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

Stravalaci, M.; Pagani, I.; Paraboschi, E. M.; Pedotti, M.; Doni, A.; Scavello, F.; Mapelli, S. N.; Sironi, M.; Varani, L.; Matkovic, M.; Cavalli, A.; Cesana, D.; Gallina, P.; Pedemonte, N.; Capurro, V.; Clementi, N.; Mancini, N.; Invernizzi, P.; Rappuoli, R.; Duga, S.; Bottazzi, B.; Uguccioni, M.; Asselta, R.; Vicenzi, E.; Mantovani, A.; Garlanda, C.

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in COVID-19. The present study was designed to conduct a systematic investigation of the interaction of humoral fluid phase pattern recognition molecules (PRM) with SARS-CoV-2. Out of 10 PRM tested, the long pentraxin PTX3 and Mannose Binding Lectin (MBL) bound the viral Nucleoprotein and Spike, respectively. MBL bound trimeric Spike, including that of variants of concern, in a glycan-dependent way and inhibited SARS-CoV-2 in three in vitro models. Moreover, upon binding to Spike, MBL activated the lectin pathway of complement activation. Genetic polymorphisms at the MBL locus were associated with disease severity. These results suggest that selected humoral fluid phase PRM can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.