Periodic Reporting for period 1 - iRhomADAM (Uncovering the role of the iRhom2-ADAM17 interaction in inflammatory signalling)
Reporting period: 2020-09-01 to 2022-08-31
This project aims to shed light on some of the action plans that cells use once they detect that they were infected with a virus. More specifically, in this project I am studying the role of a protein called iRhom2 in the cells' response to viruses. iRhom2 is an elusive protein that normally resides in membranes that encapsulate our cells or in membranes that are found inside the cells. Not much is known about its function, but previous work from our group and from other groups shows that iRhom2 is involved in cancer and in inflammation. My aim was to expand the knowledge on iRhom2 to the distinct immune action plan called "the antiviral response". So far my work is showing that while iRhom2 is important in inflammation, when it comes to antiviral activity, iRhom2 actually tunes that action plan down. I am currently still working on understanding exactly what iRhom2 does in this cellular program, with a special emphasis on what are the features that allow it to promote inflammation while suppressing antiviral activity. If iRhom2 is chosen as a drug target for chronic inflammation (inflammation that is not restricted in time and in place), it is essential to understand its full role in immunity, in order to make sure that the future drug has no serious side effects.
My approach to understanding how iRhom2 is operating in the cells was to use existing knowledge on the cell's response to viral infection to design experiments, without preexisting assumptions on what iRhom2 might be doing in this context. My results demonstrate that iRhom2 is acting before the massive production of the key protein interferon-beta, suggesting that iRhom2 could be involved in regulating its production. Additionally, I also saw that while the overall outcomes of inflammation and of antiviral activity happen simultaneously, iRhom2 is regulating each one of them in a different mechanism of action. I am currently working on pinpointing the exact role of iRhom2 in antiviral immunity. Specifically, what other proteins it interacts with and under what conditions.
In order to understand the wider immune context of iRhom2, I used a type of immune cells called macrophages, which were generated from mouse bone marrow by my colleagues in the lab. These cells were treated with the same treatment that simulates viral infection, and then their total RNA was isolated and sequenced, in order to characterise the differences between cells with iRhom2 and cells without it. So far, these cells exhibit significant changes in their overall immune activity, as well as their energy production. These results need to be validated in additional cell lines, and then combined with the mechanistic knowledge, to shed light about the global role of iRhom2 in this pathway.
iRhom2 was suggested as a drug target for conditions of chronic inflammation. Understanding the full role of iRhom2 in the immune response will shed light on its true potential as a drug target, since it will provide essential information in order to predict side effects of that treatment. Having this knowledge will help us make educated decisions on how viable it actually is as a drug target, and secondly, we may be able to develop very specific treatments that will affect some functions and not others. This knowledge could save time and money on trials that are bound to fail due to significant side effects. This is particularly important when considering steps of pre-clinical experiments on animals: With better knowledge, some these experiments may turn out to be unnecessary and could be spared.