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Developmental-associated Dysregulation Of Innate Anti-microbial Immunity In Early Life As A Determinant Of Susceptibility To Atopic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$570,334.00
Summary
Previous NHMRC-sponsored research from the applicants has demonstrated that one of the strongest risk factors for subsequent development of asthma is having chest infections during infancy that are so severe that they trigger symptoms of fever and wheeze. It is not known what predisposes susceptible infants to these severe infections, and this project will attempt to define the mechanisms of susceptibility.
Innate lymphoid cells (ILCs) are found in the lining of the intestine and are part of the intricate crosstalk between the food we eat, good bacteria, epithelial cells and other immune cells. Without ILCs, the body is susceptible to infections through the intestinal tract. I will investigate the signals from nerve cells that control that activity of ILCs during infection to give us insights into pathways that activate ILCs in situations where they are reduced or inactive.
Targeting Caspase 8 In T-Cell Homeostasis And Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,215,780.00
Summary
Chronic infectious diseases such as HIV, hepatitis B and tuberculosis impose a massive global health burden and new treatments are desperately needed. This proposal investigates a new approach to improve immune responses and clear chronic infections. Our multidisciplinary team will define the molecular and cellular biology underlying this approach and translate our findings by re-purposing a drug already approved for other indications in humans.
A cellular hub for the organisation of T cell priming. This project aims to delineate the cellular interactions involved in the initiation of immune responses by utilising advanced in vivo imaging. Adaptive immunity in vertebrates functions via the acquisition of signals by immune cells via complex interactions with other immune cells, yet these exchanges are difficult to observe and define. This project expects to provide insights into the mechanisms that underpin effective cell-mediated immune ....A cellular hub for the organisation of T cell priming. This project aims to delineate the cellular interactions involved in the initiation of immune responses by utilising advanced in vivo imaging. Adaptive immunity in vertebrates functions via the acquisition of signals by immune cells via complex interactions with other immune cells, yet these exchanges are difficult to observe and define. This project expects to provide insights into the mechanisms that underpin effective cell-mediated immune responses. The expected outcomes are to generate fundamental new knowledge about immune responses and enhance capacity to study the immune system. This could benefit future development of new vaccines and therapies to improve health.Read moreRead less
Defining the immunological roles of stromal cells within lymphoid tissues. The populations of endothelial and mesenchymal cells that construct the lymphoid tissues are being revealed as key players in the priming and orchestration of immune responses. Yet, fundamental knowledge of the molecular makeup and the functions of these stromal cells, particularly their roles in immune responses, is sorely lacking. This project will utilise a multidisciplinary approach including advanced imaging and bioi ....Defining the immunological roles of stromal cells within lymphoid tissues. The populations of endothelial and mesenchymal cells that construct the lymphoid tissues are being revealed as key players in the priming and orchestration of immune responses. Yet, fundamental knowledge of the molecular makeup and the functions of these stromal cells, particularly their roles in immune responses, is sorely lacking. This project will utilise a multidisciplinary approach including advanced imaging and bioinformatics to dissect the functions of the lymphoid stromal cells and their roles in the swelling of lymphoid tissues during immune responses. This will provide vital information about the biology of these understudied cells and reveal the ways in which they support the generation of immunity.Read moreRead less
Sphingosine-1-phosphate receptor 5: a novel regulator of T cell immunity. T cells provide critical immune protection against infection and cancer. However, the pathways that regulate these immune cells are not fully understood. T cells express a molecule called S1P5 that has an unknown function in these cells. In this proposal, we reveal new evidence that this molecule is an unappreciated and crucial regulator of T cell behaviour. Using state-of-the-art techniques and novel genetic tools, this p ....Sphingosine-1-phosphate receptor 5: a novel regulator of T cell immunity. T cells provide critical immune protection against infection and cancer. However, the pathways that regulate these immune cells are not fully understood. T cells express a molecule called S1P5 that has an unknown function in these cells. In this proposal, we reveal new evidence that this molecule is an unappreciated and crucial regulator of T cell behaviour. Using state-of-the-art techniques and novel genetic tools, this project aims to discover the involvement of S1P5 in the immune response, and determine how S1P5 can be controlled to enhance protective T cell immunity. The expected outcomes are to generate fundamental new knowledge that will have significance for regulation of the immune response. Read moreRead less
Cellular Activation And Apoptosis In Response To Foreign Cytoplasmic DNA
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DN ....Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DNA) is found within the membrane-bound nucleus of the cell. The presence of DNA outside the nucleus in the cytoplasm is abnormal, and is detected as an indication of viral infection. This causes either death of the cell, or activation to produce anti-viral molecules. We have identified a protein from the cytoplasm of cells which binds specifically to DNA. This protein, X is found in association with foreign DNA within 5 minutes of it being introduced into the cell. In this project we propose to confirm that X recognises foreign DNA and initiates cellular activation or death. Other molecules to which X binds during this process will be identified. This project is relevant to a number of problems in health and disease as well as biotechnology. In both gene therapy and biotechnology, DNA is introduced into cells in order to allow those cells to make specific proteins. The cell sees the introduced DNA as a potential viral infection, and it responds in ways which limit the production of the desired proteins. Lupus is an autoimmune disease with high levels of DNA in circulation. X is proposed as a protein involved lupus in mouse models. We suggest that DNA taken up by cells is recognised by X and this contributes to the disease. Understanding the means by which DNA is recognised in the cytoplasm may allow the development of much more efficient processes for gene therapy and protein production in biotechnology, and more effective lupus and antiviral therapies.Read moreRead less
HIV is one of the highest public health priorities of our time. Traditional vaccines have been unsuccessful highlighting the need for alternative approaches to HIV vaccine design. We propose to modify a novel technology developed initially for targeted drug delivery, termed “capsules”, for the purpose of inducing an immune response. This is a generic technology with applications for other infectious diseases and cancer and brings together disparate disciplines of nanochemistry and immunology.
Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contr ....Imaging the generation and recall of protective antiviral immune responses in vivo. Our understanding of the in vivo dynamics of cellular immune responses to infectious diseases is poor. This project will utilise advanced intravital imaging combined with novel tools to dissect the cellular events involved in the generation and recall of T cell responses to localised virus infection, combined with a detailed functional analysis of the lymphoid organ stroma. Such fundamental information will contribute to the development of new generation vaccines and therapies to protect against tissue-specific infectious diseases, cancers and autoimmune diseases.Read moreRead less