NK cells in COVID-19 - from disease to vaccination

Natural killer (NK) cells participate in the host innate immune response to viral infection. Conversely, NK cell dysfunction and hyperactivation can contribute to tissue damage and immunopathology. Here, we review recent studies with respect to NK cell activity during infection with human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Discussed are initial reports of patients hospitalized with coronavirus disease 2019 (COVID-19), which revealed prompt NK cell activation during the acute disease state. Another hallmark of COVID-19, early on observed, was a decrease in numbers of NK cells in the circulation. Data from patients with acute SARS-CoV-2 infection as well as from in vitro models demonstrated strong anti-SARS-CoV-2 activity by NK cells, likely through direct cytotoxicity as well as indirectly by secreting cytokines. Additionally, we describe the molecular mechanisms underlying NK cell recognition of SARS-CoV-2 infected cells, which involve triggering of multiple activating receptors including NKG2D as well as loss-of-inhibition through NKG2A. Discussed is also the ability of NK cells to respond to SARS-CoV-2 infection via antibody dependent cellular cytotoxicity. With the respect to NK cells in the pathogenesis of COVID-19, we review studies demonstrating how hyperactivation and misdirected NK cell responses could contribute to disease course. Finally, while knowledge is still rather limited, we discuss current insights suggesting a contribution of an early NK cell activation-response in the generation of immunity against SARS-CoV-2 following vaccination an anti-SARS-CoV-2 mRNA vaccines.