Evolutionary Events Shaping The Genome Of Cryptococcus Neoformans And Their Effects On Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Recurring infection in patients with fungal meningitis caused by Cryptococcus neoformans is typically caused by persistence of the original infection rather than reinfection with a new strain. Our analysis of relapse strains shows that small-scale alterations frequently occur at the chromosome ends - regions containing important pathogenesis-related genes in other pathogens. We seek to characterise this microevolution further to understand how it contributes to the success of this pathogen.
Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SF ....Understanding T cell trafficking and function during antigenic interference. Science generally studies antigenic stimulation in isolation, by measuring immunity towards antigens derived from a single pathogen. However, as mammals can harbour more than one infection at any given time, we established a model of antigenic interference using different antigens derived from two unrelated pathogens, influenza A (IAV) and Semliki Forest virus (SFV). Our data show that prior exposure to either IAV or SFV greatly perturbs T cell dynamics. This proposal will study, at cellular and molecular levels, T cell trafficking, function and clonal distribution during antigenic interference, thus advance fundamental knowledge on T cell immunity during antigenic competition, and provide a new paradigm on how we research T cell immunity.Read moreRead less
Redefining the immune landscape of the human ocular surface. At the ocular surface, the cornea and limbus need to mount effective immune responses to maintain corneal transparency for clear vision. The current paradigm is that the human cornea houses the same innate immune cell subsets (dendritic cells and macrophages) as naïve mice in pathogen-free facilities. Our pilot data challenge this premise, with early evidence that innate and adaptive cells (T cells) coexist in normal human corneas. Int ....Redefining the immune landscape of the human ocular surface. At the ocular surface, the cornea and limbus need to mount effective immune responses to maintain corneal transparency for clear vision. The current paradigm is that the human cornea houses the same innate immune cell subsets (dendritic cells and macrophages) as naïve mice in pathogen-free facilities. Our pilot data challenge this premise, with early evidence that innate and adaptive cells (T cells) coexist in normal human corneas. Integrating state-of-the-art techniques, we will advance understanding of immune regulation at the human ocular surface by comprehensively defining immune cell biology and dynamics. We will define the effect of age on immune cells in these tissues, and relationships between the tear proteome and cell behaviours.Read moreRead less
Defining the microenvironmental regulators of spleen function and immunity. The spleen is an important organ that is present in almost all vertebrates and is a critical site for the induction of systemic immune responses. The current paradigms of spleen biology are mostly derived from rodent studies, but the cellular biology of the spleen in humans remains poorly defined. Using novel tools, advanced transcriptomics and imaging techniques this project aims to reveal the functions of stromal cells ....Defining the microenvironmental regulators of spleen function and immunity. The spleen is an important organ that is present in almost all vertebrates and is a critical site for the induction of systemic immune responses. The current paradigms of spleen biology are mostly derived from rodent studies, but the cellular biology of the spleen in humans remains poorly defined. Using novel tools, advanced transcriptomics and imaging techniques this project aims to reveal the functions of stromal cells in the spleen in humans and to define the fundamental roles of spleen stromal cells in long-lived immunity. The anticipated outcomes are to build Australia’s research capacity and to generate new knowledge of significance for our fundamental understanding of the spleen and the role of this tissue in the immune system.Read moreRead less
The molecular basis of T cell receptor cross-reactivity between MHC and MR1. This project aims to investigate how newly discovered immune cells, known as 'MR1T' cells, function in the body. Preliminary evidence shows that MR1T cells can kill stressed cells. This project expects to generate new knowledge describing precisely how MR1T cells target and kill stressed cells. Expected outcomes of this project include to refine research techniques and models, foster interinstitutional collaborations, a ....The molecular basis of T cell receptor cross-reactivity between MHC and MR1. This project aims to investigate how newly discovered immune cells, known as 'MR1T' cells, function in the body. Preliminary evidence shows that MR1T cells can kill stressed cells. This project expects to generate new knowledge describing precisely how MR1T cells target and kill stressed cells. Expected outcomes of this project include to refine research techniques and models, foster interinstitutional collaborations, and further develop our theory on MR1T cell function. This project should provide significant benefits, such as publication of research articles in high impact journals and generation of experimental tools sought after by researchers in the field.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE240100827
Funder
Australian Research Council
Funding Amount
$458,737.00
Summary
Delineating the developmental requirements for stem-like T cells. Stem-like CD8 T cells are critical for sustaining long-term systemic T cell activity. The signalling required for their development, however, remains elusive. Integrating multidisciplinary expertise, cutting-edge technology and highly innovative methods, this project aims to define the signalling cues provided by tissue microenvironment that control the development and maintenance of stem-like T cells, and thereby dictate systemic ....Delineating the developmental requirements for stem-like T cells. Stem-like CD8 T cells are critical for sustaining long-term systemic T cell activity. The signalling required for their development, however, remains elusive. Integrating multidisciplinary expertise, cutting-edge technology and highly innovative methods, this project aims to define the signalling cues provided by tissue microenvironment that control the development and maintenance of stem-like T cells, and thereby dictate systemic immunity. This project is expected to generate fundamental knowledge on basic immunology and T cell biology, which can benefit the academic, public health and biotechnology sectors by enhancing the international standing of Australian research on basic immunology and fostering new commercial opportunities. Read moreRead less
Deciphering the immune complexity that orchestrates T cell activation. The adaptive immune system consists of a complex cellular network that can efficiently distinguish exogenous required inputs, such as nutrients, from those that are potentially harmful like pathogens. Such ‘friend-foe’ discrimination has its molecular basis in a multitude of receptors with specificity to certain ligands. Critically, however, it is unclear how such discrimination is mechanistically regulated at the functional ....Deciphering the immune complexity that orchestrates T cell activation. The adaptive immune system consists of a complex cellular network that can efficiently distinguish exogenous required inputs, such as nutrients, from those that are potentially harmful like pathogens. Such ‘friend-foe’ discrimination has its molecular basis in a multitude of receptors with specificity to certain ligands. Critically, however, it is unclear how such discrimination is mechanistically regulated at the functional level. We have developed new and sophisticated experimental models that will allow us to systematically dissect and unfold the complexity of the adaptive immune system and address this critical knowledge gap. Expected outcomes will critically advance our general understanding of a fundamental biological principle.Read moreRead less
Regulation of lung immune-epithelial networks sensing environmental change. This study aims to uncover how lung epithelial cells engage with immune cells and determine their cellular and molecular wiring to ensure homeostatic maintenance and essential repair processes of lung tissues. Maintenance of lung epithelial-immune networks is essential to maintain normal lung tissue structure and function, and to induce immune responses to protect against microbial challenges or inhaled potentially toxic ....Regulation of lung immune-epithelial networks sensing environmental change. This study aims to uncover how lung epithelial cells engage with immune cells and determine their cellular and molecular wiring to ensure homeostatic maintenance and essential repair processes of lung tissues. Maintenance of lung epithelial-immune networks is essential to maintain normal lung tissue structure and function, and to induce immune responses to protect against microbial challenges or inhaled potentially toxic substances. Understanding this molecular program of epithelial-immune cell-mediated sensing/repair will be essential to understand how tissue-repair processes can be driven in the lung, an organ critical for respiration and thus life.Read moreRead less
How do unconventional T cells die? Mammalian cells die via several different mechanisms, each of which is tightly controlled at a molecular level. The choice of death pathway depends on the trigger and cell type. This project will investigate the mechanisms controlling death of T cells, including conventional T cells, and unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in normal conditions and during inflammation. It combines methods we developed to study MAIT cells ....How do unconventional T cells die? Mammalian cells die via several different mechanisms, each of which is tightly controlled at a molecular level. The choice of death pathway depends on the trigger and cell type. This project will investigate the mechanisms controlling death of T cells, including conventional T cells, and unconventional T cells, such as mucosal-associated invariant T (MAIT) cells, in normal conditions and during inflammation. It combines methods we developed to study MAIT cells in vivo with expertise in cell death analysis. This project is expected to elucidate the complex mechanisms controlling T cell survival/death and increase our fundamental understanding of cell death mechanisms of activated T cells.Read moreRead less
Defining novel immune checkpoints controlled by stromal cells. This project seeks to use innovative approaches to elucidate the mechanisms that define the earliest steps required to generate immune responses. The proposal builds on discoveries, including novel preliminary data, from a team with world-leading expertise in immunology, virology and stromal cell biology. The expected findings will provide fundamental insights into novel cellular and molecular interactions between stromal tissue comp ....Defining novel immune checkpoints controlled by stromal cells. This project seeks to use innovative approaches to elucidate the mechanisms that define the earliest steps required to generate immune responses. The proposal builds on discoveries, including novel preliminary data, from a team with world-leading expertise in immunology, virology and stromal cell biology. The expected findings will provide fundamental insights into novel cellular and molecular interactions between stromal tissue components and immune cells that initiate and regulate immune responses. Expected benefits include fundamental advances in knowledge, as well as insights that will ultimately benefit biotechnology and therapeutic applications, and in this way support research priorities linked to advanced manufacturing and health.
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