A model of the interaction between the Spike protein of the Omicron variant and MBL (in blue). The mutations in Omicron (in red) are not present on the sites of interaction with MBL, which suggests that the antiviral properties of MBL are conserved for this variant. Credit: Ospedale San Raffaele.
When it comes to the immune response to SARS-CoV-2 it’s antibodies that get most of the attention. But when the virus enters the body, it’s another mechanism, called innate immunity, that springs into action first, and fights the early stage of infection before antibodies are developed. An international team led by Italian scientists has found out how, possibly informing a path to a new class of drugs.
Antibodies are sophisticated tools that bind to specific molecular targets. It takes time for the immune system to produce them after first encountering a pathogen or a vaccine. Innate immunity, the first line of defence, is a cruder but faster mechanism that takes action before antibodies, and later complements them. Among its weapons are pattern recognition molecules, including blood plasma proteins that work like sensors. They recognize microbial components, such as carbohydrates on viral envelopes, or distress chemical signals sent by cells under attack, and trigger inflammation to fight the threat.
Scientists from IRCCS Humanitas Research Hospital, and San Raffaele Scientific Institute in Milan tested 12 pattern-recognition molecules from the innate immunity system against SARS-CoV-2. They found one, mannose-binding-lectine (MBL), that interacts with the spike proteins of every known variant of the virus, and activates a cascade of chemical reactions that can stop SARS-CoV-2 from entering cells1.
The researchers then studied how the gene coding for MBL varies in the general population and in infected people. “We found that some genetic variants, that cause a lower concentration of the molecule in blood plasma, correlate with a greater severity of symptoms”, says Elisa Vicenzi, head of the Viral Pathogenesis and Biosafety Unit at San Raffaele Hospital, one of the authors of the study. “It could mean that people with those variants have a greater risk of severe disease, but as for now we have only found correlation, not causation,” she says.
The study projects the possibility of using the gene encoding for MBL as a marker to identify patients who are more at risk. “After the publication, we received a number of emails from people asking us to analyse their DNA to ascertain if they have a sort of natural shield against SARS-CoV-2 and can avoid vaccination”, says Vicenzi. “Let’s be clear, we haven’t identified any variant that grants protection against SARS-CoV-2”. Innate immunity anticipates and cooperates with antibodies and T lymphocytes, she explains, but does not substitute them, so the best way to be protected from severe COVID-19 is to get vaccinated.
Scientists have considered a therapeutic role for MBL too. “It has strong antiviral activity and it binds to any known SARS-CoV-2 variant, even Omicron,” says Alberto Mantovani, the Scientific Director at Humanitas Research Hospital, one of the paper’s authors. “It would be a precious addition to our armoury of vaccines and drugs”.
Vicenzi says that such a treatment could be administered as a throat spray in the first stages of infection, when the virus is replicating in the upper respiratory tract and before it reaches the lungs.
Clinical trials have not started yet, but the use of MBL as a drug is not entirely new. It has been safely infused to patients with cystic fibrosis and chronic lung infections2 to strengthen their innate immunity as it binds to a number of microbes. “We are just beginning to explore the idea of a new class of medications developed from pattern recognition molecules”, Vicenzi concludes.
