Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

Münz, Christian

doi:10.1038/s41579-019-0249-7

Cited by 299 publications

(324 citation statements)

References 141 publications

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“…Recently, Ranaviruses, have been detected by eDNA analysis in environmental water samples from susceptible host species habitats, and demonstrated a strong relationship between environmentally-shed viral load and host tissue viral load 45 . Our application of eDNA approaches to detect ChHV5 in sea water is particularly significant given that unlike more immediate acting pathogens, there is generally a long lag time (years or decades) between infection and tumor formation [87][88][89] for pathogen-induced cancers. This delay can hamper our understanding of infection dynamics and initiating events, making the ability for ongoing monitoring and surveillance critical.…”

Section: Mechanisms Of Viral Exposurementioning

confidence: 99%

Mutational, transcriptional and viral shedding dynamics of the marine turtle fibropapillomatosis tumor epizootic

Yetsko

Farrell

Stammnitz

et al. 2020

Preprint

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Sea turtle populations are directly and indirectly under threat from a range of anthropogenic processes. Perhaps the most visibly apparent of these is the disfiguring tumor disease epizootic (animal epidemic) known as fibropapillomatosis. Fibropapillomatosis continues to spread geographically, with prevalence of the disease also growing at a number of affected sites globally. Environmental exposures seem key to inducing tumor development, possibly through weakening host immune systems to the point of enabling pathogen-induced tumor formation. However, we do not yet understand the precise molecular and mutational events driving fibropapillomatosis tumor formation and progression. Similarly, many open questions remain about the role of the herpesvirus (chelonid herpesvirus 5, ChHV5) associated with the disease as a potential co-trigger, and whether its occurrence within tumors is causative or opportunistic. Without improved understanding of the basic biology of this disease epizootic, treatment, containment and mitigation options are severely hampered.To address fundamental questions relating to the oncogenic signaling, mutational spectrum, viral load, viral transcriptional status (lytic or latent) and spread, we employed transcriptomic profiling, whole genome sequencing, immunohistochemistry and environmental (e)DNAbased monitoring of viral shedding. In particular we focused on the mutational landscape of tumors and assessing the transcriptional similarity of external (skin) and internal (visceral organs) tumors, and the oncogenic signaling events driving early stage tumor growth and post-surgical tumor regrowth. These analyses revealed that internal fibropapillomatosis tumors are molecularly distinct from the more common external tumors. However, our molecular analyses also revealed that there are a small number of conserved potentially therapeutically targetable molecular vulnerabilities in common between internal and external tumors, such as the MAPK, Wnt, TGFβ and TNF oncogenic signaling pathways. We also determined that the tumor genomes can harbor copy number gains, indicating potentially viral-independent oncogenic processes. Genes within such mutated genomic regions have known roles in human skin cancer, including MAPK-associated genes. Turtles attempt to mount an immune response, but in some animals this appears to be insufficient to prevent tumor development and growth. ChHV5 was transcriptionally latent in all tumor stages sequenced, including early stage and recurrent tumors. We also revealed that the tumors themselves are the primary source of viral shedding into the marine environment and, if they are surgically removed, the level of ChHV5 in the water column drops.Together, these results offer an improved understanding of fibropapillomatosis tumorigenesis and provide insights into the origins, therapeutic treatment, and appropriate quarantine responses for this wildlife epizootic. Furthermore, they provide insights into human pathogen-induced cancers, particularly mechanisms which are difficult to s...

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Section: Mechanisms Of Viral Exposurementioning

confidence: 99%

Mutational, transcriptional and viral shedding dynamics of the marine turtle fibropapillomatosis tumor epizootic

Yetsko

Farrell

Stammnitz

et al. 2020

Preprint

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“…It has adapted during evolution in a species-specific manner by gene family expansions and contractions to environmental factors that challenge the majority of a species with grave morbidity and mortality prior to reproduction [2,3]. Among these are the human γ-herpesviruses Epstein Barr virus (EBV) or human herpesvirus 4 and Kaposi sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 which are widely distributed in the human population and threaten their host with tumor induction [4,5]. Indeed, EBV persistently infects more than 95% of human adults, and more than 70% are seropositive for KSHV in some areas of Sub-Saharan Africa, the cradle of humankind.…”

Section: Epstein Barr Virus and Kaposi Sarcoma-associated Herpesvirusmentioning

confidence: 99%

“…The lesions in the human immune system of patients with primary immunodeficiencies identify T lymphocytes as the main components of the immune control of the two γ-herpesviruses, cytotoxic CD8 + T and NK cells for EBV and IFN-γ producing T cells for KSHV [13][14][15]. In contrast to the protective function of cytokines against KSHV, cytokine production due to T cell hyperactivation during ill-controlled EBV infection can lead to immune pathologies, including the symptomatic primary EBV infection, called infectious mononucleosis (IM) and hemophagocytic lymphohistiocytosis (HLH) [4,16,17]. In rare cases, these immune pathologies might also develop into autoimmune diseases, with the central nervous system (CNS)-affecting autoimmune disease multiple sclerosis (MS) being a likely candidate [18].…”

Section: Epstein Barr Virus and Kaposi Sarcoma-associated Herpesvirusmentioning

confidence: 99%

The Role of Dendritic Cells in Immune Control and Vaccination against γ-Herpesviruses

Münz

2019

Viruses

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The two human oncogenic γ-herpesviruses, Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV), are prototypic pathogens that are controlled by T cell responses. Despite their ubiquitous distribution, persistent infections and transforming potential, most carriers’ immune systems control them for life. Therefore, they serve as paradigms of how near-perfect cell-mediated immune control can be initiated and maintained for decades. Interestingly, EBV especially quite efficiently avoids dendritic cell (DC) activation, and little evidence exists that these most potent antigen-presenting cells of the human body are involved in the priming of immune control against this tumor virus. However, DCs can be harnessed therapeutically to expand virus-specific T cells for adoptive transfer therapy of patients with virus-associated malignancies and are also currently explored for vaccinations. Unfortunately, despite 55 and 25 years of research on EBV and KSHV, respectively, the priming of their immune control that belongs to the most robust and durable immune responses in humans still remains unclear.

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“…In this state, the full lytic program is not induced due to an incomplete expression cascade of viral lytic genes; thus, infectious particles are not produced. Abortive lytic replication and its associated viral gene expressions are implicated in the pathogenesis of EBV-associated malignancies [17, 21, 22]. Transient lytic gene expressions in newly infected B-cells is essential for the emergence of lymphoblastoid cell lines [23].…”

Section: Introductionmentioning

confidence: 99%

Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection

Inagaki

Sato

Ito

et al. 2020

Preprint

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36 Viral infection induces dynamic changes in transcriptional profiles. Virus-37 induced and anti-viral responses are intertwined during the infection. Epstein-38 Barr virus (EBV) is a human gammaherpesvirus that provides a model of 39 herpesvirus latency. To measure the transcriptome changes during the 40 establishment of EBV latency, EBV-negative Akata cells were infected with 41 EBV-EGFP and observed by transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 42 10, and 14 days after infection. We found transient downregulation of mitotic 43 division-related genes, reflecting reprograming of cell growth by EBV. Moreover, 44 a burst of viral lytic gene expression was detected in the early phase of 45 infection. Experimental and mathematical investigations demonstrated that 46 infectious virions were not produced in the pre-latent phase, suggesting the 47 presence of an abortive lytic infection. Finally, we conducted fate mapping using 48 recombinant EBV, enabling the noninvasive, continuous observation of infected 49 cells during EBV infection. Our tracking analysis provided direct evidence that 50 the abortive lytic infection in the pre-latent phase converges to latent infection 51 during EBV infection of B-cells, shedding light on novel roles of viral lytic 52 gene(s) in establishing latency. 53 54 Author summary 55Viral infection is a complex process that activates both virus-triggered and 56 host anti-viral responses. This process has classically been studied by snapshot 57 analysis such as microarray and RNA-seq at discrete time points as population 58 averages. Snapshot data lead to invaluable findings in host-pathogen 59 interactions. However, these "snapshot" omics, even from a single cell, lack 60 temporal resolution. Because the behavior of infected cells is highly dynamic 61 and heterogenous, continuous analysis is required for deciphering the fate of 62 infected cells during viral infection. Here, we exploited fate mapping techniques 63 with recombinant Epstein-Barr virus (EBV) to track the infected cells and 64 recorded a log of lytic gene expression during EBV infection. Our continuous 65 observation of infected cells revealed that EBV established latency in B-cells via 66 an abortive lytic infection in the pre-latent phase. 67 PubMed PMID: 19553389. 595

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Latency and lytic replication in Epstein–Barr virus-associated oncogenesis

Cited by 299 publications

References 141 publications

Mutational, transcriptional and viral shedding dynamics of the marine turtle fibropapillomatosis tumor epizootic

Mutational, transcriptional and viral shedding dynamics of the marine turtle fibropapillomatosis tumor epizootic

The Role of Dendritic Cells in Immune Control and Vaccination against γ-Herpesviruses

Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection

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