Dataset Information

Human polyomavirus BKV infection of endothelial cells results in interferon pathway induction and persistence.

ABSTRACT: Polyomavirus BKV is highly prevalent among humans. The virus establishes an asymptomatic persistent infection in the urinary system in healthy people, but uncontrolled productive infection of the virus in immunocompromised patients can lead to serious diseases. In spite of its high prevalence, our knowledge regarding key aspects of BKV polyomavirus infection remains incomplete. To determine tissue and cell type tropism of the virus, primary human epithelial cells, endothelial cells and fibroblasts isolated from the respiratory and urinary systems were tested. Results from this study demonstrated that all 9 different types of human cells were infectable by BKV polyomavirus but showed differential cellular responses. In microvascular endothelial cells from the lung and the bladder, BKV persistent infection led to prolonged viral protein expression, low yield of infectious progeny and delayed cell death, in contrast with infection in renal proximal tubular epithelial cells, a widely used cell culture model for studying productive infection of this virus. Transcriptomic profiling revealed the activation of interferon signaling and induction of multiple interferon stimulated genes in infected microvascular endothelial cells. Further investigation demonstrated production of IFN? and secretion of chemokine CXCL10 by infected endothelial cells. Activation of IRF3 and STAT1 in infected endothelial cells was also confirmed. In contrast, renal proximal tubular epithelial cells failed to mount an interferon response and underwent progressive cell death. These results demonstrated that microvascular endothelial cells are able to activate interferon signaling in response to polyomavirus BKV infection. This raises the possibility that endothelial cells might provide initial immune defense against BKV infection. Our results shed light on the persistence of and immunity against infection by BKV polyomavirus.

SUBMITTER: An P

PROVIDER: S-EPMC6338385 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Human polyomavirus BKV infection of endothelial cells results in interferon pathway induction and persistence.

An Ping P Sáenz Robles Maria Teresa MT Duray Alexis M AM Cantalupo Paul G PG Pipas James M JM

PLoS pathogens 20190108 1

Polyomavirus BKV is highly prevalent among humans. The virus establishes an asymptomatic persistent infection in the urinary system in healthy people, but uncontrolled productive infection of the virus in immunocompromised patients can lead to serious diseases. In spite of its high prevalence, our knowledge regarding key aspects of BKV polyomavirus infection remains incomplete. To determine tissue and cell type tropism of the virus, primary human epithelial cells, endothelial cells and fibroblas ...[more]

PMID: 30620752

Similar Datasets

Project description:IntroductionPolyomavirus (BKV) infection can lead to major complications and damage to the graft in kidney transplant recipients (KTRs). We investigated whether pretransplant BK serostatus and BK-specific cell-mediated immunity (CMI) predicts post-transplant BK infection.MethodsA total of 93 donor-recipient pairs who underwent kidney transplantation (KT) and 44 healthy controls were examined. Assessment of donor and recipient BKV serostatus and BKV-CMI in recipients was performed prior to transplantation using BKV-IgG ELISA and BKV-specific IFN-g ELISPOT assays against five BK viral antigens (LT, St, VP1, VP2, and VP3). BK viremia was diagnosed when blood BKV-DNA of 104 copies/mL or more was detected during follow-up periods.ResultsAnti-BKV IgG antibody was detected in 74 (79.6%) of 93 KTRs and in 68 (73.1%) of 93 KT donors. A greater percentage of KTRs who received allograft from donors with high levels of anti-BKV IgG had posttransplant BK viremia (+) than KTRs from donors with low anti-BKV IgG (25.5% [12/47] vs. 4.3% [2/46], respectively; P = 0.007). Pretransplant total BKV-ELISPOT results were lower in BK viremia (+) patients than in patients without viremia (-) 20.5 [range 9.9-63.6] vs. 72.0 [43.2 - 110.8]; P = 0. 027). The sensitivity and specificity of the total BKV-ELISPOT assay (cut-off ≤ 53 spots/3×105 cells) for prediction of posttransplant BK viremia were 71.4 (95% CI: 41.9-91.6) and 54.4 (42.8-65.7), respectively. The combination of high donor BKV-IgG, low recipient BKV-IgG, and low total BKV-ELISPOT results improved specificity to 91.1%.DiscussionOur study highlights the importance of pretransplant BKV-IgG serostatus and BKV-specific CMI in predicting posttransplant BKV infection in KTRs. The combination of high donor BKV-IgG, low recipient BKV-IgG, and low total BKV-ELISPOT results predicted BK viremia after KT. Pretransplant identification of patients at highrisk for BK viremia could enable timely interventions and improve clinical outcomes of KTRs.

Project description:Merkel cell polyomavirus (MCPyV) has been associated with approximately 80% of Merkel cell carcinoma (MCC), an aggressive and increasingly incident skin cancer. The link between host innate immunity, viral load control, and carcinogenesis has been established but poorly characterized. We previously established the importance of the STING and NF-κB pathways in the host innate immune response to viral infection. In this study, we further discovered that MCPyV infection of human dermal fibroblasts (HDFs) induces the expression of type I and III interferons (IFNs), which in turn stimulate robust expression of IFN-stimulated genes (ISGs). Blocking type I IFN downstream signaling using an IFN-β antibody, JAK inhibitors, and CRISPR knockout of the receptor dramatically repressed MCPyV infection-induced ISG expression but did not significantly restore viral replication activities. These findings suggest that IFN-mediated induction of ISGs in response to MCPyV infection is not crucial to viral control. Instead, we found that type I IFN exerts a more direct effect on MCPyV infection postentry by repressing early viral transcription. We further demonstrated that growth factors normally upregulated in wounded or UV-irradiated human skin can significantly stimulate MCPyV gene expression and replication. Together, these data suggest that in healthy individuals, host antiviral responses, such as IFN production induced by viral activity, may restrict viral propagation to reduce MCPyV burden. Meanwhile, growth factors induced by skin abrasion or UV irradiation may stimulate infected dermal fibroblasts to promote MCPyV propagation. A delicate balance of these mutually antagonizing factors provides a mechanism to support persistent MCPyV infection. IMPORTANCE Merkel cell carcinoma is an aggressive skin cancer that is particularly lethal to immunocompromised individuals. Though rare, MCC incidence has increased significantly in recent years. There are no lasting and effective treatments for metastatic disease, highlighting the need for additional treatment and prevention strategies. By investigating how the host innate immune system interfaces with Merkel cell polyomavirus, the etiological agent of most of these cancers, our studies identified key factors necessary for viral control, as well as conditions that support viral propagation. These studies provide new insights for understanding how the virus balances the effects of the host immune defenses and of growth factor stimulation to achieve persistent infection. Since virus-positive MCC requires the expression of viral oncogenes to survive, our observation that type I IFN can repress viral oncogene transcription indicates that these cytokines could be explored as a viable therapeutic option for treating patients with virus-positive MCC.

Dataset Information

Human polyomavirus BKV infection of endothelial cells results in interferon pathway induction and persistence.

Publications

Human polyomavirus BKV infection of endothelial cells results in interferon pathway induction and persistence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets