The Promise and Peril of Natural Killer Cell Therapies in Pulmonary Infection

Rajaram, Sanjeeth; Canaday, Laura M.; Ochayon, David E.; Rangel, Kelly; Ali, Ayad; Gyurova, Ivayla E; Krishnamurthy, Durga; Fletcher, Jonathan S.; Reighard, Seth D.; Cox, Andrew D.; Weirauch, Matthew T.; Kottyan, Leah C.; Deshmukh, Hitesh; Zacharias, William J.; Borchers, Michael T.; Waggoner, Stephen N.

doi:10.1016/j.immuni.2020.04.018

Cited by 19 publications

(19 citation statements)

References 15 publications

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“…9 Highly activated NK cells have been shown to worsen lung injury in respiratory infection models, and the use of therapeutic tools to improve NK cell functions should, thus, be carefully considered in severe cases of COVID-19. 10 However, our data, showing a decrease in NK cell numbers and a dysfunctional state of these cells in the blood and lungs of COVID-19 patients, suggest that NK cells do not participate in the exaggerated inflammatory response observed in ARDS. Thus, therapies targeting PD-(L)1, NKG2A and CD39 should be investigated as means of boosting NK cell antiviral immunity in patients at early stages of SARS-CoV-2 infection.…”

mentioning

confidence: 50%

Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19

et al. 2020

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confidence: 50%

Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19

et al. 2020

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“…However, a recent study found that levels of six pro-inflammatory cytokines (IL-1b, IL-1Ra, IL-6, IL-8, IL-18, and TNF-α) implicated in the cytokine storm in COVID-19 patients did not differ significantly from levels in cytokine storms caused by other conditions. They suggest that it is therefore possible that increased levels of proinflammatory cytokines in the context of severe COVID-19 may simply reflect an increased viral burden rather than an exuberant immune response and suggest that immunotherapies should therefore be used with caution (147).…”

Section: Nk Cell Role In Coronavirus Immunopathologymentioning

confidence: 99%

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

et al. 2020

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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.

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“…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).…”

Section: Natural Killer Cells As a Therapeutic Option For Airway Infementioning

confidence: 98%

“…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).…”

Section: Natural Killer Cells As a Therapeutic Option For Airway Infementioning

confidence: 98%

Airway Natural Killer Cells and Bacteria in Health and Disease

2020

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Natural killer (NK) cells are innate lymphoid cells at the interface between innate and adaptive immunity and mostly studied for their important roles in viral infections and malignant tumors. They can kill diseased cells and produce cytokines and chemokines, thereby shaping the adaptive immune response. Nowadays, NK cells are considered as a strong weapon for cancer immunotherapy and can for example be transduced to express tumor-specific chimeric antigen receptors or harnessed with therapeutic antibodies such as the so-called NK engagers. Whereas a large body of literature exists about the antiviral and antitumoral properties of NK cells, their potential role in bacterial infections is not that well delineated. Furthermore, NK cells are much more heterogeneous than previously thought and have tissue-characteristic features and phenotypes. This review gives an overview of airway NK cells and their position within the immunological army dressed against bacterial infections in the upper and predominantly the lower respiratory tracts. Whereas it appears that in several infections, NK cells play a non-redundant and protective role, they can likewise act as rather detrimental. The use of mouse models and the difficulty of access to human airway tissues for ethical reasons might partly explain the divergent results. However, new methods are appearing that are likely to reduce the heterogeneity between studies and to give a more coherent picture in this field.

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The Promise and Peril of Natural Killer Cell Therapies in Pulmonary Infection

Cited by 19 publications

References 15 publications

Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19

Identification of druggable inhibitory immune checkpoints on Natural Killer cells in COVID-19

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

Airway Natural Killer Cells and Bacteria in Health and Disease

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