IMMUNOLOGY AND MICROBIOLOGY
David Waters, Dorota Stephanowicz
Teresa Williams, Jorinke Koops, Kirsten van Norel
The laboratory’s research is centred on understanding how the lung repairs itself after inflammatory insult and how in susceptible people, abnormal repair responses
- contribute to the severity and chronicity of disease and
- impact on treatment.
The group’s primary disease interests are asthma and idiopathic pulmonary fibrosis (IPF), although the interplay between these cells likely plays a significant role in several other chronic lung diseases such as chronic obstructive pulmonary disease (COPD). In recent years the research team, in collaboration with others nationally and internationally has led a paradigm shift in the understanding of the pathobiology of asthma, revealing the airway epithelium as an importantcontributor to disease pathogenesis.
This included the first mechanistic description of intrinsic biochemical and functional differences between airway epithelial cells from asthmatic and healthy children. Given that remodelling of asthmatic airways can occur prior to a diagnosis of asthma, this data suggests that epithelial abnormalities may be causative rather than a product of the disease.
As a follow on from that study, the team then showed that asthmatic epithelial cells, despite having greater proliferative potential are very inefficient at repairing mechanically induced wounds, due in part to epigenetic inhibition of fibronectin deposition. More recently, the group was the first to discover and characterise a population of stem/progenitor cells that resides within the epithelium of human airways. Similarly, the group were the first to show that a population of human airway epithelial cells undergo an epithelial to mesenchymal transition.
In both latter studies, there were a disproportionately larger number of cells involved in asthmatic epithelium when compared to non-asthmatic epithelium. This data suggests that the asthmatic epithelium is more plastic and not differentiating appropriately. The research program which focuses on mechanisms of fibrosis, pioneered the study of the transcription factor signal transducer and activator of transcription, STAT3 in fibroblast biology.
It was the first study to show intrinsic dysregulated activation of STAT3 in a population of fibroblasts taken from the lungs of patients with IPF. The significance of this observation led the team to develop and characterise dysregulated STAT3 in complex mouse models. In related preclinical studies, the group have shown that modulation of the transcription factor complex β-catenin/CBP using the small molecule inhibitor ICG-001 significantly attenuates fibrosis in a mouse model of lung fibrosis.
Significantly, therapeutic dosing (after established disease) reversed fibrosis and improved survival. Given that ICG-001 improves epithelial cell restitution, the group are now investigating its potential in severe asthma and COPD.
Fiona Eyers, Kyra Minahan, Jessica Weaver
Sara Hadjigol, Thi Hiep Nguyen
Current research in this laboratory primarily aims at defining the key cellular and molecular processes that underlie the development of allergic disease (lung, skin and gastrointestinal tract) and of viral (RSV and influenza) and bacterial induced pulmonary inflammation.
The group are particularly interested in the molecular events that predispose to remodelling of the airways in chronic disease and the subsequent impact on lung function. In particular, projects are focusing on the biology of CD4+ Th2 cells, CD8+ T cells and eosinophils, and in signalling arrangements between cytokine and chemokine systems that pertain to allergic disease, infection induced pathogenesis and exacerbation of asthma.
The aim is to develop integrative concepts on molecular mechanisms of pathogenesis by employing an approach that is multifactorial ranging from transgenic systems to the identification of novel gene products.
The laboratory has established in vivo models of asthma (acute and chronic), allergic cutaneous disease and of eosinophil and lymphocyte homing to sites of allergen provocation or infection. Novel mechanisms to attenuate allergic and infection induced disease are also being explored.
The group have also established models of chronic obstructive pulmonary disease (COPD).
NHMRC ECR Research Fellows
Boehringer Post-doctoral Fellows
Andrew Jarnicki, Shaan Gellatly
Tegan Hunter, Matthew Bowman, Chloe Harrison, Kristy Wheeldon, Nathalie Kiaos
Krishna Sunkara, Alexandra Brown, Prema Nair, Tatt-Jhong Haw, Andrew Deane, Gang Liu, Bernadette Jones, Celeste Harrison, Duc Nguyen, Kamal Dua, Zhe Lu, Kurtis Budden, David Skerrett-Byrne, Daniel Hampsey, Sandra Rutting
This laboratory’s work has made internationally important contributions and led to the identification of novel avenues for therapy that are under further study.
This has been achieved through the development of novel mouse models that recapitulate the hallmark features of these human disease.
These models are employed in integrated approaches (infection, immunity & physiology with particular expertise in lung function analysis) to understand human diseases, and develop new treatment strategies.
Research outcomes have a translational goal and the studies are conducted in parallel with collaborative human studies with clinical collaborators.
In 2015 the group have progressed with their major interests in studying the pathogenesis and developing new therapies for respiratory diseases, particularly asthma and chronic obstructive pulmonary disease and infections that exacerbate them.
Professor Phil Hansbro is an NHMRC Principal Research Fellow and internationally recognised research leader in the study of respiratory diseases, such as asthma, chronic obstructive airway disease and infections and is developing interests in lung cancer.
He has a wide network of national and international collaborators.
Roberta Karpathy, Susanne Johansson, Bronwyn Davies, Rebecca Ingham, Camila Salum de Oliveira, Amanda Kelly, Min Yuan Quah, Yvonne Wong, Penny Yates, Jack Hockley, Olivia Lisle.
Lincoln Smith, Sophie Wells
This research focuses on the use of live viruses for the treatment of cancer, a growing field called oncolytic virotherapy. A/Prof Shafren is the chief scientific officer of Viralytics Ltd., which has been conducting human clinical trials of live Coxsackievirus A21 (CVA21) to treat cancer patients. CVA21 is a small virus belonging to the Picornaviridae family.
The virus is one of the many causes of the common-cold and infections in humans are usually asymptomatic.
The serendipitous discovery that CVA21 could selectively destroy melanoma cells through the targeting of over-expressed viral-entry receptors forms the basis of Viralytics Ltd.’s intellectual property. CVA21 is being commercialised under the tradename of CAVATAK™ and has applications for other malignancies including lung and bladder cancer.
The team is based at Hunter Medical Research Institute and co-ordinates the multi-site human clinical trials being conducted in the USA and UK and performs the laboratory testing associated with patient samples collected from the different centres. By December 2015, significant progress in Part A of the STORM trial was made, designed to establish the safety profile of CAVATAK™ and to determine an effective intravenous dosing schedule for successful tumour targeting when given as a single agent in patients with advanced solid tumours.
Updated clinical data from biopsies of tumour tissue from melanoma, non-small cell lung cancer and metastatic bladder cancer patients confirmed the successful systemic tumour delivery as CAVATAK™ was detected in tumours following three intravenous doses of virus. Infection of the tumour by CAVATAK™ can potentially enhance anti-cancer responses by increasing levels of immune-cell infiltration, stimulating a potential systemic anti-tumour immune response and increasing the levels of target immune-checkpoint molecules for potential checkpoint inhibitor combination strategies.
Part B of the STORM study (KEYNOTE 200) is being undertaken in a collaboration with Merck, and is designed to assess the safety and efficacy of intravenously delivered CAVATAK™ in combination with pembrolizumab (KEYTRUDA) in patients with advanced non-small cell lung cancer or metastatic bladder cancer. KEYTRUDA is a checkpoint inhibitor designed to block the molecule PD-1 (programmed death receptor -1) resulting in enhanced T-cell responses against tumour cells.
In addition to this, the group carries out preclinical research using CVA21 and other related enteroviruses, for the treatment of melanoma, malignant glioma, non-small cell lung cancer and pancreatic cancer. The team is also responsible for developing methods of manufacturing and purification of these viruses for commercial purposes.
Punnam Veerati, Camille Esneau, Teresa Williams, Winnie Li
The laboratory focuses on the interplay between common respiratory viruses and chronic respiratory diseases such as asthma and COPD.
Acute respiratory infections are a major cause of morbidity and mortality in humans worldwide, with infants and young children especially susceptible.
A number of pathogens are responsible for acute respiratory infections but in most cases they are caused by viruses – the most common being rhinovirus.
Viral respiratory infections represent the most widespread infectious disease in developed and developing countries with the burden of disease caused by the primary infection and their complications such as exacerbations of asthma and COPD being considerable.
The research can be divided into the following themes:
- Identification of asthmatic and COPD airway epithelial cell susceptibility factors that predispose to virus induced lower respiratory tract disease
- Development of (human and mouse) pre-clinical rhinovirus infection airways disease models
- Rhinovirus replication in differentiated human bronchial epithelial cells
- Development (with industry partners) of therapeutics to prevent/treat respiratory viral infections and exacerbation of chronic airway diseases
- Innovative approaches to rhinovirus vaccine development
Md. Khadem Ali
The laboratory’s research programs aim to inform novel targets for the development of improved therapeutic strategies for severe, steroid-resistant asthma, infection-associated respiratory and reproductive tract diseases and neurodegenerative diseases such as Alzheimer’s and multiple sclerosis.
Infection & severe asthma: The group are developing an understanding of the immunological and pathophysiological interactions between lung infections and asthma and have shown for the first time that earlylife, but not adult, infection enhances the severity of asthma in later life. Infection during asthma in adults results in the development of a phenotype resembling severe, steroid-resistant, neutrophilic asthma. More recently, the group have commenced investigations into the mechanisms that underpin infection and high fat diet/obesity-induced severe asthma.
Infection & reproductive tract disease: The group have recently begun investigating the immunobiology of Chlamydia infection and its role in the pathogenesis of Chlamydia reproductive tract and brain disease.
This has been extended further by investigating the association between infection and cigarette smoking with a number of other diseases including Alzheimer’s and other neurodegenerative disorders.
Dr Horvat has also recently initiated a program that focuses on investigating the interplay between iron, infection and immunity in lung and the effect this has on respiratory disease.
The group’s research examines molecular mechanisms of disease in the gastrointestinal tract, including inflammatory bowel disease (IBD), food allergy, colorectal cancer and necrotising enterocolitis. Through clinical and industry collaboration, the laboratory has a strong focus on translating fundamental understanding of disease into rationallydesigned,
clinical interventions. As part of the Priority Research Centre for Digestive Health and Neurogastroenterology, the research explores how mucosal tissues and commensal microbiota respond to the metabolic changes that occur in tissues during mucosal inflammation.
In particular, the group are interested in how intestinal tissues function and repair with the reduced oxygen availability that is characteristic of inflammation. The group are also interested in how this inflammation alters host-microbial interactions and how these changed interactions influence the progression and resolution of mucosal diseases. The
ultimate goal of this research is to understand how these processes may be pharmacologically manipulated with novel compounds for therapeutic benefit, and to identify potential biomarkers of cellular processes which will allow for better diagnose of gastrointestinal (GI) disease.