Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2

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

Research output: Contribution to journalArticlepeer-review


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-91 NK cells exhibit an activated and mature phenotype with higher expression of CD16 (Fcg RIII; 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-91 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.

Original languageEnglish (US)
Issue number1
StatePublished - Jan 2023
Externally publishedYes


  • antibody-dependent cell cytotoxicity
  • COVID-19
  • natural killer cells
  • SARS-CoV-2
  • Siglec-7
  • Siglec-9

ASJC Scopus subject areas

  • Microbiology
  • Virology


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