Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome
ABSTRACT Individuals with metabolic dysregulation of cellular glycosylation often experience severe influenza disease, with a poor immune response to the virus and low vaccine efficacy. Here, we investigate the consequences of aberrant cellular glycosylation for the glycome and the biology of influe...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-04-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.02983-21 |
| _version_ | 1818047989688565760 |
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| author | Irina V. Alymova John F. Cipollo Lisa M. Parsons Nedzad Music Ram P. Kamal Wen-Pin Tzeng Cynthia S. Goldsmith Joseph N. Contessa Kevan L. Hartshorn Jason R. Wilson Hui Zeng Shane Gansebom Ian A. York |
| author_facet | Irina V. Alymova John F. Cipollo Lisa M. Parsons Nedzad Music Ram P. Kamal Wen-Pin Tzeng Cynthia S. Goldsmith Joseph N. Contessa Kevan L. Hartshorn Jason R. Wilson Hui Zeng Shane Gansebom Ian A. York |
| author_sort | Irina V. Alymova |
| collection | DOAJ |
| description | ABSTRACT Individuals with metabolic dysregulation of cellular glycosylation often experience severe influenza disease, with a poor immune response to the virus and low vaccine efficacy. Here, we investigate the consequences of aberrant cellular glycosylation for the glycome and the biology of influenza virus. We transiently induced aberrant N-linked glycosylation in cultured cells with an oligosaccharyltransferase inhibitor, NGI-1. Cells treated with NGI-1 produced morphologically unaltered viable influenza virus with sequence-neutral glycosylation changes (primarily reduced site occupancy) in the hemagglutinin and neuraminidase proteins. Hemagglutinin with reduced glycan occupancy required a higher concentration of surfactant protein D (an important innate immunity respiratory tract collectin) for inhibition compared to that with normal glycan occupancy. Immunization of mice with NGI-1-treated virus significantly reduced antihemagglutinin and antineuraminidase titers of total serum antibody and reduced hemagglutinin protective antibody responses. Our data suggest that aberrant cellular glycosylation may increase the risk of severe influenza as a result of the increased ability of glycome-modified influenza viruses to evade the immune response. IMPORTANCE People with disorders such as cancer, autoimmune disease, diabetes, or obesity often have metabolic dysregulation of cellular glycosylation and also have more severe influenza disease, a reduced immune response to the virus, and reduced vaccine efficacy. Since influenza viruses that infect such people do not show consistent genomic variations, it is generally assumed that the altered biology is mainly related to host factors. However, since host cells are responsible for glycosylation of influenza virus hemagglutinin and neuraminidase, and glycosylation is important for interactions of these proteins with the immune system, the viruses may have functional differences that are not reflected by their genomic sequence. Here, we show that imbalanced cellular glycosylation can modify the viral glycome without genomic changes, leading to reduced innate and adaptive host immune responses to infection. Our findings link metabolic dysregulation of host glycosylation to increased risk of severe influenza and reduced influenza virus vaccine efficacy. |
| first_indexed | 2024-12-10T10:14:33Z |
| format | Article |
| id | doaj.art-095f9dcce64c41e49f7af6c76063a223 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-10T10:14:33Z |
| publishDate | 2022-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-095f9dcce64c41e49f7af6c76063a2232022-12-22T01:53:02ZengAmerican Society for MicrobiologymBio2150-75112022-04-0113210.1128/mbio.02983-21Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral GlycomeIrina V. Alymova0John F. Cipollo1Lisa M. Parsons2Nedzad Music3Ram P. Kamal4Wen-Pin Tzeng5Cynthia S. Goldsmith6Joseph N. Contessa7Kevan L. Hartshorn8Jason R. Wilson9Hui Zeng10Shane Gansebom11Ian A. York12Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAFood and Drug Administration, Center for Biologics Evaluation and Research, DBPAP, Silver Spring, Maryland, USAFood and Drug Administration, Center for Biologics Evaluation and Research, DBPAP, Silver Spring, Maryland, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAInfectious Diseases Pathology Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USADepartment of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, USADepartment of Medicine, Boston University School of Medicine, Boston, Massachusetts, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAImmunology and Pathogenesis Branch, Influenza Division, National Center for Immunization & Respiratory Diseases, Centers for Disease Control & Prevention, Atlanta, Georgia, USAABSTRACT Individuals with metabolic dysregulation of cellular glycosylation often experience severe influenza disease, with a poor immune response to the virus and low vaccine efficacy. Here, we investigate the consequences of aberrant cellular glycosylation for the glycome and the biology of influenza virus. We transiently induced aberrant N-linked glycosylation in cultured cells with an oligosaccharyltransferase inhibitor, NGI-1. Cells treated with NGI-1 produced morphologically unaltered viable influenza virus with sequence-neutral glycosylation changes (primarily reduced site occupancy) in the hemagglutinin and neuraminidase proteins. Hemagglutinin with reduced glycan occupancy required a higher concentration of surfactant protein D (an important innate immunity respiratory tract collectin) for inhibition compared to that with normal glycan occupancy. Immunization of mice with NGI-1-treated virus significantly reduced antihemagglutinin and antineuraminidase titers of total serum antibody and reduced hemagglutinin protective antibody responses. Our data suggest that aberrant cellular glycosylation may increase the risk of severe influenza as a result of the increased ability of glycome-modified influenza viruses to evade the immune response. IMPORTANCE People with disorders such as cancer, autoimmune disease, diabetes, or obesity often have metabolic dysregulation of cellular glycosylation and also have more severe influenza disease, a reduced immune response to the virus, and reduced vaccine efficacy. Since influenza viruses that infect such people do not show consistent genomic variations, it is generally assumed that the altered biology is mainly related to host factors. However, since host cells are responsible for glycosylation of influenza virus hemagglutinin and neuraminidase, and glycosylation is important for interactions of these proteins with the immune system, the viruses may have functional differences that are not reflected by their genomic sequence. Here, we show that imbalanced cellular glycosylation can modify the viral glycome without genomic changes, leading to reduced innate and adaptive host immune responses to infection. Our findings link metabolic dysregulation of host glycosylation to increased risk of severe influenza and reduced influenza virus vaccine efficacy.https://journals.asm.org/doi/10.1128/mbio.02983-21virusinfluenzahemagglutininneuraminidasepathogenicityNGI-1 |
| spellingShingle | Irina V. Alymova John F. Cipollo Lisa M. Parsons Nedzad Music Ram P. Kamal Wen-Pin Tzeng Cynthia S. Goldsmith Joseph N. Contessa Kevan L. Hartshorn Jason R. Wilson Hui Zeng Shane Gansebom Ian A. York Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome mBio virus influenza hemagglutinin neuraminidase pathogenicity NGI-1 |
| title | Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome |
| title_full | Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome |
| title_fullStr | Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome |
| title_full_unstemmed | Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome |
| title_short | Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome |
| title_sort | aberrant cellular glycosylation may increase the ability of influenza viruses to escape host immune responses through modification of the viral glycome |
| topic | virus influenza hemagglutinin neuraminidase pathogenicity NGI-1 |
| url | https://journals.asm.org/doi/10.1128/mbio.02983-21 |
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