Longitudinal Dynamics of Soluble NKG2D Ligands in Mild and Moderate Coronavirus Disease-2019

The soluble form of NKG2D (sNKG2D) ligands has been implicated in the severity of coronavirus disease-2019 (COVID-19). However, their longitudinal dynamics from the acute phase to hospital discharge and their relationships with clinical parameters are unclear. This study aimed to investigate the longitudinal dynamics of these ligands and determine their relationship with clinical parameters.

This retrospective observational cohort study evaluated 64 patients with mild or moderate COVID-19. sULBP-2, soluble MIC-A (sMIC-A), and soluble MIC-B (sMIC-B) concentrations at admission, recovery, and discharge were analyzed. Associations with patient characteristics and laboratory parameters (white blood cell count and C-reactive protein, lactate dehydrogenase, Krebs von den Lungen-6, ferritin, and interleukin-6 levels), natural killer (NK) cell and T cell counts, and severe acute respiratory syndrome coronavirus 2 viral copy numbers were examined. Principal component analysis (PCA) was performed in the moderate group, and the relationship between sNKG2D ligands and clinical parameters using hierarchical cluster analysis.

Serum sULBP-2 concentrations were significantly higher in the moderate group at both admission and discharge. In contrast, sMIC-A and sMIC-B levels did not significantly differ. Higher sULBP-2 levels at admission persisted until discharge. PCA demonstrated that admission sULBP-2 levels were associated with inflammatory components; admission sMIC-A levels were associated with components related to NK cells and lung injury. Their discharge levels both converged into a shared principal component closely associated with NK cell. Clusters characterized by older age, elevated sULBP-2, and increased inflammatory responses and lung injury markers had worse disease severity.

NKG2D ligand levels increase via distinct mechanisms during acute COVID-19 but converge toward a shared dynamics during recovery. sULBP-2 is the only sNKG2D ligand related with disease severity, and its elevation persists through discharge, suggesting prolonged impairment of NK cell function after clinical recovery. sULBP-2 may be an important biomarker of disease severity.