Mechanism of antibody-dependent enhancement in severe acute respiratory syndrome coronavirus infection

Abstract

Severe lymphopenia is a clinical feature of Severe Acute Respiratory Syndrome

(SARS) patients. However, lymphocytes do not express receptor for SARS-CoV,

neither the widely accepted viral receptor angiotensin converting enzyme 2 (ACE2)

nor the putative receptors Dendritic Cell- and Liver/lymph-Specific Intercellular

adhesion molecule-3-Grabbing Non-integrin (DC-SIGN and L-SIGN). Our group

previously showed in vitro that, SARS-CoV Spike pseudotyped particles (SARSCoVpp)

could infect human B cells only when inoculated in presence of anti-SARSCoV

Spike immune serum. Such observations raised concerns about the possible

occurrence of antibody-dependent enhancement (ADE) of infection, a phenomenon

during which a virus bounded by antibodies could gain entry into cells through

mechanisms involving complement receptors or Fc receptors. Recently, we have

demonstrated the participation of the human Fc gamma receptor II (hFcγRII)

molecules in granting SARS-CoV an opportunity to infect human immune cells.

The aim of this study was to decipher the molecular mechanism leading to antibodymediated,

FcγRII-dependent infection of immune cells by SARS-CoV. By using

transduction experiment, I highlighted that different members of the hFcγRII family

(namely hFcγRIIA, hFcγRIIB1 and hFcγRIIB2) could confer susceptibility to ADE of

SARS-CoVpp infection. I further demonstrated that purified anti-viral

immunoglobulin G, but not other soluble factor(s) from heat-inactivated immune

serum, was the determinant for occurrence of ADE infection. Additionally, with the

development of a cell-cell fusion assay, I illustrated that in contrast to the ACE2-

dependent pathway, ADE infection did not occur at the plasma membrane, but rather

require internalization of virus/antibodies immune complexes by the target cells. In

line with this hypothesis, my results using a panel of FcγRII-expressing mutants

demonstrated that binding of immune complexes to cell surface FcγRII was a

prerequisite but was not sufficient to trigger ADE infection. In these experiments,

only FcγRII signaling-competent constructions conferred susceptibility to ADE of

SARS-CoVpp infection.

Altogether my results point toward a role of the anti-SARS-CoV Spike IgG in vitro in

granting SARS-CoV an opportunity to infect cells bearing signaling-competent

FcγRII receptors. If further confirmed, such observations could have implications for

understanding SARS-CoV tropism and SARS pathogenesis, as well as warrant for

careful design of SARS vaccines and immunotherapy based on anti-viral antibodies.