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Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity

Daniel W. Heindel, Sujeethraj Koppolu, Yue Zhang, Brian Kasper, Lawrence Meche, Christopher Vaiana, Stephanie J. Bissel, Chalise E. Carter, Alyson A. Kelvin, Bin Zhang, Bin Zhou, Tsui-Wen Chou, Lauren Lashua, Ted M. Ross, Elodie Ghedin, Lara K. Mahal
doi: https://doi.org/10.1101/2020.04.21.054098
Daniel W. Heindel
1Biomedical Research Institute, Department of Chemistry, New York University, NY
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Sujeethraj Koppolu
1Biomedical Research Institute, Department of Chemistry, New York University, NY
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Yue Zhang
1Biomedical Research Institute, Department of Chemistry, New York University, NY
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Brian Kasper
1Biomedical Research Institute, Department of Chemistry, New York University, NY
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Lawrence Meche
1Biomedical Research Institute, Department of Chemistry, New York University, NY
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Christopher Vaiana
1Biomedical Research Institute, Department of Chemistry, New York University, NY
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Stephanie J. Bissel
2Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Chalise E. Carter
3Center for Vaccines and Immunology, University of Georgia, GA
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Alyson A. Kelvin
4Department of Pediatrics, Dalhousie University, Halifax, NS, Canada
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Bin Zhang
5Department of Genetics and Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, NY
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Bin Zhou
6Center for Genomics & Systems Biology, Department of Biology, New York University, NY
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Tsui-Wen Chou
6Center for Genomics & Systems Biology, Department of Biology, New York University, NY
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Lauren Lashua
6Center for Genomics & Systems Biology, Department of Biology, New York University, NY
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Ted M. Ross
3Center for Vaccines and Immunology, University of Georgia, GA
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Elodie Ghedin
6Center for Genomics & Systems Biology, Department of Biology, New York University, NY
7Department of Epidemiology, School of Global Public Health, New York University, NY
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Lara K. Mahal
1Biomedical Research Institute, Department of Chemistry, New York University, NY
8Department of Chemistry, University of Alberta, Edmonton, AB, CANADA
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  • For correspondence: lkmahal@ualberta.ca
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ABSTRACT

Influenza virus infections cause a wide variety of outcomes, from mild disease to 3-5 million cases of severe illness and ~290,000-645,000 deaths annually worldwide. The molecular mechanisms underlying these disparate outcomes are currently unknown. Glycosylation within the human host plays a critical role in influenza virus biology. However, the impact these modifications have on the severity of influenza disease has not been examined. Herein, we profile the glycomic host responses to influenza virus infection as a function of disease severity using a ferret model and our lectin microarray technology. We identify the glycan epitope high mannose as a marker of influenza virus-induced pathogenesis and severity of disease outcome. Induction of high mannose is dependent upon the unfolded protein response (UPR) pathway, a pathway previously shown to associate with lung damage and severity of influenza virus infection. Also, the mannan-binding lectin (MBL2), an innate immune lectin that negatively impacts influenza outcomes, recognizes influenza virus-infected cells in a high mannose dependent manner. Together, our data argue that the high mannose motif is an infection-associated molecular pattern on host cells that may guide immune responses leading to the concomitant damage associated with severity.

SIGNIFICANCE Influenza virus infection causes a range of outcomes from mild illness to death. The molecular mechanisms leading to these differential host responses are currently unknown. Herein, we identify the induction of high mannose, a glycan epitope, as a key mediator of severe disease outcome. We propose a mechanism in which activation of the unfolded protein response (UPR) upon influenza virus infection turns on expression of high mannose, which is then recognized by the innate immune lectin MBL2, activating the complement cascade and leading to subsequent inflammation. This work is the first to systematically study host glycomic changes in response to influenza virus infection, identifying high mannose as a key feature of differential host response.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 23, 2020.
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Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity
Daniel W. Heindel, Sujeethraj Koppolu, Yue Zhang, Brian Kasper, Lawrence Meche, Christopher Vaiana, Stephanie J. Bissel, Chalise E. Carter, Alyson A. Kelvin, Bin Zhang, Bin Zhou, Tsui-Wen Chou, Lauren Lashua, Ted M. Ross, Elodie Ghedin, Lara K. Mahal
bioRxiv 2020.04.21.054098; doi: https://doi.org/10.1101/2020.04.21.054098
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Glycomic analysis of host-response reveals high mannose as a key mediator of influenza severity
Daniel W. Heindel, Sujeethraj Koppolu, Yue Zhang, Brian Kasper, Lawrence Meche, Christopher Vaiana, Stephanie J. Bissel, Chalise E. Carter, Alyson A. Kelvin, Bin Zhang, Bin Zhou, Tsui-Wen Chou, Lauren Lashua, Ted M. Ross, Elodie Ghedin, Lara K. Mahal
bioRxiv 2020.04.21.054098; doi: https://doi.org/10.1101/2020.04.21.054098

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