Impact Of Adaptive Natural Killer Cells, KLRC2 Genotype and Cytomegalovirus Reactivation On Late Mortality In Patients With Severe Covid-19 Lung Disease

Abstract

Objective: COVID-19 infection results in severe lung disease in a small but significant number of infected patients. The etiopathogenesis 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 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 viremia was documented in 11 patients, with a survival of 25% vs 80% in those without viremia with viral load correlating with mortality. ANK cells were markedly depressed in all patients at day 15. However, persistently low ANK cells at 30 days along with an inversely high NKG2C-/NKG2A+ inhibitory NK cells significantly correlated with high CMV viremia as well as mortality, irrespective of KLRC2 genotype. Day 30 ANK cells were significantly lower in KLRC2 deletion group. IFN-gamma and Perforin release were 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 severe 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

“…Downregulation of NKG2A has also been shown to be a marker for immunological and clinical recovery in COVID-19(Zheng et al, 2020). Our group has demonstrated correlation between high expression of NKG2A and marked suppression of NKG2C, with adverse outcome following severe COVID-19 lung disease, despite viral clearance(Jaiswal et al, 2021a). Hence, it might be inferred that if any intervention can achieve the reverse, i.e., downregulation of NKG2A and upregulation of NKG2C expression, this might offer protection against COVID-19.…”