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

Creators: 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.

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.

Additional Information

© 2021 Elsevier Inc. Received 23 March 2021, Revised 27 June 2021, Accepted 11 August 2021, Available online 18 August 2021. This work was supported by NIH grant R01AI163395 to W.M.; George Mason University Fast Grants to M.S.L. and P.J.B.; P20GM125498 (awarded to UVM Translational Global Infectious Disease Research Center) to E.A.B.; le Ministère de l'Économie et de l'Innovation du Québec, Programme de soutien aux organismes de recherche et d'innovation, Foundation du CHUM, Canadian Institutes of Health Research (CIHR) foundation grant 352417 and Rapid Research Funding Opportunity FRN440388 to J.D.D. and G.A.D.; Canada Research Chair on Retroviral Entry no. RCHS0235 950-232424 to A.F.; Canada's COVID-19 Immunity Task Force (CITF) and Canada Foundation for Innovation (CFI) 41027 to A.F. and D.E.K. and 36287 to J.D.D. and G.A.D.; FRQS Merit Research Scholarship to D.E.K.; CIHR fellowships to J.P., S.P.A., and G.B.-B.; MITACS Accélération postdoctoral fellowship to R.G.; Fred Hutch COVID-19 Research Fund to L.S. and A.T.M. The views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Uniformed Services University, US Army, the Department of Defense, or the US Government. Author contributions: Conceptualization, P.D.U., P.K., A.F., W.M., I.U., and J.P.; methodology, P.D.U., I.U., J.P., M.S.L., E.A.B., M.L.,W.M., A.F., and P.K.; investigation, I.U., P.D.U., J.P., H.S., K.S., K.C., L.S., A.T.M., S.P.A., G.B.-B., M.B., S.D., R.G., C.F., Y.C., A.T., G.G., C.B., H.M., G.A.D., J.D.D., D.E.K., J.R., and M.P.; writing – original draft, P.D.U.; writing – review & editing, P.D.U., P.K., A.F., W.M., I.U., J.P., L.S., and A.T.M.; funding acquisition, A.F., L.S., A.T.M., P.J.B.; resources, A.F., P.J.B., C.B.W., and M.M.; supervision, P.D.U., W.M., P.K., A.F., and P.J.B. The authors declare no competing interests. Data and code availability: All the data that support the findings of this study are available from the lead contact upon request. Additional supplemental items that include raw data for generating all graphs shown in figures and videos are available at Mendeley Data, V3, https://doi.org/10.17632/2wwzg4pb8n.3. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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