Glycan recognition by collectin-11 drives SARS-CoV-2 infectivity and membrane injury of respiratory epithelial cells

TL;DR

SARS-CoV-2 uses a protein called collectin-11 to increase its infectivity and damage respiratory cells, offering a new target for treatment.

Contribution

The study reveals a novel mechanism where collectin-11 enhances SARS-CoV-2 infectivity and cell injury through glycan recognition.

Findings

SARS-CoV-2 binds collectin-11 to activate complement but is resistant to lysis, enabling immune escape.

Collectin-11 binding increases SARS-CoV-2 infectivity of respiratory epithelial cells independently of complement.

Infected cells are vulnerable to membrane injury from collectin-11 and complement, which can be blocked by L-fucose.

Abstract

SARS-CoV-2 infection of the respiratory tract continues to be a health risk even among immunized individuals suggesting that localized factors could maintain viral infection and transmission. Here, we show that although the locally produced innate immune-surveillance molecule collectin-11 (CL-11) is bound by SARS-CoV-2 to trigger complement activation, the virus is resistant to complement lysis offering a means of immune escape. Moreover, we reveal CL-11 binding enhances SARS-CoV-2 infectivity of respiratory epithelial cells (RECs) by a complement-independent mechanism affording highly transmissible variants of SARS-CoV-2 a survival advantage. Additionally, SARS-CoV-2-infected RECs are vulnerable to membrane injury by self-generated CL-11 and complement. These insights provide a strong rationale for CL-11 blockade to reduce SARS-CoV-2 infection and injury of the respiratory tract.

SARS-CoV-2 respiratory-tract infection affects both vaccinated and unvaccinated persons suggesting factors besides adaptive immunity are operative. We investigated the role of collectin-11 (CL-11), an epithelial-secreted carbohydrate-binding lectin that drives innate immunity and eliminates pathogens by complement activation. SARS-CoV-2, despite binding CL-11 to activate complement, was resistant to lysis. Remarkably, opsonization by CL-11 enhanced virus production by infected respiratory epithelial cells independently of complement. Furthermore, infected cells expressing SARS-CoV-2 spike protein displayed enhanced vulnerability to CL-11 binding and membrane attack by complement. The mechanism of enhanced infectivity was ablated in the presence of L-fucose, which occupied the extended carbohydrate-binding cleft of CL-11 in a crystallographic analysis of complexes between L-fucose and CL-11. Our study suggests pathogenicity of SARS-CoV-2 is related to complement-resistance together with enhanced infectivity and injury of respiratory epithelial cells mediated by locally released CL-11.

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