Natural killer cells associated with SARS-CoV-2 viral RNA shedding, antibody response and mortality in COVID-19 patients

Abstract

Coronavirus disease 2019 (COVID-19) is a novel infectious viral disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two consecutively negative SARS-CoV-2 viral RNA test ( interval ≥ 24 hours), improved respiratory symptoms and obvious absorption of inflammation in pulmonary imaging are the discharge criteria for COVID-19 patients. The clearance profile of viral RNA in the upper respiratory tract specimens, including nasopharyngeal swab and/or oropharyngeal swabs, is related to innate immune cells such as Natural Killer cells. A total of 168 patients were included for the study. In this cohort, non-severe and severe groups showed significant differences in white blood cells, neutrophils, lymphocytes, basophils and platelets counts, as well as in infection related parameters such as CRP and serum cytokine IL-6. For lymphocyte subsets tests at admission, the severe group displayed significantly lower cell counts than the non-severe group. Higher counts of total T cells, CD4 + T cells, CD8 + T cells, and NK cells in peripheral blood showed a significant correlation with the shorter time taken to obtain the first negative viral RNA test and first positive IgM/ IgG antibody test. The number of B cells was only correlated with time to achieve the first positive IgM/IgG test. The count of NK cells was also correlated with a higher level of IgG antibody (p = 0.025). The lymphocytopenia group had a significantly worse survival rate (p = 0.022) and a longer duration (p = 0.023) of viral shedding than the normal lymphocyte count group. A lower NK cell count correlates the most with the worse survival rate (p<0.001) and a longer duration (p<0.001) of viral shedding. This study suggests the potential value of allo-Natural Killer cell therapy as an universal COVID-19 treatment strategy.

Keywords: Antibody response; COVID-19; Natural killer cell; RNA viral shedding; SARS-CoV-2.

Fig. 1

Survival and hazardous analysis. In lymphocytopenia subgroups analysis, p = 0.022 for survival and p = 0.023 for viral shedding duration. In NK cell lymphocytopenia p < 0.001 for survival and p < 0.001 for viral shedding duration

Fig. 2

The innate and adaptive immune response to SARS-CoV-2 infection. Hypothesis of the innate and adaptive immune response to SARS-CoV-2 infection. NK cells have direct killing effect on SARS-CoV-2 infected cells, as well as participate in antibody-dependent cellular cytotoxicity. Through inhibiting and activating receptors, NK cells recognize infected cells. Once activated, the degranulation of NK cells induces the releasing of perforin and granzyme which directly lyse infected cells. NK cells express CD16A, which participates in antibody-dependent cellular cytotoxicity. Meanwhile, NK cells also interact with dendritic cells in antigen presenting process and affect adaptive immune response. Monocytes can secret IL-6 that acts as inflammatory cytokine, resulting in the activation of other immune cells