Covid-19: discovered a new mechanism of immune resistance

It is in the innate immunity a new mechanism of resistance to Covid-19 and its variants, including Omicron. The international study coordinated by Humanitas Research Hospital and IRCCS San Raffaele Hospital, published in Nature Immunology, deepens the knowledge of the first line of defence of the body, in particular the “ancestors of antibodies”, and the ability to interact with the virus.

Even innate immunity, the first line of defense that plays a key role in pathogen resistance, plays its part against Sars-CoV-2 and its variants, including Omicron. This is the discovery published in Nature Immunology by Matteo Stravalaci, researcher at Humanitas, and Isabel Pagani, researcher at IRCCS San Raffaele Hospital, and by a team of scientists coordinated by Alberto Mantovani    scientific director of Humanitas and emeritus professor of Humanitas University, Cecilia Garlanda    researcher and professor at Humanitas University, and Elisa Vicenzi, head of the Research Unit in Viral Pathogenesis and Biosecurity at IRCCS San Raffaele Hospital.

The study also involved Fondazione Toscana Life Science with Rino Rappuoli, the Institute for Research in Biomedicine of Bellinzona and Queen Mary University of London in an international effort to investigate the molecules present in blood and biological fluids and that function as “ancestors of antibodies” (the so-called Ante-antibodies).

Innate immunity, the first line of defence of our organism, solves 90% of the problems caused by contact with bacteria and viruses. It precedes and accompanies adaptive immunity, the more specific line of defence, of antibodies and T cells, which can be boosted with vaccines. Starting from March 2020, thanks to the support of Dolce&Gabbana, the team of researchers at Humanitas has focused on the study of the interaction between Covid and innate immunity, an area of strong competence of the working group of Prof. Mantovani and Prof. Garlanda.

“Years ago, we identified some genes that are part of a family of antibody ancestors. Focusing on the interaction between these and Sars-CoV-2, we discovered that one of these molecules of innate immunity, called Mannose Binding Lectin (MBL), binds to the Spike protein of the virus and blocks it – explains Prof. Alberto Mantovani -. At the appearance of Omicron, Sarah Mapelli, bio-informatics researcher at Humanitas, has immediately extended the analysis on the structure of the protein in collaboration with the group of Bellinzona, discovering that MBL is able to see and recognize Omicron, in addition to the classic variants of the virus such as Delta”.

The study then continued with the genetic analysis of data from patients in the hospital, cross-referenced with those from databases around the world, conducted by Prof. Rosanna Asselta of Humanitas University. “It turned out that genetic variations of MBL are associated with severity of Covid-19 disease – deepens Prof. Cecilia Garlanda -. Now it will be a matter of assessing whether this molecule can serve as a biomarker to guide physicians’ choices in the face of such diverse and changing manifestations of the disease.”

The researchers are also evaluating whether MBL can be a candidate preventive/therapeutic agent since it is a molecule functionally similar to an antibody, which virus variants, at least the known ones, cannot escape. “In our evaluation of potential drugs anti-SARS- CoV-2 – explains Dr. Elisa Vicenzi of IRCCS San Raffaele Hospital – MBL demonstrates important antiviral activity that could be an additional weapon against circulating variants, including Omicron”.

At the moment there are no data on the interaction between this protective mechanism of the first line of defence and the immune response induced by vaccines. “To date, we know that this mechanism of innate resistance ‘sees’ Omicron too – continues Prof. Alberto Mantovani – and therefore probably contributes to the fact that, although this variant is recognized in a minor form by antibodies, the first line of defence holds. This does not change what we already know thanks to the data: vaccines give significant and fundamental protection and remain our safety belt”.

Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules – Nature Immunology

Matteo Stravalaci1,2,§, Isabel Pagani3,§, Elvezia Maria Paraboschi1,2, Mattia Pedotti4 , Andrea Doni1, Francesco Scavello1, Sarah N. Mapelli1, Marina Sironi1, Chiara Perucchini1, Luca Varani4, Milos Matkovic4, Andrea Cavalli4,5, Daniela Cesana6, Pierangela Gallina6 , Nicoletta Pedemonte7, Valeria Capurro7, Nicola Clementi8, Nicasio Mancini8, Pietro Invernizzi9,10, Rafael Bayarri-Olmos11, Peter Garred11, Rino Rappuoli12,13, Stefano Duga1,2, Barbara Bottazzi1, Mariagrazia Uguccioni4,2, Rosanna Asselta1,2, Elisa Vicenzi3,* Alberto Mantovani,1,2,14,*, Cecilia Garlanda1,2,*

1. IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano (Milan), Italy;
2. Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele (Milan), Italy;
3. Viral Pathogenesis and Biosafety Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
4. Institute for Research in Biomedicine, Università della Svizzera italiana (USI), Bellinzona, Switzerland.
5. Swiss Institute of Bioinformatics, Lausanne, Switzerland
6. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget); IRCCS, San Raffaele Scientific Institute, Milan, Italy.
7. UOC Medical Genetics, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147 Genova, Italy.
8. Laboratory of Microbiology and Virology, IRCCS Scientific Institute and Vita-Salute San Raffaele University, Milan Italy.
9. Division of 25 Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
10. European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
11. Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Copenhagen University Hospital, Denmark.
12. Monoclonal Antibody Discovery Lab, Fondazione Toscana Life Sciences, Siena, Italy.
13. Faculty of Medicine, Imperial College London, London, UK.
14. The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London

§ equally contributed
* corresponding