Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2
ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2023-02-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03393-22 |
| _version_ | 1811163383930552320 |
|---|---|
| author | Pratima Saini Opeyemi S. Adeniji Devivasha Bordoloi Jennifer Kinslow Jeff Martinson Danielle M. Parent Kai Ying Hong Jane Koshy Abhijeet J. Kulkarni Netanel F. Zilberstein Robert A. Balk James N. Moy Leila B. Giron Russell P. Tracy Ali Keshavarzian Kar Muthumani Alan Landay David B. Weiner Mohamed Abdel-Mohsen |
| author_facet | Pratima Saini Opeyemi S. Adeniji Devivasha Bordoloi Jennifer Kinslow Jeff Martinson Danielle M. Parent Kai Ying Hong Jane Koshy Abhijeet J. Kulkarni Netanel F. Zilberstein Robert A. Balk James N. Moy Leila B. Giron Russell P. Tracy Ali Keshavarzian Kar Muthumani Alan Landay David B. Weiner Mohamed Abdel-Mohsen |
| author_sort | Pratima Saini |
| collection | DOAJ |
| description | ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9– NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9– CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance. |
| first_indexed | 2024-04-10T06:44:14Z |
| format | Article |
| id | doaj.art-9b30c013c37148c591071bf5b0975101 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-10T06:44:14Z |
| publishDate | 2023-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-9b30c013c37148c591071bf5b09751012023-02-28T14:06:24ZengAmerican Society for MicrobiologymBio2150-75112023-02-0114110.1128/mbio.03393-22Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2Pratima Saini0Opeyemi S. Adeniji1Devivasha Bordoloi2Jennifer Kinslow3Jeff Martinson4Danielle M. Parent5Kai Ying Hong6Jane Koshy7Abhijeet J. Kulkarni8Netanel F. Zilberstein9Robert A. Balk10James N. Moy11Leila B. Giron12Russell P. Tracy13Ali Keshavarzian14Kar Muthumani15Alan Landay16David B. Weiner17Mohamed Abdel-Mohsen18The Wistar Institute, Philadelphia, Pennsylvania, USAThe Wistar Institute, Philadelphia, Pennsylvania, USAThe Wistar Institute, Philadelphia, Pennsylvania, USARush University, Chicago, Illinois, USARush University, Chicago, Illinois, USAUniversity of Vermont, Burlington, Vermont, USAThe Wistar Institute, Philadelphia, Pennsylvania, USAThe Wistar Institute, Philadelphia, Pennsylvania, USAThe Wistar Institute, Philadelphia, Pennsylvania, USARush University, Chicago, Illinois, USARush University, Chicago, Illinois, USARush University, Chicago, Illinois, USAThe Wistar Institute, Philadelphia, Pennsylvania, USAUniversity of Vermont, Burlington, Vermont, USARush University, Chicago, Illinois, USAThe Wistar Institute, Philadelphia, Pennsylvania, USARush University, Chicago, Illinois, USAThe Wistar Institute, Philadelphia, Pennsylvania, USAThe Wistar Institute, Philadelphia, Pennsylvania, USAABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9– NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9– CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.https://journals.asm.org/doi/10.1128/mbio.03393-22SARS-CoV-2COVID-19natural killer cellsSiglec-7Siglec-9antibody-dependent cell cytotoxicity |
| spellingShingle | Pratima Saini Opeyemi S. Adeniji Devivasha Bordoloi Jennifer Kinslow Jeff Martinson Danielle M. Parent Kai Ying Hong Jane Koshy Abhijeet J. Kulkarni Netanel F. Zilberstein Robert A. Balk James N. Moy Leila B. Giron Russell P. Tracy Ali Keshavarzian Kar Muthumani Alan Landay David B. Weiner Mohamed Abdel-Mohsen Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2 mBio SARS-CoV-2 COVID-19 natural killer cells Siglec-7 Siglec-9 antibody-dependent cell cytotoxicity |
| title | Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2 |
| title_full | Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2 |
| title_fullStr | Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2 |
| title_full_unstemmed | Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2 |
| title_short | Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2 |
| title_sort | siglec 9 restrains antibody dependent natural killer cell cytotoxicity against sars cov 2 |
| topic | SARS-CoV-2 COVID-19 natural killer cells Siglec-7 Siglec-9 antibody-dependent cell cytotoxicity |
| url | https://journals.asm.org/doi/10.1128/mbio.03393-22 |
| work_keys_str_mv | AT pratimasaini siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT opeyemisadeniji siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT devivashabordoloi siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT jenniferkinslow siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT jeffmartinson siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT daniellemparent siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT kaiyinghong siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT janekoshy siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT abhijeetjkulkarni siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT netanelfzilberstein siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT robertabalk siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT jamesnmoy siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT leilabgiron siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT russellptracy siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT alikeshavarzian siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT karmuthumani siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT alanlanday siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT davidbweiner siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 AT mohamedabdelmohsen siglec9restrainsantibodydependentnaturalkillercellcytotoxicityagainstsarscov2 |