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NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake.

ABSTRACT: Epstein Barr virus (EBV) causes a highly prevalent and lifelong infection contributing to the development of some malignancies. In addition to the key role played by T cells in controlling this pathogen, NK cells mediate cytotoxicity and IFNγ production in response to EBV-infected B cells in lytic cycle, both directly and through antibody (Ab)-dependent activation. We recently described that EBV-specific Ab-dependent NK cell interaction with viral particles (VP) bound to B cells triggered degranulation and TNFα secretion but not B cell lysis nor IFNγ production. In this report we show that NK cell activation under these conditions reduced B cell transformation by EBV. NK cells eliminated VP from the surface of B cells through a specific and active process which required tyrosine kinase activation, actin polymerization and Ca2+, being independent of proteolysis and perforin. VP were displayed at the NK cell surface before being internalized and partially shuttled to early endosomes and lysosomes. VP transfer was encompassed by a trogocytosis process including the EBV receptor CD21, together with CD19 and CD20. Our study reveals a novel facet of the antibody-dependent NK cell mediated response to this viral infection.

SUBMITTER: Alari-Pahissa E

PROVIDER: S-EPMC8409624 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake.

Alari-Pahissa Elisenda E Ataya Michelle M Moraitis Ilias I Campos-Ruiz Miriam M Altadill Mireia M Muntasell Aura A Moles Anna A López-Botet Miguel M

PLoS pathogens 20210820 8

Epstein Barr virus (EBV) causes a highly prevalent and lifelong infection contributing to the development of some malignancies. In addition to the key role played by T cells in controlling this pathogen, NK cells mediate cytotoxicity and IFNγ production in response to EBV-infected B cells in lytic cycle, both directly and through antibody (Ab)-dependent activation. We recently described that EBV-specific Ab-dependent NK cell interaction with viral particles (VP) bound to B cells triggered degran ...[more]

PMID: 34415956

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Project description:The main target cells for Epstein-Barr virus (EBV) infection and persistence are B lymphocytes, although T and NK cells can also become infected. In this paper, we characterize the EBV present in 21 pediatric and adult patients who were treated in France for a range of diseases that involve infection of T or NK cells. Of these 21 cases, 5 pediatric patients (21%) and 11 adult patients (52%) were of Caucasian origin. In about 30% of the cases, some of the EBV genomes contain a large deletion. The deletions are different in every patient but tend to cluster near the BART region of the viral genome. Detailed investigation of a family in which several members have persistent T or NK cell infection by EBV indicates that the virus genome deletions arise or are selected independently in each individual patient. Genome sequence polymorphisms in the EBV in these T or NK cell diseases reflect the geographic origin of the patient and not a distinct type of EBV (the 21 cases studied included examples of both type 1 and type 2 EBV infection). Using virus produced from type 1 or type 2 EBV genomes cloned in bacterial artificial chromosome (BAC) vectors, we demonstrate infection of T cells in cord blood from healthy donors. Our results are consistent with transient infection of some T cells being part of normal asymptomatic infection by EBV in young children. IMPORTANCE EBV contributes to several types of human cancer. Some cancers and nonmalignant lymphoproliferative diseases involving T or NK cells contain EBV. These diseases are relatively frequent in Japan and China and have been shown sometimes to have deletions in the EBV genome in the disease cells. We identify further examples of deletions within the EBV genome associated with T or NK cell diseases, and we provide evidence that the virus genomes with these deletions are most likely selected in the individual cases, rather than being transmitted between people during infection. We demonstrate EBV infection of cord blood T cells by highly characterized, cloned EBV genomes and suggest that transient infection of T cells may be part of normal asymptomatic infection by EBV in young children.

Project description:The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.

Project description:UnlabelledEpstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses.ImportanceThis report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor.

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NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake.

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NK cells eliminate Epstein-Barr virus bound to B cells through a specific antibody-mediated uptake.

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