Marek’s disease virus prolongs survival of primary chicken B-cells by inducing a senescence-like phenotype

Abstract

Marek’s disease virus (MDV) is an alphaherpesvirus that causes immunosuppression and deadly lymphoma in chickens. Lymphoid organs play a central role in MDV infection in animals. B-cells in the bursa of Fabricius facilitate high levels of MDV replication and contribute to dissemination at early stages of infection. Several studies investigated host responses in bursal tissue of MDV-infected chickens; however, the cellular responses specifically in bursal B-cells has never been investigated. We took advantage of our recently established in vitro infection system to decipher the cellular responses of bursal B-cells to infection with a very virulent MDV strain. Here, we demonstrate that MDV infection extends the survival of bursal B-cells in culture. Microarray analyses revealed that most cytokine/cytokine-receptor-, cell cycle- and apoptosis-associated genes are significantly down-regulated in these cells. Further functional assays validated these strong effects of MDV infections on cell cycle progression and thus, B-cell proliferation. In addition, we confirmed that MDV infections protect B-cells from apoptosis and trigger an accumulation of the autophagy marker Lc3-II. Taken together, our data indicate that MDV-infected bursal B-cells show hallmarks of a senescence-like phenotype, leading to a prolonged B-cell survival. This study provides an in-depth analysis of bursal B-cell responses to MDV infection and important insights into how the virus extends the survival of these cells.

The immune cell landscape and response of Marek’s disease resistant and susceptible chickens infected with Marek’s disease virus

“…The host response to MDV within macrophages from both MD resistant and susceptible lines showed significant gene regulatory changes with stronger virally induced responses in cells from susceptible birds (n = 1,265 genes regulated) 12 . Among lymphocytes, B cells are infected early following MDV entry into the lung and a large (n = 2,186) in vitro DEG response was found in MDV-infected B cells compared to control B cells, with an enrichment for cytokine-cytokine receptor activation pathways 13 . While these studies have yielded gene expression signals relevant to the host immune response to MDV infection in specific cell types or as aggregate transcriptomes, the context of coregulation of molecular pathways by all cell types has been missing.…”

Purinergic signaling during Marek’s disease in chickens

“…MD-susceptible and resistant chickens have significant differences in the metabolism of lipoprotein; LDL lipoprotein fraction increases with growth in the susceptible line 111 . Moreover, MD increases production of ROS leading to oxidative stress in the susceptible chickens 112 , 113 . Whereas this imbalance in the ambient redox level promotes oxidation of native LDL (oxLDL), thus the higher hepatic expression of P2Y1 and P2Y2 (Fig.…”

Immune escape of avian oncogenic Marek’s disease herpesvirus and antagonistic host immune responses

“…The route by which MDV particles spread from infected B cells to activated T cells and different organs leading to systemic infection should not be overlooked, although the presence of B cells acting as the initial targets of MDV infection has recently been verified to not be an essential step in the activation and consequent infection of a larger number of CD4 + T cells 90 , 91 . Interestingly, in addition to inducing the apoptosis of uninfected B cells, leading to immunosuppression, MDV prolongs the survival of infected B cells by inducing a senescence-like phenotype, which may promote the persistence of viruses and thus allow more time to recruit and infect T cells 92 . Strikingly, MHC-II molecules, which are embedded in the membranes of APCs such as macrophages, dendritic cells, and B cells, play a crucial role in activating B-cell proliferation and differentiation 93 .…”