Impact of adaptive natural killer cells, KLRC2 genotype and cytomegalovirus reactivation on late mortality in patients with severe COVID‐19 lung disease

Abstract

Objective SARS‐CoV‐2 infection results in severe lung disease in up to 50% of hospitalised patients. The aetiopathogenesis in a subset of such patients, who continue to have progressive pulmonary disease following virus clearance, remains unexplored. Methods We investigated the role of NKG2C+/NKG2A− adaptive natural killer (ANK) cells, KLRC2 genotype and cytomegalovirus (CMV) reactivation in 22 such patients. Results The median duration of virus positivity was 23 days, and the median duration of hospitalisation was 48 days. The overall survival at 60 days in this group was 50%. Older age and comorbidities impacted survival negatively. CMV viraemia was documented in 11 patients, with a survival of 25% vs 80% in those without viraemia with viral load correlating with mortality. Both NK and T cells were markedly depressed in all patients at day 15. However, only persistently low ANK cells at 30 days along with an inversely high NKG2C−/NKG2A+ inhibitory NK cells significantly correlated with high CMV viraemia and mortality, irrespective of KLRC2 genotype. However, day 30 ANK cells were significantly lower in the KLRC2 deletion group. The release of IFN‐γ and perforin was severely compromised in all patients at day +15, with significant improvement in the survivors at day +30, but not in those with adverse outcome. Conclusion Patients with progressive lung disease even after negative SARS‐CoV‐2 status, with persistently reduced and functionally compromised ANK cells, are more likely to have CMV reactivation and an adverse outcome, independent of KLRC2 genotype.

Impact of an Immune Modulator Mycobacterium-w on Adaptive Natural Killer Cells and Protection Against COVID-19

“…However, in CMV-exposed patients, these NKG2C + ANK cells have been found to proliferate in response to a variety of viral pathogens, including HIV, Hepatitis C Virus (HCV), Hantavirus, influenza, and pox viruses ( 16 , 28 – 31 ). The unique nature of this non-antigen-specific recall response against a wide variety of pathogens puts NKG2C + ANK cells at the forefront in the battle against novel pathogens such as SARS-CoV-2 ( 3 , 32 – 36 ), where the antigen-specific adaptive response generated from T and B cells are absent at the outset of the pandemic.…”

“…In the context of SARS-CoV-2 infection, in vitro studies have demonstrated that the viral spike protein-1 (SP-1) upregulates NKG2A on NK cells and HLA-E on the infected lung epithelial cells, causing a strong inhibition of cytotoxicity of NK cells ( 43 ). Our group has demonstrated a correlation between the high expression of NKG2A, the suppression of NKG2C, and the adverse outcome following severe COVID-19 lung disease, despite viral clearance ( 36 ). It is possible that the adverse effect of KLRC2 deletion genotype as reported earlier ( 32 ), was mitigated by Mw.…”

Impact Of an Immune Modulator Mycobacterium-w On Adaptive Natural Killer Cells and Protection Against COVID-19

“…However, in CMV exposed patients, these NKG2C + ANK cells have been found to proliferate in response to a variety of viral pathogens, including HIV, HCV, Hantavirus, influenza, and pox viruses[16; 26; 27; 28; 29]. The unique nature of this non-antigen specific recall response against a wide variety of pathogens, puts NKG2C + ANK cells at the forefront in the battle against novel pathogens such as SARS-CoV-2 [3; 30; 31; 32; 33; 34], where antigen-specific adaptive response generated from T and B cells are absent at the outset of the pandemic.…”

“…In the context of SARS-CoV-2 infection, in-vitro studies have demonstrated that the viral spike protein-1 (SP-1) upregulates NKG2A on NK cells and HLA-E on the infected lung epithelial cells, causing a strong inhibition of cytotoxicity of NK cells[40]. Our group has demonstrated a correlation between high expression of NKG2A, suppression of NKG2C, and adverse outcome following severe COVID-19 lung disease, despite viral clearance[34]. It is possible that the adverse effect of KLRC2 deletion genotype as reported earlier[30], was mitigated by Mw.…”

NK cell dysfunction is linked with disease severity in SARS‐CoV‐2 patients

“…48 Among these, the interaction of NKG2C/CD94 with HLA-E ligand stimulate the NK cell responses against virus-infected cells. [49][50][51] The reliable evidence indicated that there are a direct relationship between the absence of NKG2C receptor with virus infections severity. 52 The similar result was reported by Jordier et al in 2020.…”