Natural Killer Cells in SARS-CoV-2 Infection: Pathophysiology and Therapeutic Implications

Abstract

Natural Killer (NK) cells are lymphocytes of the innate immunity that play a crucial role in the control of viral infections in the absence of a prior antigen sensitization. Indeed, they display rapid effector functions against target cells with the capability of direct cell killing and antibody-dependent cell-mediated cytotoxicity. Furthermore, NK cells are endowed with immune-modulatory functions innate and adaptive immune responses via the secretion of chemokines/cytokines and by undertaking synergic crosstalks with other innate immune cells, including monocyte/macrophages, dendritic cells and neutrophils. Recently, the Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally. Although the specific role of NK cells in COVID-19 pathophysiology still need to be explored, mounting evidence indicates that NK cell tissue distribution and effector functions could be affected by SARS-CoV-2 infection and that a prompt NK cell response could determine a good clinical outcome in COVID-19 patients. In this review, we give a comprehensive overview of how SARS-CoV-2 infection interferes with NK cell antiviral effectiveness and their crosstalk with other innate immune cells. We also provide a detailed characterization of the specific NK cell subsets in relation to COVID-19 patient severity generated from publicly available single cell RNA sequencing datasets. Finally, we summarize the possible NK cell-based therapeutic approaches against SARS-CoV-2 infection and the ongoing clinical trials updated at the time of submission of this review. We will also discuss how a deep understanding of NK cell responses could open new possibilities for the treatment and prevention of SARS-CoV-2 infection.

Keywords: COVID-19; NK cells; SARS-CoV-2 infection; immunotherapy; memory-like; single cell sequencing.

Figure 1

Schematic representation of COVID-19 effects on NK cells. Acute SARS-CoV-2 infection affects the number of circulating NK cells and their phenotype. Indeed, due to the local and systemic inflammation, NK cells in COVID-19 patients are characterized by a signature attributable to cell activation and inflammation as well as to cell exhaustion and hyporesponsiveness. These alterations in NK cell phenotype determine an impairment of NK cell effector functions in terms of IFN-γ and TNF-α production, degranulation cytolytic potential and ability to control virus replication.

Figure 2

scRNA-seq profiling of NK cells from COVID-19 patients.(A) A total of 16 678 cells were embedded by Uniform Manifold Approximation and Projection (UMAP) plots in 13 clusters at a resolution level of 0.2. Each dot within the UMAP corresponds to one single cell colored according to cell cluster.(B) Ballon plots showing the expression of canonical NK cell markers in the 13 clusters identified as NK cells. Balloon size corresponds to the frequency of marker-positive cells and balloon color corresponds to the marker expression level of marker-positive cells.(C) Heatmap depicting the top 50 unique DEGs with adj. P value ≤ 0.05. Scale represents normalized counts centered and scaled across cells.(D) Ballon plots showing the expression of 33 NK cell markers to define cluster (Cl) identities. Balloon size corresponds to the frequency of marker-positive cells and balloon color corresponds to the marker expression level of marker-positive cells.(E) Heatmap showing the distribution of the 7 NK cell clusters among the 3 groups of subjects analyzed.