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

Irfan Ullah; Jérémie Prévost; Mark S Ladinsky; Helen Stone; Maolin Lu; Sai Priya Anand; Guillaume Beaudoin-Bussières; Kelly Symmes; Mehdi Benlarbi; Shilei Ding; Romain Gasser; Corby Fink; Yaozong Chen; Alexandra Tauzin; Guillaume Goyette; Catherine Bourassa; Halima Medjahed; Matthias Mack; Kunho Chung; Craig B Wilen; Gregory A Dekaban; Jimmy D Dikeakos; Emily A Bruce; Daniel E Kaufmann; Leonidas Stamatatos; Andrew T McGuire; Jonathan Richard; Marzena Pazgier; Pamela J Bjorkman; Walther Mothes; Andrés Finzi; Priti Kumar; Pradeep D Uchil

doi:10.1016/j.immuni.2021.08.015

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

Immunity. 2021 Sep 14;54(9):2143-2158.e15. doi: 10.1016/j.immuni.2021.08.015. Epub 2021 Aug 18.

Authors

Irfan Ullah¹, Jérémie Prévost², Mark S Ladinsky³, Helen Stone⁴, Maolin Lu⁴, Sai Priya Anand⁵, Guillaume Beaudoin-Bussières², Kelly Symmes¹, Mehdi Benlarbi⁶, Shilei Ding⁶, Romain Gasser², Corby Fink⁷, Yaozong Chen⁸, Alexandra Tauzin², Guillaume Goyette⁶, Catherine Bourassa⁶, Halima Medjahed⁶, Matthias Mack⁹, Kunho Chung¹, Craig B Wilen¹⁰, Gregory A Dekaban¹¹, Jimmy D Dikeakos⁷, Emily A Bruce¹², Daniel E Kaufmann², Leonidas Stamatatos¹³, Andrew T McGuire¹⁴, Jonathan Richard², Marzena Pazgier⁸, Pamela J Bjorkman³, Walther Mothes¹⁵, Andrés Finzi¹⁶, Priti Kumar¹⁷, Pradeep D Uchil¹⁸

Affiliations

¹ Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
² Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada.
³ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
⁴ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA.
⁵ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada.
⁶ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada.
⁷ Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5B7, Canada.
⁸ Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
⁹ Universitätsklinikum Regensburg, Innere Medizin II - Nephrologie, Regensburg 93042, Germany.
¹⁰ Departments of Laboratory Medicine and Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
¹¹ Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5B7, Canada; Molecluar Medicine Research Laboratories, Robarts Research Institute, University of Western Ontario, London, ON N6A 5B7, Canada.
¹² Division of Immunobiology, Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405. USA.
¹³ Vaccine and Infectious Disease Division, Fred Hutchinson Center, Seattle, WA 98195, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA.
¹⁴ Vaccine and Infectious Disease Division, Fred Hutchinson Center, Seattle, WA 98195, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA.
¹⁵ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: walther.mothes@yale.edu.
¹⁶ Centre de Recherche du CHUM, Montreal, QC H2X 0A9, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC H2X 0A9, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada. Electronic address: andres.finzi@umontreal.ca.
¹⁷ Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: priti.kumar@yale.edu.
¹⁸ Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: pradeep.uchil@yale.edu.

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.

Keywords: COVID-19; Fc effector functions; SARS-CoV-2; bioluminescence imaging; human ACE2 transgenic mice; monocytes; nanoluciferase; natural killer cells; neutralizing antibodies; pathogenesis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Angiotensin-Converting Enzyme 2 / genetics
Animals
Antibodies, Neutralizing / genetics
Antibodies, Neutralizing / metabolism*
Antibodies, Viral / genetics
Antibodies, Viral / metabolism*
Brain / pathology*
Brain / virology
COVID-19 / immunology*
COVID-19 / therapy
Cells, Cultured
Disease Models, Animal
Humans
Immunoglobulin Fc Fragments / genetics
Luciferases / genetics
Luminescent Measurements
Lung / pathology*
Lung / virology
Male
Mice
Mice, Transgenic
SARS-CoV-2 / physiology*
Testis / pathology*
Testis / virology

Substances

Antibodies, Neutralizing
Antibodies, Viral
Immunoglobulin Fc Fragments
Luciferases
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding