Helicobacter pylori infection Suitability: Honours Project leaders: Prof Richard Ferrero, Dr Le Ying e: richard.ferrero@hudson.org.au, le.ying@hudson.org.au Project description: During cell division, bacteria remodel their cell walls, resulting in the release of low molecular weight fragments of peptidoglycan, known as muropeptides. The muropeptides from Gram-negative bacteria are recognised by host cells via the actions of the innate immune molecule, NOD1, resulting in the induction of a pro-inflammatory signalling cascade. Preliminary data suggest that Helicobacter pylori exploits the NOD1 signalling pathway to maintain tissue homeostasis during chronic infection. This project will test the hypothesis that H. pylori can alter its muropeptide composition to actively engage the NOD1 pathway thereby preventing pre-cancerous changes in the stomach and thus favouring its survival in vivo. This project will involve a variety of techniques, including primary cell culture, mouse infection, histology, cytokine ELISA and qPCR. Keywords: innate immunity, infection, signal transduction, gastric disease, cancer
Keywords: Innate immunity, infection, extracellular vesicles, exosomes
Defining the role of a novel NLR protein in B cell lymphomagenesis associated with chronic Helicobacter infection Suitability: Honours Project leaders: Prof Richard Ferrero, Dr Le Ying e: richard.ferrero@hudson.org.au, le.ying@hudson.org.au Project description: Our laboratory has for the first time identified a new NOD-like receptor (NLR) protein in the regulation of inflammation in response to chronic Helicobacter pylori infection. Specifically, we have shown that conditional knockout mice lacking this NLR exhibit an accelerated formation of gastric B cell mucosa-associated lymphoid tissue (MALT), consistent with the early stages of MALT lymphoma, in response to chronic Helicobacter infection. The overall aims of the project are to investigate how this novel NLR prevents B cell lymphomagenesis induced by chronic infection and whether this protein may play much broader functions in the host immune system.
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Host-Pathogen Interactions Host cell death signalling and susceptibility to Salmonella infection
Keywords: Innate immunity, bacterial pathogenesis, hostpathogen interaction, cell signalling pathways
Understanding the biochemical mechanisms of Salmonella virulence proteins Suitability: Honours, BMedSci (Hons), Short projects, PhD/Doctorate
Suitability: Honours, BMedSci (Hons), PhD
Project leader: Dr Jaclyn Pearson, Prof Elizabeth Hartland
Project leader: Dr Jaclyn Pearson
e: jaclyn.pearson@hudson.org.au, elizabeth.hartland@hudson.org.au
e: jaclyn.pearson@hudson.org.au Project description: Enteric bacterial pathogens such as Salmonella spp. and enteropathogenic E. coli deliver “effector” proteins directly into host cells via specialised secretion systems which exert specific enzymatic activity on host proteins to subvert host responses and prolong infection. Our recent work characterised an effector protein from pathogenic E. coli as a cysteine protease that cleaves and inactivates all mammalian RIP homotypic interaction motif (RHIM) proteins including RIPK1, RIPK3, TRIF and DAI. RHIM proteins are key immune signalling factors that mediate inflammation, apoptosis and necroptosis. Dysregulated immune responses and cell death form the basis of much human disease pathogenesis. This study aims to understand the role of RHIM proteins in controlling Salmonella and other enteric infections. Research methods will include: cell culture, mouse infection model, molecular biology, protein purification, bacteriology, confocal microscopy, western blot, mass spectrometry. Keywords: Bacterial pathogenesis, necroptosis, cell death signalling, innate immunity.
Regulation of TNF signalling in Salmonella infection
Project description: Pathogenic serovars of Salmonella are the causative agents of a spectrum of disease states, including typhoid fever, self-limiting gastroenteritis, and invasive bacteremia. Australia has one of the highest incidences of Salmonellosis in the developed world. Pathogenesis is dependent on the activity of two distinct type III secretion systems (T3SS), encoded by genetic regions termed Salmonella pathogenicity islands (SPI). The SPI-1 T3SS is associated with bacterial invasion as well as activation of innate immune signalling, and the SPI-2 T3SS is associated with intracellular survival in immune and epithelial cells, replication and systemic infection. While the importance of the SPI-1 T3SS to Salmonella pathogenesis is well established, the function of many SPI2 encoded effectors remains unknown. This project aims to investigate the role of a subset of relatively uncharacterised SPI-2 effectors in Salmonella virulence. Overall this project will provide critical insights into the pathogenic mechanisms of an important public health issue and provide the basis for potential future therapeutic development. Research methods will include: molecular biology, protein purification, bacteriology, cell culture, confocal microscopy, western blot, mass spectrometry, protein-protein interactions. Keywords: Bacterial pathogenesis, Salmonella, type III effector proteins, innate immunity, cell signalling pathways.
Suitability: Honours, PhD Project leader: Dr Jaclyn Pearson, Dr Kate Lawlor e: jaclyn.pearson@hudson.org.au, kate.lawlor@hudson.org.au Project description: The regulation of host immune and cell death signalling is central to the pathogenesis of many human diseases. We have recently gained some exciting new preliminary data that suggests Salmonella enterica serovar Typhimurium induces the degradation of host proteins that regulate tumour necrosis factor receptor (TNFR1) signalling, thus regulate cell death and innate immune responses. This project aims to understand how the bacterium, Salmonella mediates degradation of these critical immune signalling factors and what the implications are for pathogen survival within the host and disease outcomes for the host. Research methods include: molecular biology, protein purification, bacteriology, cell culture, confocal microscopy, western blot, potential mouse experimental work.
Understanding the molecular basis of virulence in invasive Salmonella lineages Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSc(Hons), Short projects Project leader: Dr Jaclyn Pearson e: jaclyn.pearson@hudson.org.au Project description: Pathogenic enteric bacteria often occupy distinct ecological niches, and have evolved specific genomic characteristics that enable host and environmental adaptation, with resulting changes in virulence (manifested by clinical disease severity) and transmissibility. For example, Salmonella is an example of a genus in which there is a genomic signature for either a gastrointestinal or an extra-intestinal lifestyle, whereby functions required for promoting growth in the gastrointestinal tract are lost when the lineage becomes invasive. This project aims to integrate epidemiological, genomic and molecular microbiological data to understand the host and pathogen factors that result in invasive
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salmonellosis. This information will inform our understanding of the evolutionary pressures that lead to the emergence of highly adapted clones that persist in the food chain. Using a combination of molecular genetics, cell biology approaches and established infection models, we will test the role of these evolving factors in the initiation of infection and progression of disease. Research methods include: bacteriology, bacterial genomics, cell culture, molecular biology, protein purification, confocal microscopy, western blot, potential mouse infection model. Keywords: Salmonellosis, food borne, invasive bacteria, inflammation, molecular biology, genomics, epidemiology.
Identifying novel biomarkers of paediatric inflammatory bowel disease Suitability: PhD/Doctorate, Honours Project leader: Dr Jaclyn Pearson, Dr Edward Giles, e: jaclyn.pearson@hudson.org.au, edward.giles@monashhealth.org Project description: Inflammatory bowel disease (IBD) is an incurable lifelong disease for one in 200 Australians, including more than 10,000 children, that causes severe inflammation of the gut. It’s often so severe that sufferers need to be hospitalised and may require surgery. Currently IBD is kept under control using drugs that suppress the immune system, but these become less effective over time and can have significant side effects, leaving patients with an increased risk of colorectal cancer. The ongoing and chronic nature of IBD impacts a young patient’s emotional, physical and social wellbeing, causing severe embarrassment and disruption to their education, employment and relationships. Overall, a better understanding of the true causes of IBD are needed to develop new and more effective treatments. We have strong evidence that disruptions in ‘programmed cell death’ in the gut plays a major role in the development of IBD. In collaboration with paediatric gastroenterologist, Edward Giles, we aim to specifically identify these cellular disruptions in a cohort of 200 young IBD patients from the IBD clinic at the Monash Medical Centre in Melbourne. This study will be providing a new and specific target for IBD treatments that we hope will be more effective with less side effects. Keywords: Inflammatory Bowel Disease, cell death, microbiome, inflammation
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Innate Immune Responses to Infection
Innate immune responses to the human microbiota Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSci (Hons) Project leader: Prof Elizabeth Hartland
Intracellular bacterial pathogens and cell intrinsic immunity Suitability: PhD/Doctorate, Masters by Research, Honours Project leader: Prof Elizabeth Hartland e: elizabeth.hartland@hudson.org.au Project description: 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 lifethreatening 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 characterize 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.
e: elizabeth.hartland@hudson.org.au Project description: The study of host-pathogen interactions has significantly advanced our understanding of bacterial virulence, infection and the host immune response. However, until recently these studies have largely ignored the role of the resident microbiome. Although the commensal microbiome is known to provide some protection against infection by mucosal pathogens, we know little about the interactions between pathogens, the specific elements of the microbiome and the innate immune response at mucosal surfaces. Classical bacterial pathogens have evolved specific virulence factors to compete with resident commensals as well as subvert host immune responses. In addition, many bacterial infections are treated with antibiotics causing further disruption to the microbiome. To understand how the mucosa and microbiome communities respond to disruption by pathogen infection and antibiotic treatment, we will use an iPSC-derived tissue system and defined human microbiome communities to map the mechanisms underlying infection resistance, tissue repair and ongoing inflammation, as well as identify potentially protective human microbiome communities and isolates. Keywords: microbiome, innate immunity, commensal bacteria, intestinal microbiota, mucosal immune responses
Keywords: microbiology, Legionella, Burkholderia, innate immunity, cell biology
Translocated effector proteins of intestinal bacterial pathogens Suitability: PhD/Doctorate, Masters by Research, Honours Project leader: Prof Elizabeth Hartland e: elizabeth.hartland@hudson.org.au Project description: 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, termed effector proteins, into host cells via specialized protein secretion systems. We work on a range of 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. Keywords: microbiology, inflammation, cellular biology, innate immunity, bacterial diseases
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Microbiota and Systems Biology Characterization of microbiota composition in paediatric inflammatory bowel disease Suitability: PhD/Doctorate, Honours, BMedSci (Hons), Masters by Research Project leaders: Dr Sam Forster, Dr Ed Giles e: sam.forster@hudson.org.au, edward.giles@monashhealth.org Project description: The gastrointestinal microbiota, mediated by complex interactions between the patient’s immune system and environment, is now associated with diseases as diverse as infections, inflammatory bowel diseases and cancers. Paediatric Inflammatory bowel disease (PIBD) is a chronic incurable condition, affecting children and teenagers, that is increasing in incidence. Changes in the microbiota reflect the development of IBD and are a potential target for therapy or even cure. This project combines expertise in the culturing and phenotypic analysis of the human gastrointestinal microbiota published recently (Nature, 2016) to discover and characterize the bacterial community present in PIBD. These insights will lead to identification of novel biomarkers and predict potential clinical interventions for further experimental validation and therapeutic validation. The project represents a close collaboration between clinical and experimental elements with sample collection (ethics already established), world-leading in-vitro culturing, bacterial whole genome sequencing, phylogenetic analysis and metagenomic sequencing. Students interested in experimental or computational biology are welcome to take the opportunity to develop skills in both areas. The Centre for Innate Immunity and Infectious Diseases is a world leader in infection and inflammation with a strong record of student training and development. Keywords: microbiota, microbiome, paediatric, inflammatory bowel disease, microbiology, IBD, UC, ulcerative colitis
Characterization of human microbiota diversity across the Australian community Suitability: PhD/Doctorate, Honours, BMedSci (Hons), Masters by Research, Graduate Diploma, Short projects Project leader: Dr Sam Forster e: sam.forster@hudson.org.au The microbial communities associated with every surface of our bodies are incredibly diverse, yet we know practically nothing about the majority of species that comprise them. Within the gastrointestinal tract,
one of the most well studied sites, we estimate there are between 100 and 2000 species and numerous genetically distinct isolates. This project will collect samples from urban, rural and traditional indigenous communities across Australia to characterise the commensal bacterial genomic diversity across the Australian community. Understanding the diversity and distribution of bacterial species will provide important knowledge and insights into how these species and strains spread between individuals and contribute to health. Keywords: microbiota, microbiology, metagenome, skin microbiota, gut microbiota, gastrointestinal microbiota, genomics, microbial genetics, computational biology, bioinformatics
High Resolution Computational Analysis of the Gastrointestinal Microbiota Suitability: PhD/Doctorate, Honours, BMedSci (Hons) Project leaders: Dr Sam Forster e: sam.forster@hudson.org.au Project description: For over 100 years the need to understand particular disease causing, bacterial isolates to treat disease has been clearly understood. Importantly, combining genomics and traditional microbiology, it is now clear that different bacterial lineages and even individual isolates may induce vastly different disease outcomes for patients. While these principles are well established for pathogenic organisms it is now evident that the vast majority of bacterial species with which we are associated likely provide beneficial functions. Similar strain and isolate level understanding are limited by our ability to identify, classify and investigate these species. In the human gastrointestinal tract alone, there are 100 trillion bacteria, representing more than 500 species, that are intimately associated with our daily lives. We have recently developed methods to culture the vast majority of the human gastrointestinal microbiota (Nature. 2016) that has unlocked high resolution, whole genome shotgun metagenomics sequencing for detailed analysis. This project will focus on analysis of over 13,000 shotgun metagenomics samples to identify key bacterial species and co-existence networks required for maintenance and reestablishment of health after microbiota perturbation. This project represents a collaboration between the Microbiota and Systems Biology Laboratory at the Hudson Institute of Medical Research, the Wellcome Sanger Institute and the European Bioinformatics Institute. Please contact Dr Sam Forster (sam.forster@hudson.org.au) for further information. Keywords: computational biology, bioinformatics, metagenomics, microbiota, machine learning, statistics, genomics, phylogeny, ecology, microbiome
Modulating gastrointestinal microbiota stimulation of the innate immune system Suitability: PhD/Doctorate, Honours, BMedSci (Hons) Project leader: Dr Sam Forster, Dr Michelle Chonwerawong, Dr Vanessa Marcelino
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e: sam.forster@hudson.org.au, Project description: The innate immune system is capable of intricately detailed detection, differentiation and elimination of pathogenic bacteria. However, the vast majority of bacteria encountered by our innate immune system are beneficial to health. Indeed, over 500 species of these commensal bacteria, containing approximately 10,000-fold more genes than the human genome exist in the human gastrointestinal tract alone. Emerging research is demonstrating the importance of these bacterial communities in maintaining health and causing or exacerbating disease. We recently developed novel methods to grow for the first time, the vast majority of bacteria from the gastrointestinal microbiota (Nature, 2016) resulting in the discovery of hundreds of novel species which require further investigation. Combined with the established experimental and computational expertise in the analysis of innate immune signalling pathways, this project will include cutting edge microbial culturing techniques, cell culture assays and advanced computational analysis to identify pro- and anti- inflammatory bacterial species. Students interested in experimental or computational elements, will have the opportunity provided to develop skills in both areas. The Centre for Innate Immunity and Infectious Diseases is a world leader in infection and inflammation with a strong record of student training and development. Please contact Dr Sam Forster (sam.forster@hudson.org.au) for more information. Keywords: innate immune response, gastrointestinal microbiota, immunology, microbiology, bioinformatics, genomics, microbiome, metagenomics, microbiota
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Nucleic Acids and Innate Immunity
Making better mRNA therapeutics Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSci (Hons) Project leader: Dr Michael Gantier e: michael.gantier@hudson.org.au
Creating a new generation of adjuvants for vaccine and cancer immunotherapy Suitability: PhD/Doctorate, Masters by Research, Honours, BMedSci (Hons) Project leader: Dr Michael Gantier e: michael.gantier@hudson.org.au Project description: Our laboratory has recently discovered that select Toll like receptor agonists could be modified to present novel adjuvant properties - with broad implications in vaccine development and cancer treatments. This project will advance our knowledge of the therapeutic applications of our discovery using cutting edge disease models to study immune responses - with a combination of in vitro and in vivo experiments. It has the potential to revolutionise adjuvants (for instance leading to less frequent vaccinations in children), and reignite immune responses against cancer cells within the tumour microenvironment. Importantly, the successful candidate is guaranteed to publish peerreviewed works related to their studies upon joining our laboratory (with a possible Thesis by publication stream for PhD students).
Project description: Despite the huge success of the Pfizer-BioNTech and Moderna mRNA vaccines in the SARSCoV-2 pandemic, unwanted inflammation due to activation of innate immune sensors remains a major challenge in the manufacture and implementation of mRNA therapeutics. Our team has recently discovered that select short, synthetic RNA molecules are strong inhibitors of the nucleic acid sensors (TLR3, 7, 9 and cGAS) (Valentin 2021 Nucl. Acids Res.). This project will investigate how our discoveries can be applied to improve the immunogenicity and production of mRNA therapeutics such as mRNA vaccines. This exciting work has the potential to directly impact how mRNA therapeutics are made. Importantly, the successful candidate is guaranteed to publish peerreviewed works related to their studies upon joining our laboratory (with a possible Thesis by publication stream for PhD students). Keywords: mRNA vaccines, mRNA therapeutics, innate immunity
Keywords: innate immunity, adjuvants, immune responses, cancer immunotherapy
Targeting auto-immune sensing of DNA damage Suitability: PhD/Doctorate, Masters by Research, Honours Project leader: Dr Michael Gantier e: michael.gantier@hudson.org.au Project description: We and others have recently discovered that DNA damage can promote inflammation through recruitment of the cGAS-STING pathway (Pepin et al., Nucleic Acids Research 2016 and 2017). In this project we propose to investigate new classes of cGAS and STING inhibitors that have the potential to help curb auto-immune sensing of DNA for instance seen in Cutaneous Lupus Erythematosus. The successful candidate will gain cutting edge practical knowledge in molecular, cellular and animal biology, working on a project with a strong translational angle. Keywords: innate immunity, inflammation, lupus
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Pattern Recognition Receptors and Inflammation
immunological assays and biochemical mechanism of action assays. These projects also offer the opportunity for the biopharma experience of drug development and potential clinical application/trials. Keywords: innate immunity, inflammation, inflammasomes, drug development
Innate immune immunometabolism: the intersection between metabolism and immunology Suitability: Honours, PhD Project leader: A/Prof Ashley Mansell e: ashley.mansell@hudson.org.au Project description: Recent discoveries have positioned mitochondrial reprogramming by Toll-like receptors (TLRs), at the centre of innate immune inflammation. Immunometabolism describes the interplay between immunological and metabolic processes which are not only critical to the immediate innate immune response to infection, but also the new paradigm of innate memory or training, the concept that myeloid lineage cells can respond more strongly to future challenge via epigenetic reprogramming. We have discovered a role for STAT3 in immunometabolism and how this regulates inflammatory gene induction, mitochondrial health, and metabolism. This project offers the opportunity to explore the molecular dynamics and mechanisms of TLR-induced mitochondrial metabolism, and the temporal influence on transcriptional and epigenetic remodelling using advanced genetic sequencing and metabolomic approaches, in conjunction with novel mouse models of dysfunctional STAT3 signalling and inflammatory disease. Keywords: innate immunity, inflammation toll-like receptors, pattern recognition receptors, cell biology, mitochondria, metabolism
Developing therapies to treat inflammasome-mediated inflammation and disease Suitability: Honours, PhD Project leader: A/Prof Ashley Mansell e: ashley.mansell@hudson.org.au Project description: Inflammasomes are implicated and associated with nearly every major disease afflicting mankind: cancer; infections, cardiovascular, neurodegenerative and metabolic diseases. There is considerable interest therefore in developing novel therapies to target inflammasome-mediated inflammation. We, and our industrial partner have developed a family of novel multi-NLRP inflammasome inhibitors. This project offers the opportunity to characterise and evaluate the efficacy of these inhibitors in in vivo models of disease, cellular 15 Centre for Innate Immunity and Infectious Diseases | Student Research Projects 2023
Regulation of Interferon and Innate Signalling Characterisation of a novel cytokine in mucosal immune responses to infections Suitability: Honours, PhD Project leaders: Dr Eveline de Geus, Prof Paul Hertzog e: eveline.degeus@hudson.org.au, paul.hertzog@hudson.org.au, Project description: We have discovered a new cytokine exclusively expressed in the female reproductive tract, which is essential for the optimal response to Sexually Transmitted Infections such as Herpes Simplex Virus (HSV) and Chlamydia and possibly HIV. It is unique for several reasons: unlike conventional cytokines, IFN epsilon (IFNe) is constitutively expressed, especially in the female reproductive tract, is not regulated by pathogens, but is regulated by hormones. This work was recently published in the prestigious journal, Science. 2013 Mar 1;339 (6123):1088-92. Current projects involve our unique repertoire of reagents including gene knockout mouse models of the female reproductive tract, as well as recombinant cytokines, antibodies, clinical patient cohorts and primary cell cultures for an ongoing study program that includes the following specific areas to characterise the mechanisms whereby this new cytokine regulates the immune response: • Molecular Biology – determining the mechanism of regulation of IFNe gene expression, • Biochemistry – characterising the mechanism of IFNe interaction with receptors and activation of novel signalling pathways, • Immunology – determining how and which immune cells are regulated in the FRT mucosa during infections and other disease, • Infectious Diseases (clinical and animal models) – determining whether hormonal regulation of IFNe makes women more susceptible to infection at certain times with pathogens such as HIV, HSV and Chlamydia, and • Cancer Biology and immunology – characterising the role of IFNe in the development and progression of uterine and ovarian cancer progression of uterine and ovarian cancer. Keywords: women’s health, reproductive / sexual health, innate immunity, infectious diseases
Systems biology of innate immune signalling Suitability: Honours, PhD
Project leader: Prof Paul Hertzog, Dr Jamie Gearing, Dr Sam Forster e: paul.hertzog@hudson.org.au, jamie.gearing@hudson.org.au, sam.forster@hudson.org.au Project description: This project studies the complex regulation of cell signalling in the innate immune response to infection and inflammation. This is performed at the genome, transcriptome, proteome and sometimes metabolome level. The objective is to understand how this immune response is balanced to achieve a protective response, rather than a disease-causing inappropriate response. The systems biology team use a combination of computational and “wet lab” approaches to discover regulatory factors, networks and molecular control pathways involved in disease pathogenesis. In order to help analyse the pathways and how they are integrated, we have a computational biology group working on the generation of methods and databases (e.g. INTERFEROME), whereby we can integrate our data with all published information on this topic. We are developing tools to predict pathways and regulatory networks, including transcription factor binding sites in gene promoters. Specific projects include: •
•
• • •
Analysis of innate immune or inflammatory “signatures” in disease (infections, inflammation, autoimmunity, cancer) Discovery of novel signalling pathways by computational predictions and practical experimentation Transcriptional regulation of gene expression Post-transcriptional regulation of gene expression Whole transcriptome (RNA-seq) analysis and integration of interferon signalling across multiple datasets
Keywords: signal transduction, innate immunity, bioinformatics, microRNAs, infectious diseases
Structure-function studies of interferon signalling Suitability: Honours, PhD, Short projects Project leaders: Dr Nicole De Weerd, Dr San Lim, Prof Paul Hertzog e: nicole.deweerd@hudson.org.au, san.lim@hudson.org.au, paul.hertzog@hudson.org.au Project description: The type I interferons (IFNs) are important in regulating host defence against cancer infectious and inflammatory disease. However, if signalling occurs at an inappropriate time, place, duration or strength it is extremely toxic or even lethal. Therefore, it is essential to understand how positive and negative signals are controlled and balanced. This process begins at the cell surface of the responding cell when the IFNs interact with two receptor components that ultimately transmit a signal into the cell. We use structural biology, biochemistry and sophisticated imaging to examine this process. Importantly we also correlate results from these studies with sophisticated systems biology assessments of signalling, biological responses in cells and model systems, ultimately in clinical studies in humans.
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Keywords: structural biology, biochemistry, protein chemistry, signal transduction, imaging
Investigation of a novel cytokine in female reproductive tract infections Suitability: Honours, PhD Project leader: Prof Paul Hertzog e: paul.hertzog@hudson.org.au Project description: We have discovered a new cytokine, interferon epsilon (IFNe) that is exclusively expressed in the female reproductive tract, which is essential for the optimal response to Sexually Transmitted Infections such as Herpes Simplex Virus and Chlamydia and possibly HIV. IFNe is expressed most abundantly by epithelial cells in the female reproductive tract. Epithelial cells that are the first line of defence against infections and not only provide a protective physical barrier against infections but they also have direct antigen presenting and antimicrobial functions to restrict and block infections with commensals and pathogens. The aim of this project is to understand for the first time the role of IFNe in the modulation of epithelial cell functions in the female reproductive tract. Techniques to be used include in vitro infection studies, primary cell culture and cell line culture, cell proliferations and migration assays, co-culture studies, real-time PCR, cytokine quantification assays. Keywords: women's health, reproductive / sexual health, immunology, innate immunity, infectious diseases.
Essential virus sensors: investigating RNA receptors in infection Suitability: PhD, Honours, BMedSci (Hons), Short projects Project leaders: Dr Natalia Sampaio, Prof Paul Hertzog e: natalia.sampaio@hudson.org.au, paul.hertzog@hudson.org.au Project description: The innate immune system is the body’s first line of defence against infection, and is necessary for our survival. Our cells have evolved specialized mechanisms for sensing viral infection to kickstart an immune response. Sensors of aberrant nucleic acids play a key role in detection of viruses. Among these, receptors that bind double-stranded RNA, such as MDA5, PKR and OASs can detect a wide array of viruses, including SARS-CoV-2, West Nile virus, and Zika. However, the activation and regulation of these receptor signalling pathways are poorly understood. This project will investigate these receptors in the context of important human pathogens, such as in respiratory infections and mosquito-borne viruses, to gain biologically relevant insight into their role in protection from disease. There will be opportunity to apply cutting-edge methods, including next-
generation sequencing, iCLIP (Individual-nucleotide resolution UV crosslinking and immunoprecipitation), CRISPR/Cas9 gene editing, and iPSC (induced pluripotent stem cells). Keywords: virus, infection, innate immunity, RNA, nucleic acid sensors, signalling
Interferon-epsilon: a novel interferon in endometrial function Suitability: PhD/Doctorate, Masters by research Project leaders: Dr Fiona Cousins, Prof Paul Hertzog e: fiona.cousins@hudson.org.au, paul.hertzog@hudson.org.au Project description: In the female reproductive tract (FRT), homeostasis is maintained to enable embryo implantation and development in parallel with priming of the immune system, which protects against localised infection. Interferon epsilon (IFNε) is a new protein of the Type I Interferon family that are important in the protection of the body from infections. Our group have shown that IFNε is most abundantly expressed in the FRT, in the endometrium, where it has an important role in protection against sexually transmitted infections. However, it is not well understood how IFNε protects the FRT from infections or what endometrial and immune factors regulate its expression. We do know that the levels of IFNε are constantly changing during the menstrual cycle, during which the endometrium is undergoing cycles of breakdown and regeneration. Importantly, factors in menstrual fluid have been shown to influence the repair of the endometrium following menses and we hypothesise that these factors also regulate IFNε expression. Endometrial epithelial cell lines will be treated with menstrual fluid or patient matched peripheral blood plasma and the impact of these fluids in IFNε gene expression determined. Similarly, supernatants from treated cell cultures will be examined for secretion of interferon-epsilon. Cell lines will be treated with IFNε at the same time as treatment with the above fluids to determine how IFNε affects the immune response induced by these fluids. Finally, expression of IFNε within immediately premenstrual, menstrual and repair phase human endometrium will be determined. Keywords: female reproductive tract, FRT, interferon, endometrium, endometriosis.
Transition to adult care in paediatric inflammatory bowel disease Suitability: Masters, Honours, BMedSci (Hons), Short projects Project leader: Dr Edward Giles e: edward.giles@monashhealth.org Project description: Inflammatory Bowel Disease is an incurable disease that affects approximately 1 in 200 young Australians, with increasing incidence worldwide. Up to 25% of patients are diagnosed <20 years of age, many in the paediatric services. Transition to adult care is a complex and high-risk time for all patients with chronic diseases, 17
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and IBD is no exception. Monash has recently established a dedicated young adult IBD clinic under Dr Ed Giles. This unique service in Australia is based on limited overseas models, however the evidence for the success of such clinics remains limited. This project would involve a combined approach of assessing the outcome of the establishment of this service through audit and prospective evaluation of patient outcomes, as well as patient satisfaction data. Please do not hesitate to contact me should you wish further information or preliminary data for this project. Keywords: inflammatory bowel disease, transition, pediatrics
Mucosal Immunology in Paediatric Inflammatory Bowel Disease Suitability: PhD/Doctorate, Honours, BMedSci (Hons) Project leader: Dr Edward Giles e: edward.giles@monashhealth.org Project description: This project involves the translation of findings from mouse models of inflammatory bowel disease (IBD) to human patients, both with IBD and healthy controls. This project explores novel targets for treatment in IBD, as well as exploring possible causes for IBD. By focusing on paediatric patients, we aim to better understand the development of the mucosal immune system and its relationship with the microbiota in early life, and how this can be disrupted in IBD. Currently there are two mouse models of colitis (IBD) with significant results supporting important new pathways for disease in IBD. The project (s) will therefore focus on identifying the importance of these pathways in human patient samples. This project will involve the handling of human samples (ethics already approved and some samples stored), and the use of such techniques as immunohistochemistry, flow cytometry and quantitative real-time PCR, as well as novel microbiome culturing and analysis. The lab has a strong record of training and supporting students regardless of previous laboratory experience.
can be defined as permanent disruption of this homeostasis. Enteric infections are a significant cause of childhood mortality worldwide, and remain a major cause of GP and hospital presentations in Australia. IBD affects 1/200 young Australians, with increasing worldwide incidence. IBD is a life-long disease that often presents in childhood. Treatments are expensive, have serious side effects and lose efficacy over time. There is an urgent need for new therapies for IBD that are effective without systemic immunosuppression. Type I interferons (T1IFN) are a family of cytokines with a single receptor and pleiotropic functions. Constitutive T1IFN is critical in maintaining intestinal homeostasis and limiting inflammation after infection or injury. We have recently identified IFNε, a novel T1IFN, in mouse and human intestinal epithelium. We propose it plays a crucial role in regulating intestinal immune responses to the microbiome. We have compelling preliminary data to support this idea, as IFNε was protective in a mouse model of IBD and limited an in vitro infection model. Other T1IFNs have been used in both IBD patients and models of infection with conflicting results about their protective effects. We now hypothesise that IFNε, expressed in the human intestinal epithelium, is an important regulator of responses to the microbiome. To move these findings from murine models to the clinic, we have recently developed a creative technique to simultaneously analyse both host immune responses from patient intestinal biopsies and the bacteria from the same sample. This allows concurrent host-microbiome analysis to tease apart their interactions. From our paediatric (P)IBD cohort (n=150), we have shown a dysregulated T1IFN response in IBD. By using cutting edge bioinformatic analysis of this extremely large dataset (>3000 bacterial isolates), we have identified a candidate Lactobacillus species associated with this T1IFN response. From this same cohort we have grown small intestinal organoids (mini-guts). These will allow us to analyse ex vivo epithelial-microbe interactions in health and IBD with both pathogens and putative commensal organisms. This patient cohort, combined with unique access to in-house IFNε reagents, will allow us to understand the role of this critical cytokine in human intestinal health and disease. We are seeking enthusiastic students to study this novel proteinmicrobiome interaction with the aim of developing new therapies for gut diseases in children and adults around the world.
Keywords: paediatric, IBD, immunology, interferon
Keywords: interferon, microbiota, IBD, colitis, gastroenteritis, mucosal immunology
A novel protein regulator of host-bacterial interactions in the gut in health and disease
Novel bacteriotherapeutics in paediatric inflammatory bowel disease
Suitability: PhD, Masters, Honours, BMedSci (Hons), Joint PhD/Exchange Program
Project leaders: Dr Edward Giles
Suitability: PhD/Doctorate, Honours, BMedSci (Hons)
Project leaders: Dr Edward Giles, Dr Eveline de Geus
e: edward.giles@monashhealth.org
e: edward.giles@monashhealth.org, eveline.degeus@hudson.org.au
Project description: Inflammatory Bowel Disease (IBD), predominantly Crohn’s Disease (CD) and Ulcerative Colitis (UC), is a chronic inflammatory condition of unknown aetiology. It is caused by an aberrant immune response to the environment, including the microbiota. IBD is incurable, with debilitating albeit hidden symptoms and an increasing incidence worldwide. The cost to the Australian economy
Project description: The healthy intestine maintains a homeostatic equilibrium between epithelial integrity, a resident immune system and a symbiotic microbiome. Intestinal infections temporarily disrupt this balance, and inflammatory bowel disease (IBD)
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was $2.7 billion in 20123. IBD affects 1 in 250 Australians aged 5-40. Over the last decade, an explosion in microbiome research in IBD has not yet affected diagnostic algorithms or treatments. I have developed a program at Hudson Institute to isolate and mechanistically characterise bacteria while simultaneously measuring host immune response to form a more complete understanding of the hostmicrobiome in IBD. My preliminary work has shown several exciting novel candidates for bacterial therapeutics and new targets for therapy. The exceptional technical resources and infrastructure that I have established in a world-leading environment will ensure transformational changes from this program, including a clinical trial of bacteriotherapy. I am seeking students to progress this working into Phase I clinical trials. Keywords: IBD, microbiota, Crohns, colitis, mucosal immunology, clinical trial
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Synergy Program
Keywords: signal transduction, innate immunity, bioinformatics, infectious diseases, microbiology, inflammation, cellular biology, microbiome
Innate Mucosal Sensing and Shaping of the Human Microbiome Suitability: PhD, Honours, Short projects Project leaders: Prof Elizabeth Hartland, Prof Paul Hertzog, Dr Sam Forster, Prof Christine Wells e: elizabeth.hartland@hudson.org.au, paul.hertzog@hudson.org.au, sam.forster@hudson.org.au Project description: The reciprocal interactions between mucosal epithelium, innate immune cells and commensal microbial communities across sites including the gastrointestinal and urogenital tract, play an essential role in health and disease. The commensal organisms sculpt the nature and the responses of the local epithelial and immune cells. Conversely, the status of these front-line innate cells influence the composition of the commensal microbiome. However, a deep understanding of these reciprocal interactions is lacking despite it being an important problem that defines the healthy state, modulates the pathogenesis of disease in mucosal sites and potentially in distant organs. This program offers student projects in multidisciplinary areas including innate immune signalling, commensal and pathogenic microbiology, systems biology and bio-engineering with complementary aims to uncover interactions enabling understanding of the microbe-host interactions that regulate mucosal immunity, define the healthy state and determine disease outcomes. This important problem will be addressed with integrated projects under the umbrella of the three following themes: 1. Characterising the impact of microbiome components on the innate response. 2. How does the host innate immune system influence the microbiome community 3. Model discovery systems for interrogation, biomarker and diagnostic discovery and in vivo sensor and delivery. One example approach will be to use iPSC-derived tissue systems and defined human microbiome communities to map the mechanisms underlying infection resistance, tissue repair and ongoing inflammation, as well as identify potentially protective human microbiome communities and isolates. The outcomes will be in knowledge gain: to define the microbiome community composition and the host response in the intestine, compared with other sites, to identify organ-specific factors; to distinguish commensal from pathogen and why an organism can be a symbiont at one site and pathogen at another. This will lead to the development of next generation diagnostics and therapeutics.
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Respiratory and Lung Disease Characterisation of innate immune responses during exacerbation of asthma and COPD Suitability: PhD/Doctorate, Masters by Research, Honours Project leaders: Dr Belinda Thomas, Prof Phil Bardin e: belinda.thomas@monash.edu, philip.bardin@monash.edu Project description: Our research is focussed on understanding how viruses and bacteria cause exacerbations of inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Previous studies in our laboratory have demonstrated that reduced innate immune responses contribute to enhanced virus infection in asthmatic persons and in a mouse model of influenza A infection. We have also demonstrated the detrimental effect of glucocorticosteroids on viral infection in these diseases (Thomas et al., Am J Resp Cell Mol Biol, 2009, Thomas et al., Sci Rep, 2014). Further studies using validated primary cell culture models and various mouse models of viral and bacterial infection are examining the mechanisms contributing to reduced host immune responses and potential therapeutic strategies to counter these adverse effects.
This currently takes the form of specific cohort studies, clinical trials, systematic reviews, and instrument (outcome tool) validation. We have large data sets suitable for datamining related to specific research questions, but are also interested in initiating new projects that build upon our team's expertise. This may include research in other chronic lung diseases such as asthma and bronchiectasis. Data collection is based clinically at Monash Health (predominantly Monash Medical Centre, Clayton), but includes other sites as required. Our team also extends into the basic science laboratory, allowing for human and/or animal tissue sampling to assist scientific research and translation from 'bench to bedside'. We have access to administrative support, IT software and data analysis packages via Monash University, patients via Monash Health, clinical equipment such as lung function testing and exercise testing equipment via Monash Health, and a range of physical activity and muscle testing equipment via the Mobile Movement and Activity Monitoring Laboratory - a joint initiative between Monash University Department of Physiotherapy and our clinical partners. Please don't hesitate to be in touch to see how we can cater a project to your needs. Small project funding may be possible (on an individual need basis), subject to competitive availability. Keywords: COPD; acute exacerbations; physiotherapy; rehabilitation; pulmonary rehabilitation; physical activity; phenotyping; eosinophils; personalised medicine; treatable traits; NIV; clinical care; instrument validation; exercise testing
Keywords: asthma, virus, bacteria, innate immunity, mouse models, infection
Improving recovery from acute exacerbations of COPD Suitability: Honours, PhD/Doctorate, Masters by Research Project leaders: Dr Christian Osadnik, Prof Phil Bardin e: christian.osadnik@monash.edu, philip.bardin@monash.edu Project description: We are currently undertaking a structured suite of projects targeting improvements in recovery from acute exacerbations of chronic obstructive pulmonary disease. These projects are led by Dr. Osadnik in close collaboration with a team of medical and allied health clinicians and researchers with an interest in the field of respiratory medicine. This includes Prof. Philip Bardin, Director of Respiratory Medicine at Monash Lung and Sleep, and Prof. Terry Haines, Head of Monash University's School of Primary and Allied Health Care. Individual projects range from small to large scale, with tailoring available to suit rapid publications or PhD candidature. Most projects relate to gaining insight into the ways we can optimise care models to enhance recovery from acute exacerbations of COPD. 21 Centre for Innate Immunity and Infectious Diseases | Student Research Projects 2023
Structural Biology of Inflammation and Cancer Research Structural and biochemical characterisation of inflammasome signaling Suitability: Honours, Masters by Research, PhD Project leader: Dr Wilson Wong e: Wilson.wong@hudson.org.au Project description: Inflammasomes are key cytoplasmic sensors that detect pathogen components to undergo conversion from inactive to active signalling platforms to drive inflammatory signalling. The activation status of inflammasomes is under tight regulation to maintain healthy homeostasis. However, mutations in inflammasome components can result in imbalance of inflammatory signalling which is the underlying basis of many autoinflammatory diseases. Our interest is focused on understanding how the activity of inflammasome is controlled and the mechanisms by which inflammasome sensors detect infections and the molecular details of inflammasome activation. In this project, we aim to investigate the interactions between AIM2 inflammasome sensor and its binding partners to determine the role of these interactions in AIM2 inflammasome activation. In particular, we will characterise the mechanism of DNA induced AIM2 oligomerisation and recruitment of core components of the inflammasome including ASC and caspase1 to form signalling inflammasome. This project will utilise a variety of techniques that include protein expression and purification, functional biochemistry and structural biology method (cryo-EM) to understand the molecular details of AIM2 inflammasome signalling. Keywords: cryo-EM, structural biology, biochemistry, inflammation, inflammasome, AIM2
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Viral Immunity and Immunopathology
cytometry, histology, western blot, ELISA, cytokine bead array, viral plaque assays etc.
Understanding the interplay between cell death, inflammation and viral replication during severe influenza virus infections
The NLRP3 inflammasome as a therapeutic target and biomarker of silicosis lung disease
Suitability: PhD/Doctorate, Honours, BMedSci (Hons)
Project leader: A/Prof Michelle Tate
Project leader: A/Prof Michelle Tate
e: michelle.tate@hudson.org.au
e: michelle.tate@hudson.org.au
Project description: Silicosis is a debilitating and untreatable lung disease characterised by chronic inflammation and permanent fibrotic scarring. The need for novel treatments of this disease has been emphasised by the recent increase in silicosis cases among workers in the Australian artificial stone benchtop industry. Treating the symptoms and preventing disease progression remains a major challenge. There is increasing evidence in the literature that the host innate NLRP3 inflammasome promotes damaging inflammatory and fibrotic disease in silicosis.
Project description: Excessive inflammation, cell death and immunopathology are characteristic features of fatal viral infections of the lung. Experts predict an influenza A virus (IAV) pandemic is inevitable and without safe and effective therapies that protect against damaging host responses, we are ill-prepared. While the molecular mechanisms involved in the induction of inflammation during IAV infection have been well studied, the pathways involved in IAVinduced cell death and their impact on immunopathology have not been fully elucidated. This project aims to gain a greater understanding of the crosstalk between cell death and inflammatory pathways and explore the therapeutic strategy of targeting cell death to limit IAV disease. We will utilise in vitro and in vivo pre-clinical infection models. Techniques that will be employed include flow cytometry, histology, western blot, ELISA, cytokine bead array, viral plaque assays etc.
Keywords: virus, innate immunity, pulmonary disease, influenza, inflammation, immunotherapies
Suitability: Honours, BMedSci (Hons)
This project aims to investigative the potential of targeting NLRP3 and identify NLRP3-associated biomarkers of disease severity and risk of progression to severe silicosis. In this project, we will utilise in vitro, in vivo and ex vivo preclinical models, as well as clinical samples. Techniques that will be employed include flow cytometry, histology, western blot, ELISA, cytokine bead array etc. Keywords: pulmonary disease, silicosis, inflammation, fibrosis, innate immunity
Keywords: influenza, virus, infection, inflammation, cell death
Novel therapies for severe influenza virus infections: Targeting the host Suitability: PhD/Doctorate, Honours, BMedSci (Hons) Project leader: A/Prof Michelle Tate e: michelle.tate@hudson.org.au Project description: Excessive inflammation and immunopathology are characteristic features of fatal viral infections of the lung. Alarmingly, experts predict an influenza A virus (IAV) pandemic is inevitable. The current COVID-19 pandemic has highlighted the catastrophic impact the emergence a novel virus can have on global health and the economy. Without safe and effective therapies that promote viral resistance and protect against damaging host responses, pandemic viruses will continue to cause significant mortalities in the future. This project aims to identify new therapeutic targets and drugs which safely promote host resistance and dampen damaging inflammation. We will utilise in vitro and in vivo pre-clinical infection models. Techniques that will be employed include flow 23 Centre for Innate Immunity and Infectious Diseases | Student Research Projects 2023
Contact our supervisors Students are encouraged to contact supervisors to discuss projects, arrange a time to visit the lab and view our facilities. Simply email the supervisor to arrange a time.
STEP 1: Find a project you are interested in. STEP 2: Email the supervisor: “I am interested in your student project. Could I arrange a time to visit you in your laboratory please?”
All the information you need to enrol is on our website, or your supervisor can help you. w: hudson.org.au/students/courses-available/
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