EBV-derived microRNAs silence immune alarm signals of the host cell

The EBV virus, first described by the English virologists Michael Epstein and Yvonne M. Barr, is found in the majority of the world’s population, but is usually held in check by the immune system. Nevertheless, the body is unable to eliminate this pathogen completely.

The team of scientists led by Prof. Wolfgang Hammerschmidt, head of the Research Unit Gene Vectors at Helmholtz Zentrum München and a member of the German Center for Infection Research (DZIF), is striving to find out the reasons behind this.

Hide-and-seek: EBV makes itself invisible

“Our new studies show that by means of microRNAs, the virus prevents the infected cell from alerting the immune system,” said Hammerschmidt, summarizing the findings. EBV usually hides in B cells, a class of white blood cells. If they are infected by EBV, the virus induces the cells to proliferate and thus to expand the reservoir of viruses. The B cells usually respond with an alarm signal to the immune system: They present molecules of the virus on their surface and secrete inflammatory cytokines to attract immune cells.

“It's just this alarm signal that's suppressed by microRNAs made by the virus,” said Manuel Albanese, a scientist in the Research Unit Gene Vectors. His colleague Takanobu Tagawa added: “The microRNAs block production of the proteins that would ring this alarm.” The two doctoral students share the lead authorship of the two publications in the Proceedings of the National Academy of Sciences and in the Journal of Experimental Medicine.*

New approach may be promising for cancer therapy

Since the EBV virus drives division of B cells and thereby causes particular forms of cancer, the researchers are considering how to apply these findings to cancer therapy. “The mechanism we discovered renders killer T cells and helper T cells inactive, even when they directly face the infected cell,” said study leader Hammerschmidt.** “If it were possible to disrupt this blockade, this could be an interesting approach to treat cancer: the immune system could then better fight tumors that are triggered by EBV.“ For other diseases, clinical studies on active substances that shut off specific microRNAs have already started, the authors say.

Further Information

* microRNAs (miRNAs) are noncoding RNAs that play an important role in gene regulation and especially in the silencing of genes. Generally, they have a size of 21 to 23 nucleotides and are very short – hence the name.

** Killer T cells (also known as CD8 T cells) can destroy the infected cells, thus preventing the virus from multiplying. Helper T cells (also called CD4 T-cells) support them and also ensure the production of antibodies against the virus.

Background:
About a year ago, scientists of the Gene Vectors Research Unit at Helmholtz Zentrum München discovered another mechanism the EBV virus uses to hide in human cells. Here the LMP2A protein plays a crucial role: http://www.helmholtz-muenchen.de/en/press-media/press-releases/2015/press-releas…

Original Publications:
Tagawa, T. & Albanese, M. et al. (2016): Epstein-Barr Viral miRNAs Inhibit Antiviral CD4+ T Cell Responses Targeting IL-12 and Peptide Processing. Journal of Experimental Medicine, doi: 10.1084/jem.20160248

Albanese, M. & Tagawa, T. et al. (2016): Epstein-Barr virus miRNAs inhibit immune surveillance by virus-specific CD8+ T cells. Proceedings of the National Academy of Sciences (PNAS), doi: 10.1073/pnas.1605884113

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en

The Research Unit Gene Vectors studies EBV's molecular functions to understand how the virus contributes to different types of disease. The scientists analyse the immune system of virus carriers to find out how EBV and other herpes viruses are kept in check, and why immune control has failed in patients with disease. They also investigate the origins of cancers of the immune system – lymphoma and leukaemia. Their ultimate goal is to develop new drugs, vaccines and cell-based therapies in order to efficiently treat or – preferentially – prevent infectious diseases and cancer. http://www.helmholtz-muenchen.de/en/agv

At the German Center for Infection Research (DZIF), over 500 scientists from 35 institutions nationwide jointly develop new approaches for the prevention, diagnosis and treatment of infectious diseases. Their aim is to translate research results into clinical practice rapidly and effectively. With this, the DZIF paves the way for developing new vaccines, diagnostics and drugs in the fight against infections. http://www.dzif.de.

Contact for the media:
Department of Communication, Helmholtz Zentrum München – German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg – Tel. +49 89 3187 2238 – Fax: +49 89 3187 3324 – E-mail: presse@helmholtz-muenchen.de

Scientific Contact at Helmholtz Zentrum München:
Prof. Dr. Wolfgang Hammerschmidt, Helmholtz Zentrum München – German Research Center for Environmental Health, Research Unit Gene Vectors, Marchioninistraße 25, 81377 München – Tel. +49 89 3187 1506, E-mail: hammerschmidt@helmholtz-muenchen.de