Optimal therapeutic activity of monoclonal antibodies against chikungunya virus requires Fc-FcγR interaction on monocytes
Engaging monocytes to battle chikungunya
Antibody-binding receptors, including Fc receptors and complement receptors, play a central role in mediating antibody-dependent immune activation. Here, Fox et al. have examined the role of Fcγ receptors and complement component 1q (C1q) in meditating the therapeutic effects of monoclonal IgG antibodies targeting chikungunya virus. Using antibody engineering in conjunction with mouse strains lacking C1q or Fcγ receptors, they report that the therapeutic effects of these antibodies are dependent on expression of Fcγ receptors. Furthermore, by depleting distinct immune cell types, they found that engagement of Fc receptors on monocytes is central in driving antibody-dependent clearance of chikungunya virus.
Abstract
Chikungunya virus (CHIKV) is an emerging mosquito-borne virus that has caused explosive outbreaks worldwide. Although neutralizing monoclonal antibodies (mAbs) against CHIKV inhibit infection in animals, the contribution of Fc effector functions to protection remains unknown. Here, we evaluated the activity of therapeutic mAbs that had or lacked the ability to engage complement and Fcγ receptors (FcγR). When administered as post-exposure therapy in mice, the Fc effector functions of mAbs promoted virus clearance from infected cells and reduced joint swelling—results that were corroborated in antibody-treated transgenic animals lacking activating FcγR. The control of CHIKV infection by antibody-FcγR engagement was associated with an accelerated influx of monocytes. A series of immune cell depletions revealed that therapeutic mAbs required monocytes for efficient clearance of CHIKV infection. Overall, our study suggests that in mice, FcγR expression on monocytes is required for optimal therapeutic activity of antibodies against CHIKV and likely other related viruses.
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Supplementary Material
Summary
Fig. S1. IM-CKV063 in combination with CHK-166 reduces clinical disease and viral RNA.
Fig. S2. Viral burden in contralateral ankle with anti-CHIKV mAb therapy.
Fig. S3. Gating scheme for infiltrating immune cells in WT mice.
Fig. S4. Similar levels of cellular infiltration in the ipsilateral feet at 7 dpi.
Fig. S5. Fc effector functions of antibody affect proinflammatory cytokine and chemokine expression.
Fig. S6. Gating scheme for infiltrating immune cells in FcRγ−/− and C1q−/− mice.
Fig. S7. NK cell depletion does not affect mAb-mediated protection.
Table S1. Proinflammatory chemokine and cytokine expression in joint tissue homogenates.
Table S2. Raw data in Excel file.
Resources
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Science Immunology
Volume 4 | Issue 32
February 2019
February 2019
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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 24 September 2018
Accepted: 11 January 2019
Acknowledgments
This work was supported by NIH grants R01 AI089591 (M.S.D.), R01 AI114816 (M.S.D.), and T32 AI007172 (J.M.F.) and NIH contract HHSN272201400058C (B.J.D.). Authors contributions: J.M.F., B.M.G., and V.R. performed experiments. J.M.F., B.M.G., G.A., and M.S.D. designed the experiments and analyzed the data. L.H., B.J.D., M.A.E., D.H.F., and S.J. contributed key reagents and methodology. J.M.F. and M.S.D. wrote the first draft of the manuscript, and all authors provided editorial comments. Competing interests: M.S.D. is a consultant for InBios and Sanofi Pasteur and is on the Scientific Advisory Board of Moderna. S.J. and L.H. are employees of MacroGenics and have equity. B.J.D. is an employee and shareholder of Integral Molecular. The authors have no additional competing interests. Data and materials availability: Mouse strains and antibodies used are available from the corresponding author upon request.
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National Institute of Allergy and Infectious Diseases: R01 AI089591
National Institute of Allergy and Infectious Diseases: R01 AI114816
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