ABSTRACT
Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy.
Subject(s)
COVID-19/metabolism , COVID-19/virology , Host-Pathogen Interactions , Lectins, C-Type/metabolism , Membrane Proteins/metabolism , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasm Proteins/metabolism , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , COVID-19/genetics , Cell Line , Cytokines , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Inflammation Mediators/metabolism , Lectins, C-Type/chemistry , Membrane Proteins/chemistry , Models, Molecular , Neoplasm Proteins/chemistry , Protein Binding , Protein Conformation , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Structure-Activity RelationshipABSTRACT
The global pandemic of 2019 coronavirus disease (COVID-19) is a great assault to public health. Presymptomatic transmission cannot be controlled with measures designed for symptomatic persons, such as isolation. This study aimed to estimate the interval of the transmission generation (TG) and the presymptomatic period of COVID-19, and compare the fitting effects of TG and serial interval (SI) based on the SEIHR model incorporating the surveillance data of 3453 cases in 31 provinces. These data were allocated into three distributions and the value of AIC presented that the Weibull distribution fitted well. The mean of TG was 5.2 days (95% CI: 4.6-5.8). The mean of the presymptomatic period was 2.4 days (95% CI: 1.5-3.2). The dynamic model using TG as the generation time performed well. Eight provinces exhibited a basic reproduction number from 2.16 to 3.14. Measures should be taken to control presymptomatic transmission in the COVID-19 pandemic.