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

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 9; pp. 2143 - 2158.e15
• Main Authors: Ullah, Irfan, Prévost, Jérémie, Ladinsky, Mark S., Stone, Helen, Lu, Maolin, Anand, Sai Priya, Beaudoin-Bussières, Guillaume, Symmes, Kelly, Benlarbi, Mehdi, Ding, Shilei, Gasser, Romain, Fink, Corby, Chen, Yaozong, Tauzin, Alexandra, Goyette, Guillaume, Bourassa, Catherine, Medjahed, Halima, Mack, Matthias, Chung, Kunho, Wilen, Craig B., Dekaban, Gregory A., Dikeakos, Jimmy D., Bruce, Emily A., Kaufmann, Daniel E., Stamatatos, Leonidas, McGuire, Andrew T., Richard, Jonathan, Pazgier, Marzena, Bjorkman, Pamela J., Mothes, Walther, Finzi, Andrés, Kumar, Priti, Uchil, Pradeep D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.09.2021
• Subjects: Angiotensin-Converting Enzyme 2 - genetics; Animals; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - metabolism; Antibodies, Viral - genetics; Antibodies, Viral - metabolism; bioluminescence imaging; Brain - pathology; Brain - virology; Cells, Cultured; COVID-19; COVID-19 - immunology; COVID-19 - therapy; Disease Models, Animal; Fc effector functions; human ACE2 transgenic mice; Humans; Immunoglobulin Fc Fragments - genetics; Luciferases - genetics; Luminescent Measurements; Lung - pathology; Lung - virology; Male; Mice; Mice, Transgenic; monocytes; nanoluciferase; natural killer cells; neutralizing antibodies; pathogenesis; SARS-CoV-2; SARS-CoV-2 - physiology; Testis - pathology; Testis - virology; COVID-19; monocytes; natural killer cells; pathogenesis; SARS-CoV-2; Fc effector functions; human ACE2 transgenic mice; bioluminescence imaging; neutralizing antibodies; nanoluciferase
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2021.08.015

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. [Display omitted] •BLI enables real-time monitoring of SARS-CoV-2 spread in vivo•SARS-CoV-2 NAbs require Fc effector function for prophylaxis and therapy•FcγR engagement by NAbs reduces virus load and limits immunopathology•Monocytes, neutrophils, and NK cells contribute to Fc-dependent NAb protection The mechanism of neutralizing antibody-mediated protection against SARS-CoV-2 is not fully understood. Ullah et. al. used bioluminescence imaging to monitor SARS-CoV-2 infection in live mice and reveal that FcγR engagement on innate immune cells by neutralizing antibodies is crucial for limiting virus spread and immunopathology, clearing infected cells, and survival.