Novel ACE2-Independent Carbohydrate-Binding of SARS-CoV-2 Spike Protein to Host Lectins and Lung Microbiota

Abstract

The immediate call for translational research in the field of coronavirus disease (COVID-19) pandemic, needs new and unexplored angles to support and contribute to this important worldwide health problem. The aim of this study is to better understand the pathogenic mechanisms underlying COVID-19, deciphering the carbohydrate-mediated interactions of the SARS-CoV-2 spike protein. We studied the carbohydrate-binding receptors that could be important for viral entry and for immune-modulatory responses, and we studied the interactions of the spike protein with the host lung microbiota. Exploring solid-phase immunoassays, we evaluated the interactions between the SARS-CoV-2 spike protein and a library of 12 different human carbohydrate-binding proteins (C-type lectins and Siglecs) involved in binding, triggering and modulation of innate and adaptive immune-responses. We revealed a specific binding of the SARS-CoV-2 spike protein to the receptors DC-SIGN, MGL, Siglec-9 and Siglec-10 that are all expressed on myeloid immune cells. In addition, because the lung microbiota can promote or modulate viral infection, we studied the interactions between the SARS-CoV-2 spike protein and a library of Streptococcus pneumoniae capsular polysaccharides, as well as other bacterial glyco-conjugates. We show specific binding of the spike protein to different S. pneumoniae capsular polysaccharides (serotypes 19F and 23F but not to serotype 14). Moreover we demonstrated a specific binding of SARS-CoV-2 spike protein to the lipopolysaccharide from the opportunistic human pathogen Pseudomonas aeruginosa, one of the leading cause of acute nosocomial infections and pneumonia. Interestingly, we identified rhamnosylated epitopes as one of the discriminating structures in lung microbiota to bind SARS-CoV-2 spike protein. In conclusion, we revealed novel ACE2-independent carbohydrate-mediated interactions with immune modulating lectins expressed on myeloid cells, as well as host lung microbiota glycoconjugates. Our results identified new molecular pathways using host lectins and signalling, that may contribute to viral infection and subsequent immune exacerbation. Moreover we identified specific rhamnosylated epitopes in lung microbiota to bind SARS-CoV-2, providing a hypothetical link between the presence of specific lung microbiota and SARS-CoV-2 infection and severity.

DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist

“…Here we investigate whether those CLRs could also play a role in SARS-CoV-2 infection and dissemination. While we were finalizing this work, a first preprint article described the binding (Elisa test) of Fc-CLR constructs, notably based on DC-SIGN and MGL, to a commercial RBD domain of the SARS-CoV-2 (Chiodo et al, 2020). Given the importance of the role played by glycan determinants in this recognition event, therefore peculiar attention must be paid to the quality of the S protein sample used.…”

The Sialoside-Binding Pocket of SARS-CoV-2 Spike Glycoprotein Structurally Resembles MERS-CoV

“…Taken together, the differential distribution of sialosides in the respiratory tract and other organs, along with limited ACE2 expression in human airway epithelia [9] would explain differential infectivity, transmission, and tropism shown by SARS-CoV-2 [36]. In connotation to this, the recent preprint report suggests that the SARS-CoV-2 spike glycoprotein recognizes different siglecs (sialic acid-binding Ig-like lectins) and C-type lectins; suggesting that spike glycoprotein interacts in ACE2-independent infection pathways with the immune cells [37]. Besides, the human ABO blood group and COVID-19 susceptibility [38,39] may relate to modulation of the sialosides distribution pattern on the target membrane, possibly regulating SARS-CoV-2 transmission and tropism [40] despite high affinity with ACE2.…”

Blood type A associates with critical COVID-19 and death in a Swedish cohort

“…In addition, there is a difference in sex distribution of 81% male in the A/AB and 69% in the B/O. Both of these effects would tend to lead to an overestimation of the effect of blood type A/AB in the present dataset, which would tend to bring the results more in line with the previously published risk profile [6].…”

“…Both blood type B and O have a galactose amine in this position, which may explain the difference between the blood groups. The spike protein of SARS-COV-2 has been shown to bind carbohydrates, and a strong affinity between the A antigen and the virus could facilitate uptake of the virus into the cells [6].…”