Type I interferon as a novel endogenous trigger of trained immunity

Student research project

Supervisor(s): Dr Andrew Fleetwood and Associate Professor Andrew Murphy

Trained immunity is a form of innate immune memory resulting in a “high-alert” immune state. We will explore whether type I interferon can build immunological memory in vivo and whether this exerts harmful effects in the setting of chronic inflammation, such as atherosclerosis.

Project summary

Immune memory is a defining feature of the adaptive immune system, but activation of the innate immune system can also result in heightened responses to re-challenge. This adaptation has been termed “trained immunity”, a de facto form of innate immune memory. Studies over the past few years have pointed to the broad benefits of trained immunity for host defence but have also suggested detrimental outcomes in chronic inflammatory disease, such as atherosclerosis.

By inducing metabolic and epigenetic changes in hematopoietic stem cells (HSCs), trained immunity drives myeloid cell expansion and the sustained generation of monocytes with a “proinflammatory” phenotype.

We have identified type I interferon as a novel endogenous signal of trained immunity in vitro. This proposal will extend these studies and explore whether type I interferon drives trained immunity in vivo, and whether this effect promotes detrimental outcomes in chronic inflammatory conditions, such as cardiovascular disease. This project aims to identify, characterise and manipulate the metabolic, epigenetic and transcriptional pathways responsible for type I interferon training in myeloid cells and their precursors. Furthermore, this project aims to determine whether type I interferon training exerts helpful or harmful effects in different disease settings. Identifying and characterising a new endogenous trigger of trained immunity will greatly strengthen our capacity to develop novel strategies to target this complex immune phenomenon.

This project will acquire the use of a wide-range of skills in animal models, cell biology and molecular biology including primary human and mouse macrophage culture, ELISA assays, metabolic readouts, enzymatic assays, flow cytometry, Western blotting and real‐time PCR.

It is suitable for a PhD or Honours student.

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