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Review
. 2020 Jun 23:11:1512.
doi: 10.3389/fimmu.2020.01512. eCollection 2020.

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

Affiliations
Review

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

Marisa Market et al. Front Immunol. .

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.

Keywords: COVID-19; NK cells; immunotherapy; innate immunity; interferon.

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Figures

Figure 1
Figure 1
Hypothesized dual role of NK cells during coronavirus pathogenesis. (A) Healthy Natural Killer (NK) cells in low-risk individuals recognize SARS-CoV-2 infected cells via recognition of viral proteins on the surface of infected cells and through sensing of cytokines and chemokines produced in response to infection. These cells are hypothesized to be able to directly induce apoptosis through death receptor ligation, antibody-dependent cell-mediated cytotoxicity (ADCC), and through the release of cytotoxic granules, in addition to indirectly targeting virally infected cells via modulation of the immune response through cytokine secretion. An effective innate immune response may be able to clear SARS-CoV-2 infection and leave the patient's lungs undamaged. (B) High risk individuals may have dysfunctional NK cells which may not recognize and respond to SARS-CoV-2 infection due to immune evasion strategies employed by the virus. It is hypothesized that an accumulation of infected epithelial cells and innate immune cells, monocyte-macrophages and neutrophils, release cytokines, and chemokines which further recruit immune cells, including NK cells, to the lungs. This may result in the induction of a cytokine storm, led by IFN-γ. This inflammatory state could act as the catalyst for the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), contributing to the significant morbidity, and mortality associated with COVID-19. SARS-CoV-2 infection is associated with reduced NK cell levels and an exhausted phenotype which may impede viral clearance, in addition to severe lung damage.
Figure 2
Figure 2
Short-list of immune modulating therapies undergoing clinical trial in COVID-19 patients and recommendations on who should receive therapy. (A) Healthy, uninfected individuals, who are at a high risk of becoming infected (through situational circumstances such as healthcare workers) would be most fit and suitable to receive investigational prophylactic therapies such as exogenous IFNs and heterologous vaccines. (B) Individuals who have tested positive for COVID-19 that are asymptomatic or have mild to moderate disease progression may benefit from receiving investigational immune stimulating therapies, including NK cell-based therapies. It is critical that investigators must be vigilant to assess the safety profile and potential immunopathologies associated with these immunotherapies. (C) In severe COVID-19 patients, the most appropriate therapies to investigate would be those that mitigate immunopathologies, such as anti-inflammatory and immunosuppressive therapies. Given the relatively low chance of toxicity and the wide range of beneficial immune effects, natural health products such as vitamin C and vitamin D can be suitable for investigation at all categories of COVID-19 patients.

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