Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy

Abstract

Neutralizing antibodies (NAbs) are effective in treating COVID-19 but the mechanism of immune protection is not fully understood. Here, we applied live bioluminescence imaging (BLI) to monitor the real-time effects of NAb treatment during prophylaxis and therapy of K18-hACE2 mice intranasally infected with SARS-CoV-2-nanoluciferase. Real time imaging revealed that the virus spread sequentially from the nasal cavity to the lungs in mice and thereafter systemically to various organs including the brain, culminating in death. Highly potent NAbs from a COVID-19 convalescent subject prevented, and also effectively resolved, established infection when administered within three days. In addition to direct neutralization, depletion studies indicated that Fc effector interactions of NAbs with monocytes, neutrophils and natural killer cells were required to effectively dampen inflammatory responses and limit immunopathology. Our study highlights that both Fab and Fc effector functions of NAbs are essential for optimal in vivo efficacy against SARS-CoV-2.

Illuminating the Fc dependence of SARS-CoV-2 neutralization

“…CV-1-mediated protection was dependent on immune cells that express Fcgamma receptors (FcgRs); specifically, depletion of neutrophils, monocytes, and natural killer cells reduced protective activity, highlighting the importance of Fcmediated effector functions in limiting viral replication. Ullah et al (2021) next tested the activity of human IgG1 nAb CV3-25. This nAb has less potent neutralizing activity in vitro but targets a more conserved region of the S protein-the S2 domain-and shows cross-neutralizing activity with the South African B.1.351 variant (Jennewein et al, 2021).…”

“…Monoclonal antibodies show efficacy in treating COVID-19, but the functional requirements for protection are unclear. In this issue of Immunity, Ullah et al (2021) develop a stable SARS-CoV-2 reporter virus and use bioluminescence imaging to longitudinally monitor infection and assess neutralizing monoclonal antibody interventions in mice. They find that antibody-mediated protection depends on the Fc domain and Fc-gamma receptor-expressing immune cells.…”

“…Other models that utilize replication-competent SARS-CoV-2 can evaluate the ability of a treatment to block any stage of the infection but are limited in utility for longitudinal studies because assessment of efficacy requires euthanasia of the animals to study viral loads in tissues. In this issue of Immunity, Ullah et al (2021) have added to the array of available models of SARS-CoV-2 infections by providing a system for the tracking of viral replication and spread within multiple organs by time-lapse bioluminescence imaging (BLI) and video.…”

“…Ullah et al describe a SARS-CoV-2 virus that expresses nanoluciferase during replication, enabling noninvasive monitoring of SARS-CoV-2 infection in vivo (Ullah et al, 2021). Using this reporter virus, the investigators were able to detect viral replication and spread within tissues over time in mice that express human ACE2 (K18-hACE2 mouse model), the major receptor for SARS-CoV-2.…”

“…The K18-hACE2 mouse strain used in this study has been well described and utilized to model SARS-CoV-1 and SARS-CoV-2 infections (McCray et al, 2007;Winkler et al, 2020). This model is useful for evaluating the impact of potential therapeutics through approximately 6-10 days of infection, after which the animals otherwise succumb to the infection (Winkler et al, 2020;Jennewein et al, 2021;Ullah et al, 2021). In concurrence with previous studies, the investigators observed that SARS-CoV-2-infected K18-hACE2 mice exhibited robust bioluminescence signal within the brain after intranasal inoculation, likely contributing to rapid lethality in the model.…”