Exhausted NK cells and cytokine storms in COVID-19: Whether NK cell therapy could be a therapeutic choice

Abstract

The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed “cytokine storm”, a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles’ heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56 dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research.

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

“…On the other hand, the CD56 neg CD16 bright NK cell subset was found to be depleted in COVID-19 patients in our study; this subset is reported to be an unconventional cytotoxic mediator for chronic diseases [15]. NK cells participate in a complex network, interacting with dendritic cells as well as T and B cells through chemokines and a variety of cytokines involved in the differentiation and function of NK cells [23,30,31,38,39].…”

Proline-specific peptidase activities (DPP4, PRCP, FAP and PREP) in plasma of hospitalized COVID-19 patients

“…Knowing that soluble FAP could originate from MSCs and that MSCs have immunosuppressive roles during over-stimulation of our immune system, as is the case with COVID-19 and sepsis, it is not surprising that FAP activity is dysregulated in these conditions. In addition, a recent study showed that FAP is expressed in natural killer (NK) cells in healthy persons [48] and it has been shown that NK cells are exhausted during the cytokine storm in COVID-19 [49] . If FAP originates from NK cells, it is plausible that FAP plasma levels decrease during periods of NK cell suppression.…”

Sustained Antibody-Dependent NK Cell Functions in Mild COVID-19 Outpatients During Convalescence

“…Also, supporting the relevance of NK cell effector functions at effective immune responses against this infection, Notarbartolo S et al showed that NK cell population is significantly expanded in individuals with mild disease (17), plausibly synergizing with the Fc-dependent characteristics of Abs. Additionally, NK cell-based therapy strategies, have now received attention to hopefully control the harmful cytokine storm induced by SARS-CoV-2 activation of infected macrophages and CD4+ T cells in severe COVID-19 patients (74)(75)(76)(77).…”