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Intracellular neutralization of viral infection in polarized epithelial cells by neonatal Fc receptor (FcRn)-mediated IgG transport

Bai, Yu and Ye, Lilin and Tesar, Devin B. and Song, Haichen and Zhao, Deming and Bjorkman, Pamela J. and Roopenian, Derry C. and Zhu, Xiaoping (2011) Intracellular neutralization of viral infection in polarized epithelial cells by neonatal Fc receptor (FcRn)-mediated IgG transport. Proceedings of the National Academy of Sciences of the United States of America, 108 (45). pp. 18406-18411. ISSN 0027-8424. PMCID PMC3215070. https://resolver.caltech.edu/CaltechAUTHORS:20111129-114918008

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Abstract

IgG was traditionally thought to neutralize virions by blocking their attachment to or penetration into mucosal epithelial cells, a common site of exposure to viruses. However, we describe an intracellular neutralizing action for an influenza hemagglutinin-specific monoclonal antibody, Y8-10C2 (Y8), which has neutralizing activity only at an acidic pH. When Y8 was applied to the basolateral surface of Madin–Darby canine kidney cells expressing the rat neonatal Fc receptor for IgG (FcRn), it significantly reduced viral replication following apical exposure of the cell monolayer to influenza virus. Virus neutralization by Y8 mAb was dependent on FcRn expression and its transport of IgG. As both FcRn and Y8 mAb bind their partners only at acidic pH, the Y8 mAb is proposed to carry out its antiviral activity intracellularly. Furthermore, the virus, Y8 mAb, and FcRn colocalized within endosomes, possibly inhibiting the fusion of viral envelopes with endosomal membranes during primary uncoating, and preventing the accumulation of the neutralized viral nucleoprotein antigen in the nucleus. Prophylactic administration of Y8 mAb before viral challenge in WT mice, but not FcRn-KO mice, conferred protection from lethality, prevented weight loss, resulted in a significant reduction in pulmonary virus titers, and largely reduced virus-induced lung pathology. Thus, this study reveals an intracellular mechanism for viral neutralization in polarized epithelial cells that is dependent on FcRn-mediated transport of neutralizing IgG.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1115348108DOIArticle
http://www.pnas.org/content/108/45/18406.abstractPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215070/PubMed CentralArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1115348108/-/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2011 National Academy of Sciences. Edited by Robert A. Lamb, Northwestern University, Evanston, IL, and approved October 6, 2011 (received for review September 29, 2011). Published online before print October 31, 2011. We thank Geoffrey J. Letchworth for critical reading of the manuscript, Peter Palese for the influenza PR8 strain, and Keith Mostov for the Madin–Darby canine kidney type II cell line; Neil Simister for helpful discussions of mouse IgG catabolism; and Senthilkumar Palaniyandi, Rongyu Zeng, Xindong Liu, Zili Li, and Yunsheng Wang for technical help. This work was supported in part by National Institutes of Health Grants AI65892 (to X.Z.), AI67965 (to X.Z.), AI73139 (to X.Z.), DK56597 (to D.C.R.), and R37 AI041239-06A1 (to P.J.B.). Y.B. and L.Y. contributed equally to this work. Author contributions: Y.B., L.Y., and X.Z. designed research; Y.B., L.Y., D.B.T., H.S., and D.Z. performed research; P.J.B. and D.C.R. contributed new reagents/analytic tools; Y.B., L.Y., P.J.B., D.C.R., and X.Z. analyzed data; and D.B.T., P.J.B., D.C.R., and X.Z. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1115348108/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHAI65892
NIHAI67965
NIHAI73139
NIHDK56597
NIHR37 AI041239-06A1
Issue or Number:45
PubMed Central ID:PMC3215070
Record Number:CaltechAUTHORS:20111129-114918008
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20111129-114918008
Official Citation:Yu Bai, Lilin Ye, Devin B. Tesar, Haichen Song, Deming Zhao, Pamela J. Björkman, Derry C. Roopenian, and Xiaoping Zhu Intracellular neutralization of viral infection in polarized epithelial cells by neonatal Fc receptor (FcRn)-mediated IgG transport PNAS 2011 108 (45) 18406-18411; published ahead of print October 31, 2011, doi:10.1073/pnas.1115348108
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27995
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:29 Nov 2011 20:53
Last Modified:03 Oct 2019 03:28

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