Pseudorabies Virus Infection Causes Downregulation of Ligands for the Activating NK Cell Receptor NKG2D

Denaeghel, Sofie; Pelsmaeker, Steffi De; Waesberghe, Cliff Van; Favoreel, Herman

doi:10.3390/v13020266

Cited by 4 publications

(6 citation statements)

References 60 publications

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“…Also activating receptor NKG2D (CD314) is expressed in NK. This finding describes the rational function of the NK cell in COVID-19 85 . In COVID-19 patients’ number of NK cells are decreased which is associated with development and severity of COVID-19 86 .…”

Section: Introductionsupporting

confidence: 63%

Cellular Therapy: The Hope for Covid-19

Nobari¹,

Rezvan²,

Dashtestani³

et al. 2022

AJMB

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Coronaviruses (CoVs) are a group of very diverse viruses that cause a broad spectrum of diseases from mild to severe enteric, respiratory, systemic diseases, and common cold or pneumonia among humans and animals. This virus is associated with Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and lung disease that lead to Acute Respiratory Distress Syndrome (ARDS). In December 2019, researchers identified a novel coronavirus type, called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), which was associated with symptoms of high fever, dry cough, headache, diarrhea, and reduction of White Blood Cells (WBC). Coronavirus-associated acute respiratory disease was named Coronavirus Disease 19 (COVID-19). No proven treatment has been discovered for COVID-19 so far, but researchers are trying to find the best effective way to treat this disease. Therefore, therapeutic strategies that facilitate the recovery of COVID-19 patients and reduce life-threatening complications are urgently needed now. Today, Mesenchymal Stem Cells (MSCs) and their secretion are utilized as one of the most applied tools to treat various diseases such as inflammation and cancer. MSC-derived vesicles are rich in various growth factors, cytokines, and interleukins that are produced and secreted under different physiological or pathological conditions. These vesicles were considered a suitable and effective tool in regeneration medicine because of their high power in repairing damaged tissues and modulating immune responses. Recently, evidence has shown MSC-derived vesicles through reduced expression of pro-inflammatory cytokines could improve damaged tissues in COVID-19 patients. In addition to MSCs and MSC-derived exosomes, Natural Killer (NK) cells, T cells, and platelet lysates were used against viral infection. In this review, we tried to provide an overview of MSC secretion and immune cells for COVID-19 therapy.

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Section: Introductionsupporting

confidence: 63%

Cellular Therapy: The Hope for Covid-19

Nobari¹,

Rezvan²,

Dashtestani³

et al. 2022

AJMB

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“…Here, we sought to evaluate whether the reovirus has developed mechanisms to impair NK cell cytotoxicity towards infected cells. We analyzed the levels of NKG2D ligands on the surface of reovirus-infected tumor cells, as NKG2D is a dominant NK cell receptor that augments NK-cell anti-viral activity ( 29 , 31 , 32 ). We infected the human melanoma cell line MNT-1, and human glioblastoma cell line U87-MG with reovirus T3D.…”

Section: Resultsmentioning

confidence: 99%

“…These ligands are overexpressed in tumor cells (33), making NKG2D-mediated recognition a prominent pathway by which NK cells identify and kill transformed cells (34). Moreover, because the expression of NKG2D ligands also enhances the cytotoxic activity of NK cells towards virus-infected cells, different viruses have developed unique mechanisms to manipulate the expression of stress-induced ligands to evade NK-mediated elimination (32,(35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

“…Natural killer (NK) cells are innate lymphoid cells which are considered to be a key factor in the defense against tumor transformation and viral infections, as they can identify a wide range of patterns associated with “danger,” and unleash a cytotoxic response towards those patterns ( 29 ). NK cell cytotoxicity is regulated by an array of activating and inhibitory receptors ( 30 ), with the NKG2D receptor being among the most prominent activating receptors of NK cells ( 29 , 31 , 32 ). The NKG2D receptor binds to eight stress-induced ligands present on the cell surface, which are split into two families: the MHC class I chain-related protein (MIC) family, which includes MICA and MICB, and the UL16-binding protein (ULBP) family, which includes ULBP1-6.…”

Section: Introductionmentioning

confidence: 99%

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Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Khaleafi,

Zeleznjak,

Cordela

et al. 2023

Front. Immunol.

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In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how reovirus infection affects the tumor microenvironment and immune response towards infected tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular ligands on tumor cells, which are ultimately key to tumor recognition and elimination by NK cells, has not been investigated. We tested how reovirus infection affects the binding of the NK Group-2 member D (NKG2D) receptor, which is a dominant mediator of NK cell anti-tumor activity. Using models of human-derived melanoma and glioblastoma tumors, we demonstrated that NKG2D ligands are downregulated in tumor cells post-reovirus-infection due to the impaired translation of these ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D ligands significantly impaired the binding of NKG2D to infected tumor cells. We further demonstrated that reduced recognition of NKG2D ligands significantly alters NK cell anti-tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based therapeutics that enhance the anti-tumor immune response.

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“…Glycoprotein D of HSV and pseudorabies virus downregulates CD112 expression, a ligand for the activating NK cell receptor DNAM-1, which results in decreased NK cell activation and reduced cytotoxicity ( 18 , 91 ). Two porcine isoforms of CD112 have been reported ( 92 ), but further study is needed to evaluate the role of porcine CD112 in human NK cell activation.…”

Section: Future Directionsmentioning

confidence: 99%

Strategies to induce natural killer cell tolerance in xenotransplantation

et al. 2022

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Eliminating major xenoantigens in pig cells has drastically reduced human antibody-mediated hyperacute xenograft rejection (HXR). Despite these advancements, acute xenograft rejection (AXR) remains one of the major obstacles to clinical xenotransplantation, mediated by innate immune cells, including macrophages, neutrophils, and natural killer (NK) cells. NK cells play an ‘effector’ role by releasing cytotoxicity granules against xenogeneic cells and an ‘affecter’ role on other immune cells through cytokine secretion. We highlight the key receptor-ligand interactions that determine the NK cell response to target cells, focusing on the regulation of NK cell activating receptor (NKG2D, DNAM1) and inhibitory receptor (KIR2DL1-4, NKG2A, and LIR-1) signaling pathways. Inhibition of NK cell activity may protect xenografts from cytotoxicity. Recent successful approaches to reducing NK cell-mediated HXR and AXR are reviewed, including genetic modifications of porcine xenografts aimed at improving pig-to-human compatibility. Future directions to promote xenograft acceptance are discussed, including NK cell tolerance in pregnancy and NK cell evasion in viral infection.

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Pseudorabies Virus Infection Causes Downregulation of Ligands for the Activating NK Cell Receptor NKG2D

Cited by 4 publications

References 60 publications

Cellular Therapy: The Hope for Covid-19

Cellular Therapy: The Hope for Covid-19

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Strategies to induce natural killer cell tolerance in xenotransplantation

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