In line with these studies, higher frequencies of the functional A-telomeric activating receptor KIR2DS4  and the inhibitory receptors KIR2DL1 and KIR2DL1/S1  are associated with severe COVID-19, whereas a higher frequency of activating receptor KIR3DS1 in the presence of HLA-B*15:01 is associated with moderate and/or moderate COVID-19 . 5. findings, NK-cell-based therapies with anti-SARS-CoV-2 activity, antifibrotic activity, and strong safety profiles for cancers may encourage the rapid application of functional NK cells as a potential therapeutic strategy to eliminate SARS-CoV-2-infected cells at an early stage, facilitate immuneCimmune cell interactions, and favor inflammatory processes that prevent and/or reverse over-inflammation and inhibit fibrosis progression, thereby helping in the fight against COVID-19. However, our understanding of the role of NK cells in COVID-19 remains incomplete, and further research around the involvement of NK cells in the pathogenesis of COVID-19 is needed. The rationale of NK-cell-based therapies for COVID-19 has to be based on the timing of therapeutic interventions and disease severity, which may be decided by the balance between beneficial antiviral and potential detrimental pathologic actions. NK cells would be more effective early in SARS-CoV-2 contamination and prevent the progression of COVID-19. Immunomodulation by NK cells towards regulatory functions could be useful as an adjunct therapy to prevent the progression of COVID-19. deletion may naturally occur, and is usually associated with a significantly low NKG2C expression level, or the absence of expression . In addition, HLA-E* 0101/0103 genetic variants occur, which are attributable to a single-nucleotide polymorphism, and the cell surface expression level of HLA-E* 0101/0101 is lower than that of HLA-E* 0103/0103 . The deletions of and, at a lower degree, the HLA-E* 0101 allele are impartial risk factors for severe COVID-19, suggesting that genetic variants in the NKG2C/HLA-E axis have a significant impact on COVID-19 severity. Detection of these variants my help identify Specnuezhenide patients at high risk of developing severe COVID-19 . Moreover, KIRs expressed on NK cells are crucial in regulating NK cell responsiveness through their binding to HLA class I ligands on cells [45,46]. A study has shown that this reduced gene coding for the activating receptor KIR2DS2 is usually associated with severe COVID-19 . In particular, the frequency of the KIR2DS2/HLA C1 functional unit was reduced in severe COVID-19, suggesting a protective effect against adverse outcomes of COVID-19, which is probably achieved through the effective activity of NK cells, and thereby contributes to viral clearance in the early stages of SARS-CoV-2 contamination . In line with these studies, higher frequencies of the functional A-telomeric activating receptor KIR2DS4  and the inhibitory receptors KIR2DL1 and KIR2DL1/S1  are associated with severe COVID-19, whereas a higher frequency of activating receptor KIR3DS1 in the presence of HLA-B*15:01 is associated with moderate and/or moderate COVID-19 . 5. Dysregulation of NK Cells in COVID-19 Patients The immune responses to SARS-CoV-2 are key determinants of COVID-19 severity and outcome [11,12]; therefore, understanding the immunological underpinnings of COVID-19 pathogenesis is critical for the prevention of SARS-CoV-2 contamination and COVID-19 treatment. NK cells are important in the immune defense against viral infections [24,56,57,58] and are the crucial responders to SARS-CoV-2 contamination [26,27,28]. However, dysregulation of NK cells has been observed, the cells exhibiting depletion and dysfunction in COVID-19 patients [26,27,28,33,34,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90] (Physique 1), accompanied by expansions of adaptive NK cells [26,77,79,89] and more mature perforin- and granzyme B-armed CD56bright NK cells [77,89], as well as the recruitment of CD34+DNAM-1brightCXCR4+ Specnuezhenide inflammatory precursors from the bone marrow . Open in a separate windows Physique 1 Schematic representation of human NK cells in healthy individual and COVID-19 patient. (A): Healthy human NK cells express the surface molecules CD56 and CD16; the inhibitory receptors MHC-I-specific killer cell immunoglobulin-like receptors (KIRs) and lectin-like CD94CNKG2A heterodimers; the activating receptors of NKG2D; natural cytotoxic receptors NKp30, NKp44, and NKp46; the cytokine receptors of IL-2, IL-12, IL-15, and IL-18; the chemokine receptors CXCR1 and CX3CR1; the Specnuezhenide effector molecules of cytokines IL-2, IFN-, and TNF-; and cytolytic granules made up of perforin and granzyme [45,46,49,52]. (B): In the peripheral blood of COVID-19 Rabbit polyclonal to KATNB1 patients, dysregulation of NK cells has been observed, the cells exhibiting depletion and Specnuezhenide dysfunction. They show increased expression levels of CD38, HLA-DR, CD69, and Ksp37, and they exhibit a skewing to exhaustion, with increased expression levels of inhibitory receptors, such as NKG2A, Tim-3, CD244, PD-1, and CD39. Activating receptors with decreased expression levels include NKG2D, Siglec-7, DNAM-1, NKp46, and CD16. As a consequence, NK cells secrete reduced amounts of cytokines, such as IL-2, IFN-, and TNF-, and show reduced degranulation, such as CD107a expression, whereas the production of chemokine MIP- is usually increased. Moreover, NK cells show increased expression levels of.