COVID-19 News: Stanford Study Discovers SARS-CoV-2 Evades Immune System’s NK Cells Via Nsp1-Induced Downregulation Of Receptor NKG2D Ligands!

COVID-19 News: Numerous studies have already validated that the SARS-CoV-2 virus is able to evade and also disarm various components of the human host’s immune system, in the process leading to immune dysfunction and also what is now being termed as COVID-19 induced immunodeficiency, which all have long term health impacts on individuals exposed to the virus.


 
https://www.thailandmedical.news/news/why-is-no-one-warning-the-masses-that-the-sars-cov-2-spike-proteins-are-causing-major-immunodeficiency-issues-in-all-infected-individuals
 
https://www.thailandmedical.news/news/covid-19-news-charlatans-promoting-immunity-debt-for-rise-in-pediatric-viral-infections!-sars-cov-2-destroying-children-s-robust-innate-system-is-the-
 
https://www.thailandmedical.news/news/warning-newer-sars-cov-2-variants-have-evolved-to-overcome-the-robust-innate-immune-system-of-children-infants-and-children-are-more-vulnerable-now
 
https://www.thailandmedical.news/news/-sars-cov-2-upregulates-cd55-complement-regulator-and-prolongs-its-activation-causing-an-immune-dysfunction-that-contributes-to-disease-severity-in-so
 
https://www.thailandmedical.news/news/yale-study-discovers-that-sars-cov-2-proteins-orf7a-and-orf3a-downregulates-mhc-i-expression-aiding-in-immune-evasion-and-immune-dysfunction
 
https://www.thailandmedical.news/news/even-mild-and-moderate-sars-cov-2-infections-causes-transcriptional-reprogramming-of-the-host-s-cd14-monocytes-resulting-in-dysfunctional-monocytes
 
https://www.thailandmedical.news/news/breaking-university-of-texas-study-discovers-that-sars-cov-2-alters-human-host-chromatin-complex-to-cause-immune-dysfunction
 
https://www.thailandmedical.news/news/virus-new s-university-of-alabama-study-alarmingly-shows-that-individuals-recovering-from-covid-19-exhibit-sustained-cellular-immune-dysregulation-
 
https://www.thailandmedical.news/news/covid-19-research-study-finds-that-sars-cov-2-orf3c-protein-localizes-to-mitochondria,-inhibiting-innate-immunity-by-restricting-ifn-%CE%92-production
 
https://www.thailandmedical.news/news/breaking-oxford-study-reveals-new-omicron-variants-and-sub-lineages-causes-impaired-t-cell-immunogenicity-with-potential-for-t-cell-immunity-escape
 
https://www.thailandmedical.news/news/uk-study-finds-that-sars-cov-2-spike-mutation-p272l-emerged-to-evade-killer-t-cells-induced-by-infection-and-inoculation
 
https://www.thailandmedical.news/news/covid-19-alert-new-study-shows-sars-cov-2-coronavirus-targets-and-destroys-t-cells,-similarly-as-what-hiv-does
 
https://www.thailandmedical.news/news/covid-19-immunity-study-finds-immune-scars-on-patients-with-lung-infections-making-them-more-vulnerable,-warning-for-coming-flu-season
 
https://www.thailandmedical.news/news/breaking-news-study-of-covid-19-recovered-patients-in-china-reveals-that-lymphocytes-are-drastically-altered-to-become-dysfunctional-with-immunity-imp
 
(Please note that there are more than 158 COVID-19 News articles in Thailand Medical New’s repository of SARS-CoV-2 research that reflects on how the SARS-CoV-2 causes immune dysfunction. Please use the site’s own search function)
 
What is important is that while researchers and scientists have been tracking the newly emerging SARS-CoV-2 variants and sub-lineages and also monitoring their immune evasiveness, very little efforts have gone into researching the detailed pathogenesis of these newly emerging variants and sub-lineages and how they are developing even newer ways to ‘disarm’ and damage the human host immune system so as to accommodate its longer periods of viral persistence.
 
A new study by researchers from Stanford University School of Medicine-USA has found that the SARS-CoV-2 coronavirus is able to evades the immune system’s NK (Natural Killer) cells via Nsp1-induced downregulation of receptor NKG2D ligands!
 
Natural killer (NK) cells, are a type of immune cells that belong to the white cell group that is critical to the innate immune system. They are a type of cytotoxic lymphocytes that has granules (small particles) with enzymes that can kill tumor cells or cells infected with a virus. They are basically cytotoxic effector cells that target and lyse virally-infected cells; many viruses therefore encode mechanisms to escape such NK cell killing.
 
The study team investigated the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells.
 
The researchers found that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells.
 
The study findings demonstrate that this escape is driven by downregulation of ligands for the activating receptor NKG2D (“NKG2D-L”).
 
Importantly, it was found that early in viral infection, prior to NKG2D-L downregulation, NK cells are able to target and kill infected cells; however, this ability is lost as viral proteins are expressed.
 
The study findings showed that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates downregulation of NKG2D-L and that Nsp1 alone is sufficient to confer resistance to NK cell killing.
 
The study findings shows that SARS-CoV-2 evades direct NK cell cytotoxicity and describes a mechanism by which this occurs.
 
The study findings were published in the peer reviewed journal: Cell Reports.
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01791-0
 
Past studies examining the immune response in COVID-19 have noted that NK cells are less abundant in the peripheral blood of severe COVID-19 patients than in healthy donors, a concurrent increase in NK cell frequency in the lungs of critically ill patients suggests that peripheral depletion of NK cells may be due to trafficking to the site of infection.
 
Detailed immune profiling has uncovered significant, severity-associated phenotypic and transcriptional changes in the peripheral NK cells that remain in the blood of COVID-19 patients.
 
For instance, in severe COVID-19, peripheral blood NK cells become activated and exhausted. They also downregulate surface level expression of the activating receptors NKG2D and DNAM-1, possibly as a consequence of internalization after ligation and exhibit defects in their ability to respond to tumor target cells and cytokine stimulation compared to NK cells from healthy donors.
 
Little is known about how NK cells respond directly to SARS-CoV-2-infected cells, though several studies have demonstrated that NK cells can suppress SARS-CoV-2 replication in vitro.
 
A recent study found that NK cells are able to mount robust antibody-mediated responses against SARS-CoV-2-infected target cells.
 
The mechanisms underlying NK cell responses to SARS-CoV-2-infected cells however are not understood.
 
The study team utilized primary NK cells from healthy donors in conjunction with replication-competent SARS-CoV-2 to create an in vitro model system that dissects the NK cell response to SARS-CoV-2-infected cells.
 
The study team focused on assessing the direct killing of infected target cells in order to better understand how the balance between SARS-CoV-2 recognition and escape contributes to disease.
 
The ability of infected cells to evade NK cell recognition requires infection to proceed long enough to allow an infected cell to express SARS-CoV-2 encoded proteins.
 
The study team demonstrated that this escape mechanism is driven by downregulation of ligands for NKG2D, a critical activating receptor on NK cells.
 
They further demonstrated that this ligand downregulation is driven by the SARS-CoV-2 Nsp1 protein and show that Nsp1 alone is sufficient to mediate direct NK cell evasion.
 
While the study team’s experimental system using a cell line with high expression of NKG2D-L could enhance the degree of bystander killing, these study findings have important implications for NK cell-mediated control of SARS-CoV-2, as preferential escape of infected cells and possible killing of bystander cells could contribute to SARS-CoV-2 pathogenesis.
 
The study findings illustrate the importance of examining the temporal dynamics of the NK cell response to SARS-CoV-2-infected cells.
 
The study findings demonstrated that NK cells are no longer able to effectively kill infected cells when added to the culture at 48 hours post-infection, after the expression of viral proteins that suppress the innate immune response.
 
The preferential killing of NKG2D-L-positive bystander cells may have important implications for lung pathology during COVID-19. NKG2D-L can be expressed by most cell types and are upregulated during viral infections, including HIV and RSV, in response to stress.
 
Hence, it is possible that NK cells may actually cause damage to the healthy tissue surrounding infected cells rather than clearing the infection, although this hypothesis has not yet been directly tested in primary lung tissue.
 
Interestingly, as NK cells appear to home to the lungs during COVID-19, the study findings indicate that the timing of NK cell trafficking to the site of infection may impact the efficacy of the NK cell response to SARS-CoV-2 infection, as there is a very narrow window for killing of infected cells before bystander killing could ensue.
 
Past studies have showed that frequency of peripheral blood NK cells in severe COVID-19 patients negatively correlated with viral load; however, this is difficult to interpret in the context of the current study data because it is unknown whether the increased NK cell frequencies observed resulted from decreased trafficking to the lungs, increased peripheral proliferation, or another mechanism.
 
The study finding that the SARS-CoV-2 protein Nsp1 mediates evasion of NK cell killing has significant implications for both the study of the immune response to coronaviruses and the development of therapeutics for COVID-19.
 
Nsp1 is highly conserved across coronaviruses and is an essential virulence factor; it has been shown to inhibit translation of host antiviral factors across multiple beta-coronaviruses.
 
Interestingly, one study found that, among nearly 50,000 SARS-CoV-2 sequences analyzed, only 2.4% had any mutations within Nsp1.
 
The SARS-CoV-2 Nsp1 also shares 84.4% of its sequence identity with SARS-CoV Nsp1. Moreover, critical motifs within Nsp1 involved in the inhibition of innate immune responses are highly conserved across many betacoronaviruses. On a practical level, the high degree of conservation of Nsp1 and its importance in coronavirus virulence have already made this protein the focus of several therapeutic strategies.
 
The current study findings demonstrate that Nsp1 is an even more attractive target than previously thought, as inhibiting the function of this protein has the potential to fully or partially rescue the NK cell response to SARS-CoV-2-infected cells
 
Though Nsp1 is a global inhibitor of host translation, the study findings demonstrate that it has an outsized effect on NKG2D-L and MHC class I surface expression compared to that of other ligands for NK cell receptors. This appears to be due to the varying stabilities of the different ligands on the cell surface, rather than explicit specificity of Nsp1 for NKG2D-L or MHC class I.
 
It has been established that NKG2D-L are rapidly turned over on the cell surface and are quickly lost upon treatment with a protein transport inhibitor such as Brefeldin A.
 
MHC class I is similarly transient on the cell surface in the presence of translation inhibition, although its stability varies with haplotype and peptide binding.
 
CD54, which was not affected by Nsp1, is highly stable for at least 48 hours, even after treatment with similar inhibitors. Thus, the differential effects of Nsp1 on various ligands for NK cell receptors are likely explained by the varying kinetics of surface turnover.
 
Importantly, one of the study findings that has been demonstrated by multiple groups is the downregulation of MHC class I upon SARS-CoV-2 infection. The mechanism of this downregulation remains unclear; while the current study findings suggest that Nsp1 is responsible for this loss, ORF3a, ORF7a, ORF6, and ORF8 have also been implicated. This could be due to differential downregulation of various HLA molecules by different SARS-CoV-2 proteins.
 
In the current study, the researchers grouped together HLAs A, B, and C as there are no commercially available antibody clones that can robustly differentiate HLAs A and B; this is an important limitation of the study.
 
According to the well-established “missing self” model of NK cell activation, the downregulation of self-MHC can induce NK cell activation through subsequent lack of inhibitory signaling through the killer cell immunoglobulin-like receptors (KIRs). Therefore, it might be expected that the downregulation of MHC by SARS-CoV-2 would enhance the ability of NK cells to lyse infected cells–precisely the opposite of what was observed in this study.
 
The study team hypothesizes that this can be explained by 1) the relative magnitudes of MHC class I and NKG2D-L downregulation on infected cells and 2) the accepted dogma in the field that missing self alone is not sufficient to cause robust NK cell activation.
 
The study team proposes that the loss of NKG2D-L is the dominant factor in the NK cell response (or lack thereof) to SARS-CoV-2.
 
Although the study focuses on direct lysis of target cells, NK cells can also kill through antibody-dependent cellular cytotoxicity (ADCC).
 
A past study found that antibody-dependent NK cell activation can overcome SARS-CoV-2’s inhibition of direct cytotoxicity, allowing healthy NK cells to mount stronger responses to infected targets.
 
The study also identified downregulation of NKG2D-L on SARS-CoV-2-infected cells through an orthogonal method. This work has significant implications for the ongoing study of COVID-19.
 
The study findings deeply interrogate a potential flaw in the ability of the immune system to mount a comprehensive immune response to COVID-19.
 
The study team demonstrated that the timing of the NK cell response to SARS-CoV-2-infected target cells is critical, with NK cells being able to control viral replication early in infection, but not after expression of viral proteins has begun.
 
In summary, the study findings showed the following:
 
-SARS-CoV-2-infected cells are inefficiently killed by activated, healthy NK cells
 
-SARS-CoV-2 strongly downregulates the ligands for the activating receptor NKG2D
 
-SARS-CoV-2 protein Nsp1 mediates downregulation of NKG2D ligands
 
-Nsp1 alone is sufficient to confer significant resistance to NK-mediated killing
 
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