Herpesviruses are very large and complex viruses. We are just beginning to understand how these pathogens manipulate our immune system to establish lifelong chronic infections. In order to develop new therapies and vaccines, it is first necessary to understand the molecular details of the intimate interplay between herpesviruses and their hosts.
Figure 1. The herpesvirus life cycle: primary infection is followed by a phase called latency. When the delicate balance between virus and immune system is disrupted, herpesviruses can reactivate from latency and enter the lytic phase, during which new virus particles are formed.
We focus on the question how herpesviruses are detected by the innate immune system and how they evade this potent first line of host defense.
Figure 2. The innate immune system plays a crucial role for detection of viral pathogens and induces important measures to defend the infected host. Pattern recognition receptors (PRR) recognize viral or aberrantly localized cellular nucleic acids soon after viral entry into the host cell. PRR then induce signaling cascades that result in the production of cytokines such as type I interferons (IFN). Type I IFN then activate a further line of defense by inducing expression of antiviral interferon-stimulated genes (ISG) via the type I IFN receptor.
Via millions of years of coevolution, herpesviruses have adapted perfectly to their respective hosts. They know exactly which switches to pull to weaken or exploit the immune response for their own benefit. One goal of our research is to identify novel viral proteins that are directly involved in manipulation of immune defenses. These proteins are potential targets for the development of new antiviral therapies. Another focus is the characterisation of the pro- or antiviral role of interferon-stimulated gene products during herpesviral infections and their mechanism of action.
Our research focuses on two members of the herpesvirus family: human herpesvirus 5, also known as cytomegalovirus (CMV), and human herpesvirus 8, Kaposi’s sarcoma-associated herpesvirus (KSHV).
Figure 3. Overview of the human herpesviruses. The herpesvirus family is divided into three subfamilies, the Alpha-, Beta-, and Gamma-herpesvirinae, which include nine herpesviruses that can infect humans.
CMV is a common pathogen, thought to infect half of the European population. In many healthy individuals, CMV infection is unrecognized - it may cause mild illness or even be completely asymptomatic. However, in patients with weakened immune systems, for example in HIV (Human immunodeficiency virus)/AIDS patients and transplant recipients, CMV infection can cause severe complications.
In addition, CMV infection of the mother during the first trimester of pregnancy can lead to infection of the fetus, which can result in permanent damage observed at birth or later in childhood. CMV-induced birth defects include mental handicap, deafness, microcephaly, and/or visual impairment. In fact, CMV is the most common pathogen responsible for mental retardation and the most common cause of non-genetic deafness in young children (Deutschlandfunk: Zytomegalie in der Schwangerschaft).
To date, we have no licensed CMV vaccine and there is only a limited selection of antiviral drugs available.
KSHV was first discovered in 1994. Since then, it has been identified as the causative agent of at least three types of cancer:
a cancer of blood vessels, known as Kaposi’s sarcoma,
a type of lymphoma, or cancer of white blood cells, known as
primary effusion lymphoma,
a form of lymph node enlargement, known as multicentric Castleman’s disease.
The goal of our research activities is to gain novel insights into the interplay between the herpesviruses CMV and KSHV and their hosts, and thus better understand how these viruses cause illness. These insights are the foundation required to develop innovative, specific therapies against herpesviruses.