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Papillomavirus oncogene silences innate immune response

Human papillomavirus type 16, the most frequent cause of cervical cancer, is able to silence a signalling molecule in the host cells that is needed for immune responses to occur. If the body is unable to defend itself against intruders, the viruses can successfully invade the cells of the cervical mucosa. Researchers from the German Cancer Research Centre have discovered that the viral E6 oncogene is responsible for this mechanism.

Human papillomaviruses - electron microscope photo © DKFZ

In the 1980s, Harald zur Hausen and his team of researchers discovered that certain human papillomavirus (HPV) types caused cervical cancer. Scientists soon found out how these pathogens led to the degeneration of cells. It is now known that the viral proteins E6 and E7 are responsible for this mechanism. The two proteins switch off different cellular control functions, thereby triggering cell proliferation.

Professor Dr. Frank Rösl and his team of researchers at the German Cancer Research Centre have now discovered another mechanism by which the E6 protein of high-risk HPV16 promotes carcinogenesis. This viral gene switches off the production of interferon-kappa. Interferons are proteins that are part of our immune system and are primarily responsible for stimulating the immune response to viruses and tumours. Interferons are produced by white blood cells and other cell types to defend the body against viruses and tumours. Interferon-kappa plays a key role in defending the body against HPV infections since it is mainly produced in skin and mucosa (keratinocytes) cells, which are the preferred hosts of the viruses. The lack of interferon-kappa also affects the function of other proteins involved in immune defence reactions.

Dr. Bladimiro Rincon-Orozco, who is part of Frank Rösl's team, has been able to show for the first time ever that HPV16 switches off the interferon-kappa gene by biochemically modifying the DNA. Such modifications of the genetic material are referred to as epigenetic mutations. The researchers initially observed on cultured HPV-infected cells that epigenetic modifications inactivated the interferon-kappa gene. They were subsequently able to confirm their previous findings using cervical cancer tissue samples.

"Interferon-kappa is an important component of innate immunity," explains Frank Rösl. This immunological defence mechanism, which is found in plants, animals and humans, is believed to be an old defence strategy in evolutionary terms and is an immediate line of defence against infection. The specific "acquired" defence against infection has to develop over time. "Viruses that switch off the production of interferon prevent infected cells from being eliminated by the innate immune system," said Rösl explaining the strategy of the cancer pathogens. The researchers now plan to test whether the administration of interferon-kappa is able to slow down and prevent the growth of cervical cancer cells and thus potentially support the treatment of this disease.

Bladimiro Rincon-Orozco, Gordana Halec, Simone Rosenberger, Dorothea Muschik, Ingo Nindl, Anastasia Bachmann, Tina Maria Ritter, Bolormaa Dondog, Regina Ly, Franz X. Bosch, Rainer Zawatzky and Frank Rösl: Epigenetic Silencing of Interferon-κ in Human Papillomavirus Type 16-Positive Cells. Cancer Res 2009; 69: (22) November 15, 2009

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/papillomavirus-oncogene-silences-innate-immune-response