Abstract
The SARS-CoV-2 infection causes severe respiratory involvement (COVID-19) in 5–20% of patients through initial immune derangement, followed by intense cytokine production and vascular leakage. Evidence of immune involvement point to the participation of T, B, and NK cells in the lack of control of virus replication leading to COVID-19. NK cells contribute to early phases of virus control and to the regulation of adaptive responses. The precise mechanism of NK cell dysregulation is poorly understood, with little information on tissue margination or turnover. We investigated these aspects by multiparameter flow cytometry in a cohort of 28 patients hospitalized with early COVID-19.Relevant decreases in CD56brightCD16+/- NK subsets were detected, with a shift of circulating NK cells toward more mature CD56dimCD16+KIR+NKG2A+ and “memory” KIR+CD57+CD85j+ cells with increased inhibitory NKG2A and KIR molecules. Impaired cytotoxicity and IFN-γ production were associated with conserved expression of natural cytotoxicity receptors and perforin. Moreover, intense NK cell activation with increased HLA-DR and CD69 expression was associated with the circulation of CD69+CD103+ CXCR6+ tissue-resident NK cells and of CD34+DNAM-1brightCXCR4+ inflammatory precursors to mature functional NK cells. Severe disease trajectories were directly associated with the proportion of CD34+DNAM-1brightCXCR4+ precursors and inversely associated with the proportion of NKG2D+ and of CD103+ NK cells.Intense NK cell activation and trafficking to and from tissues occurs early in COVID-19, and is associated with subsequent disease progression, providing an insight into the mechanism of clinical deterioration. Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches.
Highlights
Strategies to positively manipulate tissue-resident NK cell responses may provide advantages to future therapeutic and vaccine approaches. This is a detailed study of activating and inhibitory receptors in NK cells of COVID-19 patients when first admitted to the hospital for respiratory insufficiency
Subset analysis according to CD56 and CD16 expression of CD3-CD14-CD19-cells showed a significant fourfold reduction of CD16+/-CD56brightcells, with a consequent remarkable drop in the ratio between CD16+/CD56bright and CD16+CD56dim cells (Fig 1B; p
A decrease in regulatory NKG2A+KIR- circulating NK cells was detected in patients, compared to healthy uninfected donors (HD), consistent with the decreased proportion of developmentally upstream CD16+/- CD56bright cells (Fig 2A). These findings suggest an in vivo shift of NK cell Peripheral blood (PB) subsets toward more mature effector stages during early COVID-19 symptomatic disease conditions
Summary
The new strain of the large betacoronavirus family (severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2) that is spreading as a global pathogen causing coronavirus-19 disease (COVID-19) [1, 2]] has caused an ongoing global pandemic with over 23 million infections (Worldometers [http://www.worldometers.info] The Real Time Statistics Project) [3].SARS-CoV-2 is the seventh known strain of enveloped positive-strand RNA coronaviruses, which causes a range of diseases in humans [4], ranging from asymptomatic or mild nonrespiratory disease in 80–90% of cases [5,6,7] to a severe disease requiring hospitalization and intensive oxygen support in 10–20% of cases.The severity and mortality of COVID-19 is increased by age and by many comorbidities, including diabetes, obesity, and cardiovascular and pulmonary disease [8, 9]. NK cells help clear virus-infected cells through multiple mechanisms, including direct contact, cytokine or chemokine secretion, and indirectly influencing lateral and downstream adaptive immune responses via their crosstalk with dendritic cells and T cells [11,12,13]. They are markedly activated during ongoing viral infection [14, 15] and contribute to viral control [16, 17], for example by memory-like responses [12], both directly and by regulating dendritic cell maturation and adaptive responses [11, 12]. Their derangement may be deranging direct virus control, and the efficient organization of downstream T and B cell adaptive responses
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