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Source: COVID-19 Immunology  Jun 23, 2022  1 year, 7 months, 4 weeks, 21 hours, 9 minutes ago

Stanford Study Shows That The SARS-CoV-2 Coronavirus Is Able To Evade Cytotoxic Responses Of Natural Killer Cells And Cause Immune Dysfunction!

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Stanford Study Shows That The SARS-CoV-2 Coronavirus Is Able To Evade Cytotoxic Responses Of Natural Killer Cells And Cause Immune Dysfunction!
Source: COVID-19 Immunology  Jun 23, 2022  1 year, 7 months, 4 weeks, 21 hours, 9 minutes ago
COVID-19 Immunology: A new study by researchers from Stanford University School of Medicine has found that the SARS-CoV-2 coronavirus is able to evade cytotoxic responses of natural killer cells and cause immune dysfunction!

Basically, a key component of the immune system, natural killer (NK) cells are cytotoxic effector cells that respond rapidly to viral infection by targeting and lysing infected cells, and many viruses encode mechanisms to escape such NK cell killing.
The study team sought to investigate the ability of SARS-CoV-2 to modulate NK cell recognition and lysis of infected cells.
The COVID-19 Immunology study findings showed that NK cells exhibit poor cytotoxic responses against SARS-CoV-2-infected targets, preferentially killing uninfected bystander cells.
The study findings demonstrated that this escape is driven by strong downregulation of ligands for the activating receptor NKG2D on SARS-CoV-2-infected cells. Indeed, in the initial stages of viral infection, prior to NKG2D-ligand downregulation, NK cells are able to successfully target and kill infected cells; however, this ability is lost as viral proteins are expressed within infected cells.
The study findings also showed that SARS-CoV-2 non-structural protein 1 (Nsp1) mediates the downregulation of NKG2D ligands and that transfection with Nsp1 alone is sufficient to confer resistance to NK cell killing.
The study findings reveal that SARS-CoV-2 evades NK cell cytotoxic responses and describes a mechanism by which this occurs.
The study findings were published on a preprint server and are currently being peer reviewed.
This is the first study to date to reveal the mechanism as to how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escapes natural killer (NK) cell cytotoxic reactions.
Typically, the immune reaction to viral infection is influenced significantly by NK cells, which are innate lymphocytes. These cytotoxic effector cells react quickly to viral infection via addressing and lysing infected cells.
Numerous past research evaluating the immune reaction in the COVID-19 disease during the SARS-CoV-2 pandemic have found that NK cells are less prevalent in the peripheral blood of severe SARS-CoV-2 patients versus healthy donors. In addition, immune profiling has revealed substantial, severity-related transcriptional and phenotypic alterations in the peripheral NK cells that persist in SARS-CoV-2 patients' blood.
Despite the fact that multiple past studies have shown NK cells can inhibit SARS-CoV-2 replication in vitro, the mechanism via which NK cells react immediately to SARS-CoV-2-infected cells remains uncertain. This is especially crucial because several viruses adopt techniques to avoid being detected and eliminated by NK cells.
The study team from Stanford aimed to assess the capacity of SARS-CoV-2 to adjust NK cell identification and lysis of virus-infected cells.
The study team developed an in vitro model approach that analyzes the NK cell re action to SARS-CoV-2-infected cells using primary NK cells derived from healthy donors and replication-competent SARS-CoV-2. To further elucidate how the balance between SARS-CoV-2 detection and escape leads to COVID-19, they concentrated on examining the direct killing of SARS-CoV-2-infected target cells by the NK cells.
The study team used adenocarcinomic human alveolar basal epithelial (A549)-angiotensin-converting enzyme 2 (ACE2) cells, identified and lysed by NK cells and are SARS-CoV-2 infectible, as a model to study the NK cell reaction to COVID-19.
The study team introduced NK cells obtained from healthy donors preactivated overnight with interleukin 2 (IL-2) to address cells infected with SARS-CoV-2 for 48 hours to comprehend how exposure to SARS-CoV-2-infected target cells affects NK cell activity and phenotype.
The team evaluated whether SARS-CoV-2 modifies NK cells' capacity to annihilate infected target cells. Further, they explored how SARS-CoV-2-infected cells managed to escape being lysed and recognized by NK cells.
The study team examined NK group 2D-ligand (NKG2D-L) expression on the cells that persisted after being co-cultured with NK cells to investigate the relationship between NKG2D-L expression and the killing of SARS-CoV-2-infected cells. The team then tried to figure out how SARS-CoV-2 affects NKG2D-L protein expression across SARS-CoV-2-infected cells.
The study findings showed that NK cells have weak cytotoxic reactions towards SARS-CoV-2-infected targets, selectively killing non-infected bystander cells.
The study findings furthermore showed that the SARS-CoV-2-infected cells' significant downregulation of ligands for the stimulating NKG2D receptor was what caused this escape from NK cell-mediated killing.
Although, NK cells may efficiently identify and kill infected cells in the early phases of SARS-CoV-2 infection before NKG2D-L downregulation. Nevertheless, the NK cells lose this ability following the expression of viral proteins inside infected cells.
Importantly the study findings showed that, when introduced to the culture at later timestamps following SARS-CoV-2 infection, post-expression of viral proteins that dampen the innate immune response, NK cells cannot kill infected cells effectively.
As a result of only a small window existing for the elimination of the infected cells before bystander cell killing might occur, the study team noted that the timing of NK cell migration to the infection site could be crucial in deciding whether NK cells were pathogenic or protective in COVID-19.
The study findings also discovered that SARS-CoV-2 non-structural protein 1 (Nsp1) causes the downregulation of NKG2D-L. The study team also illustrated that transfection with just Nsp1 was enough to impart tolerance to NK cell killing.
This discovered observation has crucial implications for NK cell-facilitated regulation of SARS-CoV-2 since the preferred evasion of infected cells with the killing of bystander cells might lead to SARS-CoV-2 pathogenesis.
The study as a whole, deeply examines the NK cell reaction to SARS-CoV-2 and offers new information about the function of NK cells in COVID-19.
The study team discovered that SARS-CoV-2-infected cells evade being destroyed by healthy NK cells in a cell-intrinsic way, leading to the preferential destruction of non-infected bystander cells. The capability of infected cells to escape NK cell identification needs infection to last long enough to facilitate an infected cell to exhibit SARS-CoV-2 encoded proteins. Besides, the present results highlight the significance of studying the temporal dynamics of the NK cell reaction to SARS-CoV-2-infected cells.
The study team also showed that the downregulation of NKG2D-L drives the process of NK cell recognition evasion of SARS-CoV-2. The primary characteristic in the NK cell response to SARS-CoV-2, according to the findings, was the loss of NKG2D-L. The study data further demonstrated that the SARS-CoV-2 Nsp1 protein was responsible for this ligand downregulation and that Nsp1 itself was adequate to induce direct NK cell escape.
The study findings show that NK cell responses to SARS-CoV-2-infected cells might be partially or fully rescued by reducing the activity of Nsp1, proving that this protein was an even more desirable target than previously believed.
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