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. 2023 Jul 15:4:100064.
doi: 10.1016/j.crimmu.2023.100064. eCollection 2023.

High baseline frequencies of natural killer cells are associated with asymptomatic SARS-CoV-2 infection

Elizabeth K Graydon  1   2 , Allison M W Malloy  3 , Kawthar Machmach  2   4   5 , Peifang Sun  6 , Dominic Paquin-Proulx  2   4   5 , Stephen Lizewski  7 , Rhonda Lizewski  8 , Dawn L Weir  6 , Carl W Goforth  6 , Stephen K Anderson  9 , Andrew G Letizia  6 , Edward Mitre  1
Affiliations

High baseline frequencies of natural killer cells are associated with asymptomatic SARS-CoV-2 infection

Elizabeth K Graydon et al. Curr Res Immunol. .

Abstract

This study tested the hypothesis that high frequencies of natural killer (NK) cells are protective against symptomatic SARS-CoV-2 infection. Samples were utilized from the COVID-19 Health Action Response for Marines study, a prospective, observational study of SARS-CoV-2 infection in which participants were enrolled prior to infection and then serially monitored for development of symptomatic or asymptomatic infection. Frequencies and phenotypes of NK cells (CD3-CD14-CD19-CD56+) were assessed by flow cytometry. Individuals that developed asymptomatic infections were found to have higher pre-infection frequencies of total NK cells compared to symptomatic individuals (10.61% [SD 4.5] vs 8.33% [SD 4.6], p = 0.011). Circulating total NK cells decreased over the course of infection, reaching a nadir at 4 weeks, while immature NK cells increased, a finding confirmed by multidimensional reduction analysis. These results indicate that NK cells likely play a key role in controlling the severity of clinical illness in individuals infected with SARS-CoV-2.

Keywords: Asymptomatic; NK cells; Natural killer cells; SARS-CoV-2; Symptomatic.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University of the Health Sciences, Department of the Navy, Department of Defense, the U.S. Government, nor the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. AMWM, PS, SL, RL, DLW, CWG, AGL, and EM are military Service members or employees of the U.S. Government. This work was prepared as part of their official duties. Title 17, U.S.C., §105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17, U.S.C., §101 defines a U.S. Government work as a work prepared by a military Service member or employee of the U.S. Government as part of that person’s official duties.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Total NK cell frequencies, and mature NK cell frequencies prior to infection are greater in individuals that develop asymptomatic SARS-CoV-2 infection. Percentages of (A) total NK cells (CD3-CD14-CD19-CD56+) (B) immature NK cells (CD56brightCD16-), (C) mature CD16+ NK cells (CD56dimCD16+), (D) mature CD16- NK cells (CD56dimCD16-), and (E) adaptive NK cells (CD56dimCD16+NKG2C+CD57+) were compared between baseline samples from asymptomatic (n = 42) and symptomatic (n = 46) SARS-CoV-2 PCR+ individuals. Data are presented as mean value ± s.d. (*p < 0.05 by Mann Whitney U Test).
Fig. 2
Fig. 2
No correlation observed between percentage of NK cells at baseline and duration of PCR positivity or peak S gene CT value for SARS-CoV-2. Correlation between an individual's baseline NK cell percentage and the number of days they were PCR+ for SARS-CoV-2 (A) and peak S gene CT values (B) was analyzed. No significant correlations were found between the percentage of NK cells and duration of PCR+ or S gene CT value by Spearman Correlation analyses (r = 0.177, p = 0.095; r = 0.106, p = 0.322 respectively).
Fig. 3
Fig. 3
No significant differences in the expression of activating or inhibitory receptors on NK cells at baseline between asymptomatic and symptomatic individuals. Percentages of NK cells expressing (A) the activating receptors NKG2C or NKG2D, or (B), the inhibitory receptors NKG2A, KIR2DL1, KIR2DL2/L3/S2, or KIR3DL1. Percentages were calculated as the number of cells positive for the specified receptor out of the number of total NK cells (CD56+). No significant differences were observed between the asymptomatic (n = 42) vs. symptomatic (n = 46) groups for any of the receptors based on Mann Whitney U test.
Fig. 4
Fig. 4
Peripheral NK cell kinetics post-infection. Frequencies of (A) total NK cells (CD56+), (B) immature NK cells (CD56brightCD16-), (C) mature CD16+ NK cells (CD56dimCD16+), and (D) mature CD16- NK cells (CD56dimCD16-) were calculated for samples obtained from individuals at baseline and at timepoints after initial PCR+ test for SARS-CoV-2. All available samples were analyzed. Number of samples at baseline n = 87, post-PCR samples analyzed at days 0–6 (n = 27), 7–13 (n = 86), 14–20 (n = 14), 21–27 (n = 12), 28–34 (n = 24), 35–41 (n = 47), 42–48 (n = 6), 49–55 (n = 35). Analyses between timepoints were conducted using Dunnett's multiple comparisons test (**p < 0.01, ***p < 0.001, ****p < 0.0001).
Fig. 5
Fig. 5
Longitudinal UMAP analyses of NK cell clusters. UMAP analyses reveal a population of NK cells (circled) which expands from baseline (A, D, G) to 4–7 days (B, E, H) and 35 days (C, F, I) post-infection. This expansion was found when all donor samples were examined (A–C), and when examining the asymptomatic donors (D–F) and symptomatic donors (G–I) separately. Alignment with phenotypic markers reveals this population to be comprised of immature NK cells (see Supplemental Fig. 2).
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