Oropharyngeal Group A Streptococcal Colonization Disrupts Latent Epstein-Barr Virus Infection

Epstein-Barr virus (EBV) infects >90% of the human population within the first 2 decades of life and establishes reversible latent infection in B cells. The stimuli that lead to switching from latent to lytic EBV infection in vivo are still elusive. Group A streptococci (GAS) are a common cause of bacterial pharyngotonsillitis in children and adolescents and colonize the tonsils and pharynx of up to 20% of healthy children. Thus, concomitant presence of EBV and GAS in the same individual is frequent. Here, we show that EBV carriers who are colonized with GAS shed EBV particles in higher numbers in their saliva, compared with EBV carriers not colonized with GAS. Messenger RNA levels of the master lytic regulatory EBV gene BZLF1 were more frequently detected in tonsils from EBV carriers colonized with GAS than from EBV carriers not colonized. Heat-killed GAS, potentially mimicking GAS colonization, elicited lytic EBV in latently infected lymphoblastoid cell lines (LCLs) partially via Toll-like receptor 2 triggering, as did purified GAS peptidoglycan. Thus, colonization by GAS might benefit EBV by increasing the EBV load in saliva and thereby enhancing the likelihood of EBV spread to other host

Reduced frequency of cytotoxic CD56dim CD16+ NK cells leads to impaired antibody-dependent degranulation in EBV-positive classical Hodgkin lymphoma

Around 30–50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56dim CD16+ NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56dim NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL

CD4 + T cells are found within endemic Burkitt lymphoma and modulate Burkitt lymphoma precursor cell viability and expression of pathogenically relevant Epstein-Barr virus genes.

Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an IgH/c-myc translocation and the harboring of Epstein-Barr virus (EBV). Evidence accumulates that CD4 + T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4 + T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of IgH/c-myc translocation in primary B cells by employing a CRISPR/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4 + T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4 + T cells on the one hand suppress eBL development by killing pre-eBL cells lacking IgH/c-myc translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an IgH/c-myc translocation does not suffice to escape CD4 + T-cell-mediated killing in vitro, the CD4 + T-cell-mediated suppression of EBV's Latency III program in vivo may allow cells harboring an IgH/c-myc translocation and additional mutations to evade immune control and proliferate by means of deregulated c-myc activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4 + T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of IgH/c-myc translocation

Comparaison entre le dosage de l’A2aR (récepteur à l’adénosine présents sur les lymphocytes circulants) et la troponinémie hautement sensible dans le Syndrome Coronarien Chronique

Les maladies neuro-cardiovasculaires représentent la première cause de décès dans le monde. En France, en 2018, on dénombrait environ 1 595 900 patients porteurs d’un syndrome coronarien chronique (SCC) ; ce qui représente la quatrième affection de longue durée, en terme de fréquence. La coronarographie est l’examen de référence pour affirmer le diagnostic de SCC. La troponinémie est un marqueur de nécrose extrêmement sensible et spécifique. À ce jour il n’existe pas de biomarqueur recommandé par les sociétés savantes dans le diagnostic du SCC. L’objectif principal de notre étude est donc d’évaluer la précision diagnostique de l’expression de l’A2AR, chez des patients suspects de SCC. L’étude réalisée est monocentrique et rétrospective. La période d’inclusion s’étend du 11 novembre 2017 au 12 avril 2019, 323 patients furent sélectionnés. Les principaux critères d’inclusions étaient les patients entre 18 et 90 ans, suspects de SCC avec un ECG non contributif et un cycle de troponinémie inférieur au 99ème percentile. Une valeur seuil fixée à 1 UA permet d’affirmer avec une VPP de 95,16 % que le patient est porteur d’un SCC, s’il présente une expression A2AR < 1UA. La spécificité de l’expression de l’A2AR pour une valeur strictement inférieure à 1UA est de 92,21% et une sensibilité de 47,97%. L’expression des récepteurs A2A semble donc être un test diagnostic spécifique d’un SCC. Ce nouveau biomarqueur de SCC permettrait à l’avenir un diagnostic plus précoce, ainsi qu’une réduction des coûts et de l’iatrogénie liés aux différentes techniques diagnostiques actuelles

A distinct subpopulation of human NK cells restricts B cell transformation by EBV

NK cells constitute the first line of defense against pathogens and transformed cells. They mature in secondary lymphoid organs, including tonsils, where common pathogens, such as EBV, enter the host and potentially imprint differentiating cells, which then patrol the body via the blood stream. Therefore, we set out to characterize a distinct human NK cell population in tonsils that produces high amounts of the immunomodulatory and antiviral cytokine IFN-γ. We found that the tonsilar IFN-γ(high) NK cell subset is CD56(bright)NKG2A(+)CD94(+)CD54(+)CD62L(-), is present in tonsils ex vivo and is more mature than other CD56(bright) NK cells in tonsils and less mature than other NK cells in blood, shows very low plasticity even after prolonged cytokine stimulation, accumulates in tonsils of EBV carriers, and is able to potently restrict EBV-induced transformation of B cells. Thus, we characterized a distinct and stable IFN-γ(high) NK cell subpopulation that can specifically restrict malignant transformation of EBV-infected B cells. This subset should be exploited for future development of cell-based therapeutic approaches in EBV-associated malignancies

Two alternate strategies for innate immunity to Epstein-Barr virus: one using NK cells and the other NK cells and γδ T cells

Most humans become infected with Epstein-Barr virus (EBV), which then persists for life. Infrequently, EBV infection causes infectious mononucleosis (IM) or Burkitt lymphoma (BL). Type I EBV infection, particularly type I BL, stimulates strong responses of innate immune cells. Humans respond to EBV in two alternative ways. Of 24 individuals studied, 13 made strong NK and γδ T cell responses, whereas 11 made feeble γδ T cell responses but stronger NK cell responses. The difference does not correlate with sex, HLA type, or previous exposure to EBV or cytomegalovirus. Cohorts of EBV(+) children and pediatric IM patients include both group 1 individuals, with high numbers of γδ T cells, and group 2 individuals, with low numbers. The even balance of groups 1 and 2 in the human population points to both forms of innate immune response to EBV having benefit for human survival. Correlating these distinctive responses with the progress of EBV infection might facilitate the management of EBV-mediated disease

Electronic, bonding and optical properties of the LiGaGe2X6 (X = S, Se, and Te) compounds: An ab initio study

In order to gain an insight into the bonding and to characterize linear and nonlinear optical properties of three infrared LiGaGe2S6, LiGaGe2Se6, and LiGaGe2Te6 compounds, we performed an ab initio calculation based on density functional theory. The calculations determined lattice parameters, band gaps, dipole moments, and second harmonic components that commonly agreed well with the available experimental data. We show in this article, through a large body of calculations, the trend in the row of participating anions, S ⟶ Se ⟶ Te, enhances the polarization effect and the coordination structure distortions in the polyhedra groups forming the bonding pattern of the cell. This one also affects both the electronic and the optical properties, making the compounds more propitious for device-based optical applications

Co-infection of Cytomegalovirus and Epstein-Barr Virus Diminishes the Frequency of CD56dimNKG2A+KIR− NK Cells and Contributes to Suboptimal Control of EBV in Immunosuppressed Children With Post-transplant Lymphoproliferative Disorder

Post-transplant lymphoproliferative disorder (PTLD) is a rare but potentially life-threatening complication, frequently associated with Epstein-Barr virus (EBV), which develops after solid organ or stem cell transplantation. Immunosuppression received by transplant recipients has a significant impact on the development of PTLD by suppressing the function of T cells. The preferential proliferation of NKG2A-positive natural killer (NK) cells during primary symptomatic EBV infection known as infectious mononucleosis (IM) and their reactivity toward EBV-infected B cells point to a role of NK cell in the immune control of EBV. However, NK cell-mediated immune response to EBV in immunosuppressed transplant recipients who develop PTLD remains unclear. In this study, we longitudinally analyzed the phenotype and function of different NK cell subsets in a cohort of pediatric liver transplant patients who develop PTLD and compared them to those of children with IM. We found persistently elevated plasma EBV DNA levels in the PTLD patients indicating suboptimal anti-viral immune control. PTLD patients had markedly decreased frequency of CD56dimNKG2A+Killer Immunoglobulin-like receptor (KIR)− NK cells from the time of diagnosis through remission compared to those of IM patients. Whilst the proliferation of CD56dimNKG2A+KIR− NK cells was diminished in PTLD patients, this NK cell subset maintained its ability to potently degranulate against EBV-infected B cells. Compared to cytomegalovirus (CMV)-seropositive and -negative IM patients, PTLD patients co-infected with CMV and EBV had significantly higher levels of a CMV-associated CD56dimNKG2ChiCD57+NKG2A−KIR+ NK cell subset accumulating at the expense of NKG2A+KIR− NK cells. Taken together, our data indicate that co-infection of CMV and EBV diminishes the frequency of CD56dimNKG2A+KIR− NK cells and contributes to suboptimal control of EBV in immunosuppressed children with PTLD