Paolo Madeddu discusses the progress of a timely research project.
Q: Why is this research significant?
The coronavirus that causes COVID-19 enters the body through the epithelial-endothelial barrier of the lung and then spreads systemically. Its most severe manifestation is severe acute respiratory syndrome, where the epithelial-endothelial barrier is damaged to a level that fluid escapes into the alveoli. This makes it difficult for the lung to expand and allow the physiological exchanges of gases, resulting in severe hypoxia, shock and systemic organ damage. Organ damage is also caused by the virus’ ability to bring about a systemic inflammatory response and evade the immune system’s defences.
Pericytes – cells surrounding the vasculature – are essential to maintain vascular stability. We think that they can be damaged by the virus, which contributes to pulmonary and systemic damage. We also think that the damage starts very early, when the viral S protein engages with the entry receptors expressed on cells. This is sufficient to activate detrimental signals in the pericytes and eventually prepare the ground for the virus to spread.
Q: What do you aim to do?
Our research aims to determine which receptors are expressed by human cardiac pericytes (ACE2 and also CD147, which is a more controversial receptor); determine if the S protein alone can induce signalling in exposed pericytes in culture; understand the functional consequences; and verify whether we can shield pericytes by blocking the interaction between S protein and receptors.
Q: How are you progressing?
The data we have gathered confirm the entry receptor CD147 is expressed in pericytes. However, the expression of ACE2 receptors was low.
The S protein induces the phosphorylation of ERK1/2. This is a kinase enzyme involved in various cellular functions, but also used by the virus to activate RNA polymerase (the enzyme that makes copies of RNA and is used by the virus to make copies of itself). This reaction makes the pericytes less able to support the vascular network and also induces them to secrete inflammatory molecules typical of the cytokine storm. The instability is more evident in adult cells compared with young cells.
We can inhibit these reactions with an antibody directed to the CD147 receptor, which suggests this is a viable method to shield human pericytes.
Our pre-prints in BioRXiv and the Lancet have received a lot of attention to date.
Q: What’s next?
Because cardiovascular patients are more susceptible to complications from COVID-19, we want to integrate the shielding approach of vascular cells within a more general strategy to protect the human body at the early stages of the disease.
A BHF grant is funding our work for one year. This work is carried out by Dr Elisa Avolio on cardiac pericytes provided by Professor Massimo Caputo, both acting as co-PIs.
As part of Bristol’s collective research effort into COVID-19, we are seeking an additional contribution from other charities and funding agencies to work with fellow Bristol researchers to generate an aerosol containing blockers of entrance and attachment receptors.
This post first appeared in the March 2021 BHI Newsletter