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Authors:HVietzenet al. 

Journal/Pre-Print: Researchsquare 

Tags: Clinical, Immunology/Immunity 

Research Highlights 

  1. Presence of the NKG2Cdel allele is strongly associated with severe COVID–19 requiring hospitalization and ICU admission (p = 0.0006 and p<0.0001, respectively, χ2-Test).  

  1. The presence of an HLA- E*0101 allele is associated with hospitalization and hospitalization in ICU (both: p = 0.01, χ2-Test).  

  1. Both genetic variants were found to be independent risk factors for severe COVID-19.  


This study analysed the association between the genetic variation of the NK cell activating receptor NKG2C and its ligand HLA-E and COVID-19 disease severity in a cohort of 361 confirmed cases vs. 100 age and sex matched controls. The authors found a significant associationbetween NKG2C deletion and hospitalisation (p=0.0006), particularly for ICU patients (p<0.0001). HLA-E*0101/0101, which is reported to be expressed at lower levels, was also associated with disease severity. The authors conclude that deletion of the NKG2C receptor and HLA-E*0101 expression, could hinder antiviral defence potentially through a mechanism impacting on NK cell mediated immune responses.  Additional information on cohort characteristics and CMV status/reactivation would strengthen these observations that need to be corroborated in bigger cohorts.  

Impactfor SARS-CoV2/COVID19 research efforts 

Understand the immune responseto SARS-CoV2/COVID19  

This study highlightshow NK cell responses could play a crucial role in the control of SARS-Cov-2 infection  

Study Type 

  • Clinical Cohort study (e.g. drug trials) 

Strengths andlimitations of the paper 

Novelty:The study shows for the first time that the lack oexpression of the NK cell receptor NKG2C and presence of the HLA- E*0101 allele, which results in lower expression of HLA-E (the ligand for NKG2C) are associated with severity of COVID-19 infection. The literature on NK cell responses against Sars-Cov-2 is limited. NKG2C is the activating counterpart of NKG2A, which is expressed on a population of mature NK cells that expand following CMV infection/reactivation marking a subset with adaptive features and unique functionality. In the case of NKG2C sufficiency, interaction with HLA-E provides a significant activating signal, which incorporates a degree of antigenic specificity i.e through the propensity of certain CMV-derived peptides or HLA-G signal peptides to bind HLA-E and increase its surface expression. These NKG2C expressing NK cell populations could therefore conceivably play an indirect or direct role in the antiviral defence against SARs-Cov-2. This work provides an incentive for further studies to elucidate the role/contribution of NKG2C+ expressing NK cells (and T cells) during Sars-Cov-2 infection. 

Standing in the field: While NK cells are important in immune defense against DNA-viruses, there is no clear data about their role in coronaviruses immune response. NK cell levels in peripheral blood from severe SARS-CoV or SARS-CoV-2 patients have been reported to be depleted/lower than normal, but this may not necessarily reflect lower number of NK in the lungs. Currently, the relative contributions of the different NK cell subsets, including adaptive NK cell subpopulations that express NKG2C and resident NK cells in the lungs remain undefined.  In the context of infection,KLRC2deletion has been shown to be associated with impaired outcomes to CMV and HIV infectionA better understanding of the antiviral role of NK cells in COVID-19 infection and impact of NKG2C mediated responses could pave the way for new therapeutic interventions.  

Appropriate statistics:yes 

Viral model used:N/A 

Translatability: Remote- the study encourages more investigation in NK cell responseand potentially using the genotypes as predictors for disease severity 

Main limitations:  

  • Although the data presented in this study are very interesting, pointing to a new potential association/risk factor for developing severe COVID-19 disease, these observations need to be extended in larger and demographically diverse cohorts to confirm their predictive value. 

  • The present study would benefit from incorporating additional details on patient characteristics including demographics, underlying CMV serostatus (this is likely to be most relevant in the older group) and CMV ab levels and/or CMV DNA levels as a surrogate marker of CMV burden especially in the critically unwell patients along with inflammatory biomarkers.  

  • Additional details on patient co-morbidity and medication administered should be included as these could potentially impact on the HLA-E/NKG2 axis.  

  • Some further clarification is required for Figure 1 as it is not clear whether all datapoints were included for the analysis of the hospitalised patients.  

  • The authors should expand in the discussion the possible implications of these associations discussing the potential contributions of conventional NK cells versus adaptive NK cells subsets and unique resident NK cells in the lungs.  

  • NKG2 is also expressed on a subset of T cells and therefore the lack of NKG2C may not completely reflect an impact on NK cell function. This should be discussed.