COVID-19 News: Study Finds That SARS-CoV-2 Impairs Natural Killer (NK) Cells' Functions!

COVID-19 News: A new study lead by researchers from The Wistar Institute, Philadelphia, Pennsylvania-USA has found that the SARS-CoV-2 virus is able to impair natural killer cell functions.


 
The study showed that a glyco-immune checkpoint, Siglec-9 restrains antibody-dependent natural killer cell cytotoxicity against SARS-CoV-2.
 
The cytotoxic potential of NK cells is determined by the balance of opposing signals resulting from multiple activating (such as NKG2C) and inhibitory (such as NKG2A) receptors expressed on the surface of these cells.
 
Among the inhibitory receptors, NK cells express two that belong to a family of emerging glyco-immune checkpoints called Siglecs: Siglec-7 and Siglec-9.
 
Siglecs are sialic-acid-binding, immunoglobulin-like lectins that inhibit immune functions by interacting with sialoglycans (sialic acid-containing glycomic structures) on target cells and signaling through intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs).
 
Typically, in cancer, Siglec-sialoglycan interactions help tumor cells to evade NK immune surveillance.
 
However, recently, these interactions have been suggested to also help hepatitis B virus (HBV)- and HIV-infected cells to evade NK immune surveillance.
 
Despite a growing appreciation of Siglecs as glyco-immune negative checkpoints during cancer and viral infections, their role in helping SARS-CoV-2 evade immune surveillance has never been examined.
 
This is the first study to confirm that Siglec-9 helps the SARS-CoV-2 to evade the NK cells as well.
 
The study team also comprised of researchers from Rush University, Chicago, Illinois-USA and University of Vermont, Burlington, Vermont-USA.     
   
SARS-CoV-2 infection are already known to alters the immunological profiles of natural killer (NK) cells.
 
To date however, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear.
 
The study team 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.
 
Interestingly, the lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen.
 
Detailed 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.
 
The study findings 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 inhi bitory 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.
 
The study findings 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.
 
The study findings were published in the peer reviewed journal: mBio.
https://journals.asm.org/doi/10.1128/mbio.03393-22
 
Past COVID-19 News coverages had also shown that the SARs-CoV-2 virus can evade the NK cells using the NSp1 proteins.
https://www.thailandmedical.news/news/covid-19-news-stanford-study-discovers-sars-cov-2-evades-immune-system-s-nk-cells-via-nsp1-induced-downregulation-of-receptor-nkg2d-ligands
 
Other studies have also showed that the SARS-CoV-2 is able to evade the NK cells.
https://www.thailandmedical.news/news/stanford-study-shows-that-the-sars-cov-2-coronavirus-is-able-to-evade-cytotoxic-responses-of-natural-killer-cells-and-cause-immune-dysfunction
 
Past studies have also showed that severe COVID-19 is associated with alterations to NK cell profiles.
https://pubmed.ncbi.nlm.nih.gov/33060840/
 
The current study data suggest that severe COVID-19 is not only associated with alterations to the phenotypic profiles of NK cells, but also with reductions in their cytolytic and ADCC activity.
 
The study team focused on NK cells expressing Siglec-7 and/or Siglec-9.
 
Siglecs are emerging ITIM-containing, major histocompatibility complex (MHC)-independent inhibitory receptors that control host immune responses by interacting with sialoglycans on the surface of target cells.
 
Siglec-7 is expressed on almost all NK cells and binds to α2-8 Sialic acid, whereas Siglec-9 is selectively expressed on a subset of CD56dim NK cells and binds to α2-3 Sialic acid.
 
The study team identified the Siglec-7– CD56dim NK subpopulation, which is accumulated during severe COVID-19, as a dysfunctional NK subpopulation during SARS-CoV-2 infection. This is consistent with previous reports describing decreased levels of Siglec-7 as a marker for dysfunctional NK cells during HIV infection.
https://pubmed.ncbi.nlm.nih.gov/19710502/
 
https://pubmed.ncbi.nlm.nih.gov/24330394/
 
https://pubmed.ncbi.nlm.nih.gov/28810810/
 
the study team also identified the Siglec-9+ CD56dim NK subpopulation, which has never been implicated during SARS-CoV-2 infection, as a highly cytotoxic NK subpopulation.
 
This is also consistent with previous reports that this NK subpopulation exhibits high antiviral activity during HIV infection.
https://pubmed.ncbi.nlm.nih.gov/34762717/
 
Interestingly, the Siglec-9+ CD56dim NK cells have an activated phenotype (higher expression of activating receptors and lower expression of inhibitory receptors) during cancer, HBV infection, and HIV infection.
 
The study team also found that the Siglec-9+ CD56dim NK exhibits an activated phenotype with higher levels of activating/maturation receptors and markers and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9– CD56dim NK cells, during SARS-CoV-2 infection.
 
The study data showed that these cells have an activated phenotype even in healthy controls, suggesting that this cell population is naturally activated with potential cytotoxic capacity and could be exploited against several viral and nonviral infections.
 
Also, the highly activated phenotype of the Siglec-9+ CD56dim NK cells is consistent with the study team’s functional analysis demonstrating that Siglec-9+ NK cells exhibit higher ADCC than Siglec-9– NK cells.
 
The study findings are consistent with the highly cytotoxic nature of Siglec-9+ NK cells. However, the Siglec-9 receptor itself is an inhibitory receptor that restrains the cytolytic ability of these otherwise highly cytotoxic Siglec-9+ NK cells. The binding of Siglec-9 to α2-3 Sialic acid on target cells induces an inhibitory signal transduction cascade by recruiting the tyrosine phosphatase SHP-1, which counteracts the phosphorylation-mediated activation of other signaling molecules.
 
Significantly, blocking Siglec-9 further enhanced the ability of NK cells to kill target cells expressing SARS-CoV-2 antigen by ADCC.
 
The study findings are consistent with the known inhibitory function of the Siglec-9 molecule itself on these otherwise cytotoxic cells.
 
The study findings support a model in which Siglec-9+ CD56dim NK cells are cytotoxic but are restrained by the inhibitory nature of Siglec-9 receptor signaling.
 
The study findings also indicate that blocking Siglec-9 interactions is a promising strategy to unleash the full potential of the Sigec-9+ NK subpopulation that is otherwise highly cytotoxic.
 
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