Dr. Conor Finlay

Summary

Helminth infection is characterised by a type 2 immune response with polarisation of macrophages toward an M(IL-4) phenotype. It is increasingly recognised that macrophage functionality relies not only on direct cytokine signals but cellular origin and tissue environment. This programme is built around the pleural cavity, a tissue containing two predominant macrophage populations: monocyte-derived small cavity macrophages (SCMac) and large cavity macrophages (LCMac) which have a 'residency' gene expression module, conferred by the tissue niche. We will use the filarial nematode Litmosoides sigmodontis (Lito) as a model of pleural infection and as a tool to study M(IL-4) cells more generally. Mirroring divergent outcomes in human filariasis, susceptibility to Lito infection is dependent on host genotype, with striking differences in M(IL-4) cells between resistant and susceptible strains of mice. In resistant C57BL/6 mice LCMac expand greatly through proliferation and become M(IL-4) polarised. In susceptible BALB/c mice there are relatively more SCMac like cells which appear incapable of acquiring a full LCMac-residency or M(IL-4) programme. Aim 1 seeks to explain if strain differences are a result of intrinsic differences in macrophage programming, alterations of the tissue niche or due to differences in Th2 cell activity. The next 2 aims focus on resistant C57BL/6 mice as a model of type 2 immunity culminating in worm killing. Aim 2 looks upstream of macrophages to identify the cell-cell interactions in the pleural cavity and essential co-factors that drive M(IL-4) polarisation and proliferation. Aim 3 will look downstream of M(IL-4) cells to assess their contribution to worm killing and tissue integrity in the pleural cavity using mice which lack specific residency, M(IL-4) or proliferation gene modules. This programme will advance our knowledge of the activation and function of M(IL-4) cells and provide novel information on the function of the pleural space.

Funding Agency

Medical Research Council

Programme

Programme Grant

Summary

ANCA Vasculitis is a potentially lethal autoimmune disease, whereby the immune system is triggered to self-destruct - the systems normally primed to fight infection and cancer cells are incorrectly activated, resulting in damage to the blood vessels and eventually organ destruction, such as kidney failure. Auto-antibodies (proteins against oneself) bind to immune cells (neutrophils and monocytes) in the blood, improperly activating these cells and driving the development of ANCA vasculitis. The exact cause of ANCA vasculitis has yet to be discovered. Evidence suggests there is a complex interaction between a person's genetic make-up and unknown triggers in their environment. Silica dust, a common occupational hazard for construction workers amongst others, is the leading proposed environmental toxin. However, how exposure to silica influences the development of ANCA-vasculitis is unknown. We will address this by exploring the effects of silica on the same auto antibody-activated immune cells, which underpin ANCA vasculitis. These experiments will help explain the early events in ANCA vasculitis and may help to identify new treatments for this disease.

Funding Agency

TTMI - internal

Programme

Building Engagements in Health Research

Summary

Work package 2 'Immune responses and disease pathogenesis in COVID-19 patients

Funding Agency

SFI

Summary

Funding Agency

TTMI - Internal

Programme

Building Engagements in Health Research Scheme

Summary

Funding Agency

Trinity College Dublin

Programme

Dean"s Research Initiatives Fund