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Molecular model of the SARS-CoV-2 coronavirus spike protein (red) from the B.1.531 variant and its mutation site (yellow), binding to angiotensin converting enzyme 2 receptors (ACE2, blue) on host cell membranes. Credit: Juan Gaertner/SPL/Getty Images.

The ‘spike’ protein is the most studied part of the Sars-CoV-2 virus genome, because it allows the virus to enter into cells via the angiotensin-converting enzyme 2 (ACE2). A team of US and European researchers has now revealed that the spike protein modulates the location of the hormone estrogen inside cells, which could point to additional viral targets and help explain why COVID-19 has many systemic symptoms in addition to those affecting the respiratory tract.

At the height of the pandemic, several private and public teams worked on the Exscalate4CoV European-founded project for re-purposing drugs to mitigate the consequences of the virus in patients. “We found a protective role of raloxifene and other estrogen receptor modulators, and decided to investigate further,” says Marcello Allegretti, Chief Scientific Officer of Dompé Pharmaceutics and one of the senior authors of a study published in Science Advances1. Using supercomputing, scientists in Italy then identified estrogen receptors as alternative binding partners for the spike protein. Meantime, researchers at the National Institutes for Health (NIH) in the US also found that the spike protein binds human estrogen receptors, with an affinity similar to ACE2. “During the pandemic, we tested the spike protein against an array of more than 9,000 human proteins and found a strong signal from the estrogen receptor family,” says Oscar Solis, a researcher at the National Institute on Drug Abuse and first author of the study.

A collaboration between researchers in Italy and the US started and, using a hamster model of infection, demonstrated that the interaction with the spike causes the estrogen receptor to shift from nuclear to cytoplasmatic. “The spike alters the distribution of the receptor, but the exact way depends on the basal hormone receptor activation” explains Allegretti. “ In males, where estrogen is not a main hormone, the spike action deregulates the pathway, while in females, where you have a high-level of basal activation, the effect is mitigated”.

Furthermore, in infected hamsters, the team found a robust spike-estrogen receptor interaction within alveolar macrophages in the lung, that are immune cells acting as a first-line defence against SARS-CoV-2. Finally, they also found that selective modification of the spike sequence abolished the receptor’s binding without compromising its immunogenicity—a critical result to mitigate the rare side effects observed with the currently available vaccines.

The estrogen receptor is expressed throughout the body and involved in several processes, from the functioning of the immune system to mood control. “They used an elegantly unbiased approach showing the interaction between spike and estrogen receptor,” says Abhinav Diwan, a Professor at Washington University who was not involved in the study. "However, there are still many open questions on the role of estrogen in COVID-19 symptomatology." According to Solis, an interesting further development would be to see if there is a physiological link between the spike and activation of depression pathways.