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

Nat Immunol. 2022 Feb;23(2):275-286. doi: 10.1038/s41590-021-01114-w.

Matteo Stravalaci ^# ¹ ², Isabel Pagani ^# ³, Elvezia Maria Paraboschi ¹ ², Mattia Pedotti ⁴, Andrea Doni ¹, Francesco Scavello ¹, Sarah N Mapelli ¹, Marina Sironi ¹, Chiara Perucchini ¹, Luca Varani ⁴, Milos Matkovic ⁴, Andrea Cavalli ⁴ ⁵, Daniela Cesana ⁶, Pierangela Gallina ⁶, Nicoletta Pedemonte ⁷, Valeria Capurro ⁷, Nicola Clementi ⁸, Nicasio Mancini ⁸, Pietro Invernizzi ⁹ ¹⁰, Rafael Bayarri-Olmos ¹¹, Peter Garred ¹¹, Rino Rappuoli ¹² ¹³, Stefano Duga ¹ ², Barbara Bottazzi ¹, Mariagrazia Uguccioni ² ⁴, Rosanna Asselta ¹ ², Elisa Vicenzi ¹⁴, Alberto Mantovani ¹⁵ ¹⁶ ¹⁷, Cecilia Garlanda ¹⁸ ¹⁹

Affiliations

1 IRCCS Humanitas Research Hospital, Milan, Italy.
2 Department of Biomedical Sciences, Humanitas University, 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 Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy.
8 Laboratory of Microbiology and Virology, IRCCS Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.
9 Division of 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, København, Denmark.
12 Monoclonal Antibody Discovery Lab, Fondazione Toscana Life Sciences, Siena, Italy.
13 Faculty of Medicine, Imperial College London, London, UK.
14 Viral Pathogenesis and Biosafety Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. [email protected].
15 IRCCS Humanitas Research Hospital, Milan, Italy. [email protected].
16 Department of Biomedical Sciences, Humanitas University, Milan, Italy. [email protected].
17 The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK. [email protected].
18 IRCCS Humanitas Research Hospital, Milan, Italy. [email protected].
19 Department of Biomedical Sciences, Humanitas University, Milan, Italy. [email protected].
# Contributed equally.

PMID: 35102342 DOI: 10.1038/s41590-021-01114-w

Abstract

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.

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