Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies

Abstract

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.

Deep spatial profiling of COVID19 brains reveals neuroinflammation by compartmentalized local immune cell interactions and targets for intervention

“…Interestingly, we also observed a reduction in CD3 -GzmB + NK cells in diseased patients, indicative of a ~50% depletion of brain NK cells that has been described in the periphery of COVID-19 patients and is implicated in a more severe clinical course of COVID-19 15,16 . Given the profound immune activation in COVID-19 brains, we wondered whether this robust immune activation pattern in the brain stem was linked to tissue destruction and neuronal damage.…”

Natural Killer Cell Dysfunction and Its Role in COVID-19

“…Several trials are also investigation the use of oxygen therapy in the early treatment of SARS-CoV-2 infection, as previous studies have shown that this treatment effectively decreases inflammation, reducing IL-12 and TNF-α, and increasing IL10 [ 128 , 129 ]. Numerous trials are investigating the possibility that the Bacille Calmette-Guérin (BCG) vaccine, used to protect young children against tuberculosis ( Mycobacterium tuberculosis ), may offer heterologous protection against SARS-CoV-2 through trained immunity [ 130 ]. BCG vaccination may lead to epigenetic changes in monocyte and NK cell populations, resulting in an enhanced immune response to subsequent infections, particularly through increased expression of IL-1β, TNF and IL-6 [ 131 ].…”

Airway Natural Killer Cells and Bacteria in Health and Disease

“…However, what about the therapeutic indication of NK cells in infectious diseases in general and in the lungs particularly? Due to the current COVID-19 pandemic, this question has gained increased interest (108,109), and in addition, most of the papers discussed here that describe an influence of NK cells on the disease course in the airways conclude with the statement that NK cells should be targeted in respiratory infections. But it has clearly been shown that these lymphocytes can have detrimental side effects and cause significant damage to the airways, at least in viral diseases (108,109).…”

“…Due to the current COVID-19 pandemic, this question has gained increased interest (108,109), and in addition, most of the papers discussed here that describe an influence of NK cells on the disease course in the airways conclude with the statement that NK cells should be targeted in respiratory infections. But it has clearly been shown that these lymphocytes can have detrimental side effects and cause significant damage to the airways, at least in viral diseases (108,109). Available literature does not give clear indications regarding bacterial pathogenesis, but the issue was already discussed in 2012, with the question if NK cells are angels or devils in bacterial infectious diseases (50).…”