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

Matteo Stravalaci; Isabel Pagani; Elvezia Maria Paraboschi; Mattia Pedotti; Andrea Doni; Francesco Scavello; Sarah N Mapelli; Marina Sironi; Chiara Perucchini; Luca Varani; Milos Matkovic; Andrea Cavalli; Daniela Cesana; Pierangela Gallina; Nicoletta Pedemonte; Valeria Capurro; Nicola Clementi; Nicasio Mancini; Pietro Invernizzi; Rafael Bayarri-Olmos; Peter Garred; Rino Rappuoli; Stefano Duga; Barbara Bottazzi; Mariagrazia Uguccioni; Rosanna Asselta; Elisa Vicenzi; Alberto Mantovani; Cecilia Garlanda

doi:10.1038/s41590-021-01114-w

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. Epub 2022 Jan 31.

Authors

Matteo Stravalaci^#^{1

2}, Isabel Pagani^#³, Elvezia Maria Paraboschi^{1

2}, Mattia Pedotti⁴, Andrea Doni¹, Francesco Scavello¹, Sarah N Mapelli¹, Marina Sironi¹, Chiara Perucchini¹, Luca Varani⁴, Milos Matkovic⁴, Andrea Cavalli^{4

5}, Daniela Cesana⁶, Pierangela Gallina⁶, Nicoletta Pedemonte⁷, Valeria Capurro⁷, Nicola Clementi⁸, Nicasio Mancini⁸, Pietro Invernizzi^{9

10}, Rafael Bayarri-Olmos¹¹, Peter Garred¹¹, Rino Rappuoli^{12

13}, Stefano Duga^{1

2}, Barbara Bottazzi¹, Mariagrazia Uguccioni^{2

4}, Rosanna Asselta^{1

2}, Elisa Vicenzi¹⁴, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
C-Reactive Protein / immunology
C-Reactive Protein / metabolism
COVID-19 / immunology*
COVID-19 / metabolism
COVID-19 / virology
Case-Control Studies
Chlorocebus aethiops
Complement Activation
Coronavirus Nucleocapsid Proteins / genetics
Coronavirus Nucleocapsid Proteins / immunology
Coronavirus Nucleocapsid Proteins / metabolism
Female
Glycosylation
HEK293 Cells
Host-Pathogen Interactions
Humans
Immunity, Humoral*
Male
Mannose-Binding Lectin / genetics
Mannose-Binding Lectin / immunology
Mannose-Binding Lectin / metabolism
Phosphoproteins / genetics
Phosphoproteins / immunology
Phosphoproteins / metabolism
Polymorphism, Genetic
Protein Binding
Receptors, Pattern Recognition / genetics
Receptors, Pattern Recognition / immunology*
Receptors, Pattern Recognition / metabolism
SARS-CoV-2 / genetics
SARS-CoV-2 / immunology*
SARS-CoV-2 / metabolism
SARS-CoV-2 / pathogenicity
Serum Amyloid P-Component / immunology
Serum Amyloid P-Component / metabolism
Signal Transduction
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / immunology
Spike Glycoprotein, Coronavirus / metabolism
Vero Cells

Substances

Coronavirus Nucleocapsid Proteins
MBL2 protein, human
Mannose-Binding Lectin
Phosphoproteins
Receptors, Pattern Recognition
Serum Amyloid P-Component
Spike Glycoprotein, Coronavirus
nucleocapsid phosphoprotein, SARS-CoV-2
spike protein, SARS-CoV-2
PTX3 protein
C-Reactive Protein

Supplementary concepts

SARS-CoV-2 variants

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding