Dectin-1 and immune response to fungi
Dectin-1 is an NK-like C-type lectin-like receptor specific for beta-(1,3)-glucans.We have shown that it is primarily expressed by myeloid cells, such as neutrophils, monocytes, macrophages and dendritic cells where it functions as a major receptor for both soluble and particulate beta-(1,3)-glucans. We have continued to demonstrate that the receptor is non-redundant in vivo in fungal host defence, but it is part of an extensive network of pattern recognition receptors involved concurrently in the recognition of fungi with distinct and overlapping functions.
Its expression and function is regulated by the cellular activation state and the inflammatory or steady-state tissue environment and by the ability of the phagocyte to complete the engulfment of the pathogen once recognised.
We aim to continue to understand how dectin-1 regulates cellular activation and controls inflammatory responses as a model of an emerging family Syk-activating pattern recognition receptors.
Dectin-2 and immune response to fungi
We have demonstrated that dectin-2 is a C-type lectin receptor specific for carbohydrates with a ‘complex mannose-like’ structure and as such is capable of recognising carbohydrates on pathogens such as fungi and mycobacterium.
We generated specific monoclonal antibodies against dectin-2, which have shown that it is primarily expressed by macrophages and dendritic cells.
The use of these monoclonal antibodies as blocking agents has indicated that dectin-2 plays important roles alongside dectin-1 in the regulation of immune responses during fungal infections.
We aim to further elucidate the role of dectin-2 in cellular activation, host defence and immunity.
Conditional immortalisation of myeloid-precursors to model innate immunity
As part of our commitment to the replacement, refinement and reduction of animal use in experimental research we have been developing published protocols for the study of innate immune responses by neutrophils and macrophages, by conditional-immortalisation of the their precursors.
The ease with which these cells can be developed and genetically-modified has already impacted on the use of animals in research and is providing a cornerstone onto which new experimental models are being built to address the roles of select pathogen recognition systems in cellular activation events.
Macrophage biology in homeostasis and disease
We have a general interest in the biology of macrophages during homeostasis and disease and are using novel approaches to identify key pathways and processes that can be manipulated to alter macrophage biology in the living organism for possible therapeutic benefit.
Recently, we have shown that tissue resident macrophages in vascular tissues are capable of self-renewal by local proliferation. By applying specific measures of mitosis, we have monitored tissue macrophage proliferation during newborn development, adulthood and acute resolving inflammation in young adults.
Despite the vascular nature of the tissue and ease of peripheral leukocyte entry, tissue macrophages in the newborn increase in number by local proliferation. On the contrary, in the adult, tissue macrophage proliferation is considerably reduced and most likely provides homeostatic control of cell numbers.
Importantly, during an acute inflammatory response, when substantial numbers of inflammatory macrophages are recruited from the circulation, tissue-resident macrophages survive and then undergo a transient and intense proliferative burst in situ to repopulate the tissue.
Our data indicate that local proliferation is a general mechanism for the self sufficient renewal of tissue macrophages during development and acute inflammation and not one restricted to non-vascular tissues, which has implications for the therapeutic modulation of macrophage activity during the resolution of inflammation.
Collaborative and Redundant Roles of CLRs in Anti-Fungal Immunity
Myeloid cells such as macrophages, dendritic cells and neutrophils use cell surface receptors to recognize invading fungal pathogens. Various C-type lectin-like receptors including Dectin-1, Dectin-2, Mincle, Mannose receptor and DC-SIGN are involved in the recognition of various fungal cell-wall components such as beta-glucans and mannans.
These receptors concurrently induce an inflammatory response upon recognition of fungal pathogens. Therefore, anti-fungal immune responses are complex, involving a highly co-ordinated response from multiple receptors.
I aim to determine how these receptors function individually and how they work together/collaborate to induce the co-ordinated anti-fungal immune response. To achieve this aim, I will generate novel models to fully dissect the role of these receptors during anti-fungal responses.