Natural Killer Cell Dysfunction and Its Role in COVID-19

Abstract

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this “perfect balance” is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.

Peripheral Blood Immune Profiling of Convalescent Plasma Donors Reveals Alterations in Specific Immune Subpopulations Even at 2 Months Post SARS-CoV-2 Infection

“…Accordingly, the ratios of granulocytes/lymphocytes and granulocytes/CD3 + T cells were highly increased, and in both cases, the differences were statistically significant (5.16 vs. 2.02 of controls, p < 0.01 and 7.19 vs. 3.14 of controls, p < 0.01, respectively). Taken together, although the number of active COVID-19 patients included in this study was limited ( n = 11), the phenotypic changes in their WBC subpopulations detected herein are in agreement with published reports [ 21 , 22 , 23 , 24 ] and support the severe deficiency of both innate and adaptive immune responses in hospitalized patients with active COVID-19.…”

“…Using an in-house-designed 12-color flow cytometry panel, we immunophenotyped 24 distinct cell populations of both the innate (granulocytes, monocytes, NK cells) and the adaptive (T, B, NKT cells) arms of immunity and calculated a series of immune cell ratios to reveal alterations in immune cell composition after COVID-19 resolution. We first analyzed the immune profile of active COVID-19 patients to ensure the performance of our panel; in agreement with previous reports, we detected similar immune cell deficiencies, the most prominent being low T, B, and NK cells, and low granulocytes, as well as increased percentages of Th2-type cells and monocytes [ 5 , 6 , 7 , 8 , 10 , 21 , 22 , 23 , 24 ].…”

Haemophagocytic syndrome and COVID-19

“…In viral infections, a defective cytotoxicity leads to the accumulation of antigenic stimuli, perpetuating inflammation and triggering tissue damage, and recent studies in COVID-19 patients have reported a decreased NK cell function, including a negative correlation between number of NK cells and IL-6 levels [ 53 ] and a profound depletion of NK cells [ 42 ], especially in severe patients [ 54 ]. IL-6 and IL-10 have the capacity to reduce NK cell cytotoxicity (IL-6 may reduce the expression of perforin and granzyme B while IL-10 negative correlate with NK cell cytotoxicity, through a reduction in IFN- and IL-2 expression) [ 55 , 56 ]. With respect to IL-2R levels, CD25 is expressed by T cells during immune activation and its soluble form (also known as IL-2R), is released into the bloodstream [ 57 ].…”

Immunological Characteristics of Non-Intensive Care Hospitalized COVID-19 Patients: A Preliminary Report

“…CD8 + T cells have been indicated as an independent predictor for COVID-19 severity and treatment efficacy [ 8 , 20 , 21 ]. According to Liu and colleagues, decreased CD8 + was directly correlated with pulmonary involvement and pneumonia [ 22 ].…”

“…In NK cells, NKG2A leads to the decreased expression of TNFα, IL-2 and IFNγ and reduced granzyme B levels. [ 20 ] Two cytokines, IL-6 and IL-10, highly present in SARS-CoV-2 infections [ 13 ], can reduce NK cell cytotoxicity [ 24 ]. In particular, IL-6 directly reduces the expression of perforin and granzyme B.…”