HLA-E*01:01 + HLA-E*01:01 genotype confers less susceptibility to COVID-19, while HLA-E*01:03 + HLA-E*01:03 genotype is associated with more severe disease.

BACKGROUND: HLA-E interaction with inhibitory receptor, NKG2A attenuates NK-mediated cytotoxicity. NKG2A overexpression by SARS-CoV-2 exhausts NK cells function, whereas virus-induced down-regulation of MHC-Ia reduces its derived-leader sequence peptide levels required for proper binding of HLA-E to NKG2A. This leads HLA-E to become more complex with viral antigens and delivers them to CD8+ T cells, which facilitates cytolysis of infected cells. Now, the fact that alleles of HLA-E have different levels of expression and affinity for MHC Ia-derived peptide raises the question of whether HLA-E polymorphisms affect susceptibility to COVID-19 or its severity. METHODS: 104 COVID-19 convalescent plasma donors with/without history of hospitalization and 18 blood donors with asymptomatic COVID-19, all were positive for anti-SARS-CoV-2 IgG antibody as well as a group of healthy control including 68 blood donors with negative antibody were subjected to HLA-E genotyping. As a privilege, individuals hadn't been vaccinated against COVID-19 and therefore naturally exposed to the SARS-CoV-2. RESULTS: The absence of HLA-E*01:03 allele significantly decreases the odds of susceptibility to SARS-CoV-2 infection [p = 0.044; OR (95 %CI) = 0.530 (0.286 - 0.983)], suggesting that HLA-E*01:01 + HLA-E*01:01 genotype favors more protection against SARS-CoV-2 infection. HLA-E*01:03 + HLA-E*01:03 genotype was also significantly associated with more severe COVID-19 [p = 0.020; 2.606 (1.163 - 5.844) CONCLUSION: Here, our observation about lower susceptibility of HLA-E*01:01 + HLA-E*01:01 genotype to COVID-19 could be clinical evidence in support of some previous studies suggesting that the lower affinity of HLA-E*01:01 to peptides derived from the leader sequence of MHC class Ia may instead shift its binding to virus-derived peptides, which then facilitates target recognition by restricted conventional CD8+ T cells and leads to efficient cytolysis. On the other hand, according to other studies, less reactivity of HLA-E*01:01 with NKG2A abrogates NK cells or T cells inhibition, which may also lead to a greater cytotoxicity against SARS-CoV-2 infected cells compared to HLA-E*01:03. Taken together given HLA-E polymorphisms, the data presented here may be useful in identifying more vulnerable individuals to COVID-19 for better care and management. Especially since along with other risk factors in patients, having HLA-E*01:03 + HLA-E*01:03 genotype may also be associated with the possibility of severe cases of the disease.

Exhausted NK cells and cytokine storms in COVID-19: Whether NK cell therapy could be a therapeutic choice.

The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed "cytokine storm", a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles' heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research.