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Double-edged sword

As a DPhil student based at the Weatherall Institute of Molecular Medicine, I am working on the factors that regulate the expression level of angiotensin II converting enzyme type 2 (ACE2), which is the main viral entry receptor for SARS-CoV-2. Normally, ACE2 breaks down Angiotensin II to drive widening of blood vessels in order to lower blood pressure. However, SARS-CoV-2 can hijack ACE2 and use it to gain entry into host cells. ACE2 levels can be altered in people due to certain diseases such as Type 1 Diabetes or hypertension. It has been shown that ACE2 protects against lung damage that can be caused by increased Angiotensin II levels. During COVID-19 infection, ACE2 acts as a double-edged sword: high levels of ACE2 will lead to massive viral entry, but low levels will lead to lung damage.

We want to understand whether the levels of ACE2 expression change across the course of infection and work out which factors affect this expression level. Considering the clinical features of COVID-19 patients and previous studies on ACE2 regulation, we have decided to focus on four possible regulatory factors of ACE2 – cytokines/chemokines (soluble factors that alter immune responses), hypoxia (low oxygen), SARS-CoV-2 virus itself and Angiotensin II. By measuring ACE2 levels in cells following the addition of each factor, we have identified that both cytokine levels and hypoxia can alter ACE2 expression. This is related to the cytokine storm (massive increase in a collection of cytokines) and hypoxia seen in many critically ill COVID-19 patients.

We aim to reveal the link between ACE2 levels and COVID-19 disease severity by understanding how ACE2 changes during infection. Our goal is to identify the people who are most vulnerable to severe infection due to altered ACE2 expression and to provide useful information for the development of treatments that alter ACE2 levels in patients.

Zixi (Tracy) Yin (2018, DPhil Medical Sciences)

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