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.

Age-dependent NK cell dysfunctions in severe COVID-19 patients

“…However, we did not find a deficit in the cytotoxic machinery. In line with recent reports ( 27 , 52 , 53 ), we observed an increase of granzyme B and perforin, but not of FasL expression, that was more pronounced in the elderly patients ( Figures 7D–F ).…”

“…Several studies have investigated NK cell compartment in SARS-CoV-2 infected patients with a different spectrum of clinical manifestations (53), however our understanding of the potential impact of age-related differences on NK cell compartment in severe adult and elderly COVID-19 patients remains limited (37, 57) In line with other viral infections, such as hantavirus or dengue fever disease, a reduction of NK cell number has been reported in SARS-CoV-2 infection (17, 18, 58). An alteration of NK cell compartment consisting in a shift toward a more mature phenotype of NK cells, due to an enrichment of the CD56 low CD16 high subset accompanied by the reduction of CD56 high CD16 -/+ one, especially in severely ill COVID-19 patients, has also been described by several studies (27).…”

“…Several studies have investigated NK cell compartment in SARS-CoV-2 infected patients with a different spectrum of clinical manifestations ( 53 ), however our understanding of the potential impact of age-related differences on NK cell compartment in severe adult and elderly COVID-19 patients remains limited ( 37 , 57 )…”

SARS-CoV-2 Variant-Specific Infectivity and Immune Profiles Are Detectable in a Humanized Lung Mouse Model

“…In addition, although the BLT method of humanization has been shown to produce some of the most functional adaptive immune responses in humanized mouse models (albeit comparatively weak by human standards) during prolonged infection models [ 30 , 35 , 64 ] it remains to be assessed whether antigen specific B and T cells responses would develop to the relatively short-term SARS-CoV-2 infection and whether these responses also differ between VOCs. It would also be of interest to study NK cell responses in more detail as they have been implicated in mediating protective responses to SARS-CoV-2 [ 65 ]. However, one well known caveat of humanized mouse models is the lack of a well-developed human NK cell compartment in the absence of supplemented human IL-15 [ 66 , 67 ].…”

The impact of sphingosine-1-phosphate receptor modulators on COVID-19 and SARS-CoV-2 vaccination

“…Although remyelination effects are largely unproven in MS, oligodendrocyte actions are unlikely to be of major importance to COVID-19, therefore targeting this pathway is unlikely to impact on SARS-CoV-2 infection or vaccination responses. However, S1PR5 modulators may affect natural killer cell function, which may influence COVID-19 biology ( Walzer et al, 2007 , Drouillard et al, 2018 , Di Vito et al, 2022 ). However, given that the impact of these agents on natural killer cell numbers is often minimal ( Harris et al, 2020 ) and that fingolimod, which also targets S1PR5 and is not associated with a worse prognosis following SARS-CoV-2 infection ( Sormani et al, 2021 , Simpson-Yap et al, 2021 ), indicates that likewise, siponimod, ozanimod and ponesimod are unlikely to cause a worse prognosis following COVID-19 infection.…”