What is the link between natural killer cell dysfunction and the severity of COVID-19 disease?

In a recent review published in Cell biochemistry and functionResearchers evaluated the association between natural killer (NK) cell dysfunction and the severity of coronavirus disease 2019 (COVID-19) disease.

Background

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection is characterized by symptoms such as coughing, fever, and weakness. NK cells are the primary defense barrier used by the innate immune system against lung viruses. Various studies have reported that the cytotoxic role of NK cells adversely affects COVID-19 patients.

NK cell dysfunction and virus susceptibility

Although NK cells are the major immune effector cells responsible for antiviral reactions, various studies have shown that NK cells inhibit their cytotoxic function by various mechanisms during viral infection. According to recent reports, infections caused by cytomegalovirus (CMV) may regulate NKG2D ligands present on the surface of CMV-infected cells. NKG2D functions as an activating receptor expressed on NK cells present in mice and humans.In addition, the team focused on NKG2A upregulation.³⁴ In addition, downregulation of NKG2D may reduce the cytotoxicity of NK cells to CMV.

The team observed that the presence of a specific combination of NK cell receptors and their respective cellular ligands altered the outcomes associated with human immunodeficiency virus (HIV) -1. Therefore, understanding the mechanisms involved in viral jailbreak and regulating immune surveillance may help develop immune regulatory pathways. The role of NK cells in controlling COVID-19 infection is involved in destroying the infected virus by inducing apoptosis through several mechanisms such as granzymes and perforin degranulation. NK cells can also lyse target cells via receptor-mediated apoptosis and tumor necrosis factor (TNF) -related apoptosis-inducing ligands.

Several studies have reported disruption of NK cell function in patients with COVID-19 with inhibitory and dysregulation of activated receptors. In addition, a low proportion of NK cells and lymphocytes was reported in the peripheral blood of COVID-19 patients. In addition, the chemokine storms observed in COVID-19 patients can induce immune cells to invade the lungs. A direct association between high expression of CC motif chemokine ligand 3 (CCL3), CCL4, CXCL9, CXCL10, CXCL11 in infected lungs and the severity of COVID-19 disease was also reported. The team also found high levels of interleukin-6 (IL-6), IL-1Ra, CCL2, CCL8, chemokine CXC motif ligand 2 (CXCL2), CXCL8, CXCL9, and CXCL16 in patients infected with COVID-19. I noticed.

NKG2C

The team reported that the interactions that occur between ligands and their cognate receptors can activate or inhibit NK cell-mediated cytotoxicity. CD94 / NKG2 is expressed on CD8 + and N cells as a C-type lectin-like receptor. NKG2 is found in the form of five molecular species such as NKG2A, B, C, E and H.Among these, the interaction between NKG2C / CD94 and human leukocytes antigen The E (HLA-E) ligand activates the NK cell response to virus-infected cells. In addition, a direct association was observed between the severity of viral infection and the lack of NKG2C receptors.

Cytokine storm

team is, Cytokine storm The experience of COVID-19 patients is an important reason for the decline in NK cell function. In healthy people, NK cells efficiently destroy infected macrophages and other cells that cause cytokine storms, reducing cyclic numbers. Studies show that increased concentrations of IL-1, IL-6, IL-18, IL-8, IL-10, and TNF-α in COVID-19 patients suppress NK cell cytotoxicity and lung tissue. Has been shown to be damaged. One study also showed that high proportions of IL-6 cytokines reduced the expression of granzyme B and perforin in NK cells. IL-10 and IL-6 reduced the cytotoxicity of NK cells in COVID-19 patients by down-regulating the stimulation of granzyme B, IFN-α, and perforin.

NK cell-based immunotherapy

The cytotoxic activity of NK cells is inhibited in COVID-19 patients by several factors, including down-regulation of activated receptors, high levels of inhibitory receptors, and cytokine storms.

Blocking inhibitory receptors by specific monoclonal antibodies

In healthy people, normal healthy cells avoid the effects of NK cells through inhibitory interactions between receptors and ligands. Researchers observed that infiltrating cells present in COVID-19 patients avoided Nk cell-mediated killing by upregulating inhibitory cells. Therefore, blocking inhibitory receptors may enhance the antitumor immune response of NK cells. One study also showed that incubation of NK cells with anti-NKG2A such as monarizumab may improve the cytotoxic function of NK cells in COVID-19 patients.

Conclusion

Research results show that NK cells play a major role in controlling COVID-19 infection in infected patients. Researchers have observed during COVID-19 infection that they manipulate key components of the immune response, such as NK cells, regulate excessive cytokine secretion, and target inhibitory receptors with monoclonal antibodies. We believe that it is a useful approach to restore the suppression of NK cells.