A new study of 27 patients hospitalized with COVID-19 has provided a detailed map of natural killer (NK) cell responses to SARS-CoV-2 infection, revealing that specific characteristics of NK cell activation associate with different levels of disease severity. The findings are consistent with previous reports that NK cells exist in lower frequencies in the blood of patients with COVID-19 compared with healthy controls, but also show that increased numbers of certain NK cell types - adaptive NK cells specifically - correlate with severe, but not moderate, disease. Compared with adaptive immune cell responses to SARS-CoV-2, much less is known about the quick-acting innate immune response to SARS-CoV-2 and how it influences the course of disease. NK cells are innate immune cells located in the blood and abundantly in the lungs, where they act not only as rapid responders to viral infection, but also as influencers of adaptive immune responses: depending on their levels of activation, the unique "adaptive NK cell" subset can help T cells either control infection or contribute to disease.
To investigate whether NK cells' virus-controlling roles extend to SARS-CoV-2, Christopher Maucourant and colleagues analyzed NK cells taken from the blood of 27 patients with either severe or moderate COVID-19 and 17 healthy controls. They observed that NK cells were severely reduced but strongly activated in the blood of patients with COVID-19 compared with controls. The "arming" of these activated NK cells with cytotoxic effector proteins correlated with the development of severe disease, the researchers found. An additional high-dimensional analysis showed that patients with severe - but not moderate - COVID-19 harbored higher numbers of adaptive NK cells than healthy controls. Adaptive NK cells are thought to arise with cytomegalovirus (CMV) infection and remain afterward to act against future viral infections; indeed, the researchers observed the expansion of adaptive NK cells only in CMV-seropositive individuals among the COVID-19 cohort. Based on their findings, Maucourant et al. suggest several directions for future work on the role of NK cells in COVID-19, including whether NK cell activation states identified in the blood can also be found in the lungs, and how NK cell responses vary at different time points during SARS-CoV-2 infection.