Monocytes are the largest white blood cells, and they engulf and digest bacteria and cell debris. The activation of their RAGE receptor is correlated with a worse COVID-19 prognosis. Credit: Kateryna Kon/SPL/Getty Images.
Scientists have known for more than three years that the main entry point for the SARS-CoV-2 virus into the body is the ACE2 receptor. A team in Italy has now identified another receptor, called RAGE, present on the surface of certain human immune cells, which can bind to SARS-CoV-2 and allow it to enter cells, altering their function and leading to a worse prognosis.
The research1 is a collaboration between Antonella Viola’s group at the Department of Biomedical Sciences of the University of Padua, researchers from the Human Technopole group coordinated by Giuseppe Testa, the European Institute of Oncology and the University of Milan.
"Since the beginning of the pandemic, we have been studying the coronavirus using single-cell multiomics, which means mapping the genes of immune cells, cell by cell, to understand how the virus works,” explains Giuseppe Testa, corresponding author of the study at the University of Milan, and head of neurogenomics at Human Technopole.
The approach was applied to a cohort of COVID-19 patients admitted in the early stages of the pandemic and followed by Anna Maria Cattelan's team in Padua. It was a longitudinal study: the same patients were mapped at three stages of the disease: on admission, at discharge and one month after discharge. At each of these three stages, a 'snapshot' of the gene expression in the individual cells of these patients was obtained, resulting in the expression of all 20,000 genes of each cell studied.
A molecular pathway emerged that had not been associated before to viral infection: the activation of the RAGE receptor in monocytes, a type of white blood cells, was correlated with a worse COVID-19 prognosis. “RAGE activation in monocytes was already known to correlate with more severe inflammatory outcomes, diabetes and obesity, but had never been observed in the context of viral infection. This finding is also interesting because monocytes do not possess the other receptor, ACE2, which is the main gateway for SARS-CoV-2 to enter the body," explains Testa.
This result, obtained in the Padova cohort, was then validated on 13 large datasets from around the world. "The next step is to understand if there are molecules capable of counteracting the engagement of the RAGE receptor and pathway by SARS-CoV-2," concludes Testa. For the moment, by comparing the molecular responses detected during the study with those found in global databases of pharmacological compounds’ activities on human cells, the authors predicted that the drug Baricitinib, an immunosuppressant already approved in 2021 for the treatment of Covid-19, could potentially reverse the harmful effects of RAGE.
