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

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. WilenGregory 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

130 Scopus citations

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.

Original language	English
Pages (from-to)	2143-2158.e15
Journal	Immunity
Volume	54
Issue number	9
DOIs	https://doi.org/10.1016/j.immuni.2021.08.015
State	Published - 14 Sep 2021
Externally published	Yes

Keywords

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

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10.1016/j.immuni.2021.08.015

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Ullah, I., Prévost, J., Ladinsky, M. S., Stone, H., Lu, M., Anand, S. P., Beaudoin-Bussières, G., Symmes, K., Benlarbi, M., Ding, S., Gasser, R., Fink, C., Chen, Y., Tauzin, A., Goyette, G., Bourassa, C., Medjahed, H., Mack, M., Chung, K., ... Uchil, P. D. (2021). Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy. Immunity, 54(9), 2143-2158.e15. https://doi.org/10.1016/j.immuni.2021.08.015

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title = "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.",

keywords = "COVID-19, Fc effector functions, SARS-CoV-2, bioluminescence imaging, human ACE2 transgenic mice, monocytes, nanoluciferase, natural killer cells, neutralizing antibodies, pathogenesis",

author = "Irfan Ullah and J{\'e}r{\'e}mie Pr{\'e}vost and Ladinsky, {Mark S.} and Helen Stone and Maolin Lu and Anand, {Sai Priya} and Guillaume Beaudoin-Bussi{\`e}res and Kelly Symmes and Mehdi Benlarbi and Shilei Ding and Romain Gasser and Corby Fink and Yaozong Chen and Alexandra Tauzin and Guillaume Goyette and Catherine Bourassa and Halima Medjahed and Matthias Mack and Kunho Chung and Wilen, {Craig B.} and Dekaban, {Gregory A.} and Dikeakos, {Jimmy D.} and Bruce, {Emily A.} and Kaufmann, {Daniel E.} and Leonidas Stamatatos and McGuire, {Andrew T.} and Jonathan Richard and Marzena Pazgier and Bjorkman, {Pamela J.} and Walther Mothes and Andr{\'e}s Finzi and Priti Kumar and Uchil, {Pradeep D.}",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = sep,

day = "14",

doi = "10.1016/j.immuni.2021.08.015",

language = "English",

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Ullah, I, Prévost, J, Ladinsky, MS, Stone, H, Lu, M, Anand, SP, Beaudoin-Bussières, G, Symmes, K, Benlarbi, M, Ding, S, Gasser, R, Fink, C, Chen, Y, Tauzin, A, Goyette, G, Bourassa, C, Medjahed, H, Mack, M, Chung, K, Wilen, CB, Dekaban, GA, Dikeakos, JD, Bruce, EA, Kaufmann, DE, Stamatatos, L, McGuire, AT, Richard, J, Pazgier, M, Bjorkman, PJ, Mothes, W, Finzi, A, Kumar, P & Uchil, PD 2021, 'Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy', Immunity, vol. 54, no. 9, pp. 2143-2158.e15. https://doi.org/10.1016/j.immuni.2021.08.015

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T1 - Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy

AU - Ullah, Irfan

AU - Prévost, Jérémie

AU - Ladinsky, Mark S.

AU - Stone, Helen

AU - Lu, Maolin

AU - Anand, Sai Priya

AU - Beaudoin-Bussières, Guillaume

AU - Symmes, Kelly

AU - Benlarbi, Mehdi

AU - Ding, Shilei

AU - Gasser, Romain

AU - Fink, Corby

AU - Chen, Yaozong

AU - Tauzin, Alexandra

AU - Goyette, Guillaume

AU - Bourassa, Catherine

AU - Medjahed, Halima

AU - Mack, Matthias

AU - Chung, Kunho

AU - Wilen, Craig B.

AU - Dekaban, Gregory A.

AU - Dikeakos, Jimmy D.

AU - Bruce, Emily A.

AU - Kaufmann, Daniel E.

AU - Stamatatos, Leonidas

AU - McGuire, Andrew T.

AU - Richard, Jonathan

AU - Pazgier, Marzena

AU - Bjorkman, Pamela J.

AU - Mothes, Walther

AU - Finzi, Andrés

AU - Kumar, Priti

AU - Uchil, Pradeep D.

PY - 2021/9/14

Y1 - 2021/9/14

N2 - 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.

AB - 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.

KW - COVID-19

KW - Fc effector functions

KW - SARS-CoV-2

KW - bioluminescence imaging

KW - human ACE2 transgenic mice

KW - monocytes

KW - nanoluciferase

KW - natural killer cells

KW - neutralizing antibodies

KW - pathogenesis

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U2 - 10.1016/j.immuni.2021.08.015

DO - 10.1016/j.immuni.2021.08.015

M3 - Article

C2 - 34453881

AN - SCOPUS:85113837254

SN - 1074-7613

VL - 54

SP - 2143-2158.e15

JO - Immunity

JF - Immunity

IS - 9

ER -

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

Abstract

Keywords

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