Anti-Severe Acute Respiratory Syndrome Coronavirus Spike Antibodies Trigger Infection of Human Immune Cells via a pH- and Cysteine Protease-Independent FcγR Pathway

Abstract

Public health measures successfully contained outbreaks of the severe acute respiratory syndrome coronavirus (SARS-CoV) infection. However, the precursor of the SARS-CoV remains in its natural bat reservoir, and reemergence of a human-adapted SARS-like coronavirus remains a plausible public health concern. Vaccination is a major strategy for containing resurgence of SARS in humans, and a number of vaccine candidates have been tested in experimental animal models. We previously reported that antibody elicited by a SARS-CoV vaccine candidate based on recombinant full-length Spike-protein trimers potentiated infection of human B cell lines despite eliciting in vivo a neutralizing and protective immune response in rodents. These observations prompted us to investigate the mechanisms underlying antibody-dependent enhancement (ADE) of SARS-CoV infection in vitro. We demonstrate here that anti-Spike immune serum, while inhibiting viral entry in a permissive cell line, potentiated infection of immune cells by SARS-CoV Spike-pseudotyped lentiviral particles, as well as replication-competent SARS coronavirus. Antibody-mediated infection was dependent on Fc␥ receptor II but did not use the endosomal/lysosomal pathway utilized by angiotensin I converting enzyme 2 (ACE2), the accepted receptor for SARS-CoV. This suggests that ADE of SARS-CoV utilizes a novel cell entry mechanism into immune cells. Different SARS vaccine candidates elicit sera that differ in their capacity to induce ADE in immune cells despite their comparable potency to neutralize infection in ACE2-bearing cells. Our results suggest a novel mechanism by which SARS-CoV can enter target cells and illustrate the potential pitfalls associated with immunization against it. These findings should prompt further investigations into SARS pathogenesis.

Dengue virus compartmentalization during antibody-enhanced infection

“…We detected increased magnitude of viral replication in both THP-1 subclones and primary monocytes that were pre-treated with CQ or NH 4 Cl during infection under DENV and ADE conditions. Consistent with our findings, the infectivity of both human immunodeficiency virus type 1 and severe acute respiratory syndrome coronavirus were also raised following pre-treatment of lysosomotropic drugs on host cells, as the virus was able to escape lysosomal degradation and enter host cells via a separate endocytic pathway3031.…”

Middle East Respiratory Syndrome Coronavirus Spike Protein Delivered by Modified Vaccinia Virus Ankara Efficiently Induces Virus-Neutralizing Antibodies

“…Future studies will be necessary to monitor for S antibodydependent enhancement of MERS-CoV infections, as previously discussed for SARS-CoV and feline coronavirus infections (28,29,30). Furthermore, the safety and protective capacity of MVA-MERS-S immunization should be tested in animal models that reproduce MERS-CoV infections in humans.…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…Studies related to SARS vaccinehave taught us several lessons about pathogenesis and host responses to SARS-CoV, in addition to unraveling the need for caution. With certain experimental vaccines, such as the viral vector based ones, immunopathology and redirection of the viral vector to brain was reported (Czub et al, 2005;Deming et al, 2006;Kam et al, 2007;Jaume et al, 2011;Tseng et al, 2012). Subsequent studies demonstrated that a sub lingual immunization can prevent the viral vector entry into the brain (Shim et al, 2012).…”

“…Immunopathology is observed in some cases Protective in hamsters and ferrets particle vaccines (Kam et al, 2007;Jaume et al, 2011;(Kam et al, 2007;Tseng et al, 2012) Tseng et al, 2012. Hypersensitive reaction upon post-immunization viral challenge in mice (Kam et al, 2007;Tseng et al, 2012) DNA vaccines Safe and immunogenic in healthy humans Protective in mice (Yang et al, 2004) (Martin et al, 2008).…”