SARS-CoV-2 hijacks neutralizing dimeric IgA for enhanced nasal infection and injury

Abstract

Robust severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in nasal turbinate (NT) accounts for high viral transmissibility, yet whether neutralizing IgA antibodies can control it remains unknown. Here, we evaluated receptor binding domain (RBD)-specific monomeric B8-mIgA1 and B8-mIgA2, and dimeric B8-dIgA1 and B8-dIgA2 against intranasal SARS-CoV-2 challenge in Syrian hamsters. These antibodies exhibited comparably potent neutralization against authentic virus by competing with human angiotensin converting enzyme-2 (ACE2) receptor for RBD binding. While reducing viruses in lungs, pre-exposure intranasal B8-dIgA1 or B8-dIgA2 led to 81-fold more infectious viruses and severer damage in NT than placebo. Virus-bound B8-dIgA1 and B8-dIgA2 could engage CD209 as an alternative receptor for entry into ACE2-negative cells and allowed viral cell-to-cell transmission. Cryo-EM revealed B8 as a class II neutralizing antibody binding trimeric RBDs in 3-up or 2-up/1-down conformation. Therefore, RBD-specific neutralizing dIgA engages an unexpected action for enhanced SARS-CoV-2 nasal infection and injury in Syrian hamsters.

Persistent Immune and Clotting Dysfunction Detected in Saliva and Blood Plasma after COVID-19

“…Antibody-mediated disease enhancement has been reported in diverse RNA viral diseases, such as influenza, SARS-CoV-2, Dengue, and human immunodeficiency viruses infections ( 51–54 ). One team found that SARS-CoV-2 RBD-specific neutralizing dimeric IgAs isolated from nasal turbinate could facilitate viral infection, transmission, and injury in Syrian hamsters ( 55 ). Aleyd et al ( 56 ) demonstrated that IgA enhances NETosis as an effective defense mechanism to eliminate pathogens at mucosal surfaces.…”

Is SARS‐CoV‐2 viral clearance in nasopharyngeal swabs an appropriate surrogate marker for clinical efficacy of neutralising antibody‐based therapeutics?

“…Hence, assessments of antibody efficacy need to include not only the amount and the affinity of the antibody preparation but also the isotype composition. This is underscored by a report showing that monotherapy with dimeric IgA increased SARS‐CoV‐2 infectivity via DC‐SIGN, suggesting the possibility of antibody‐dependent enhancement (ADE) of infection 29 …”