Research Programme 研究计划
The Transregio contains three different project areas, which complement each other:
A) Innate immunity and immunopathogenesis
The mechanisms of interaction of immune cells with viruses and the factors involved in inducing initial anti-viral responses will be investigated. Following viral invasion, the infected host mounts a number of immediate immune responses to infection. In general, the innate immunity comes into play shortly after infection, filling an important gap in the protection against viral invasion until the appearance of specific immune responses. We will study the cellular and molecular innate immune responses in chronic viral infections including TLR, IFN, proinflamatory cytokines and NK cells and how viruses interfere with such responses by specific viral components. In addition, new pathways involved in immune recognition of chronic viruses and immune evasion shall be characterized, like DDB1 and MAPK. On the other hand, pathology of chronic viral infections might also be influenced by unbalanced immune responses. Such mechanisms shall be investigated for B cell disorders and cytokine networks in HCV infection. These fundamental studies should provide new information on disease pathogenesis and initial immunity that can be very useful for the development of therapeutic and prophylactic treatment against persistent viral infections described in the project areas B and C. This is especially true because innate immunity strongly influences adaptive immune responses against viruses, which will strengthen the collaborations between the projects in the areas A and B.
B) Adaptive immune responses, immune escape, and immune modulation
The contest between viruses and hosts is never-ending, but a virus has the advantage that it can undergo evolution more rapidly. Not surprisingly, viruses have developed a number of mechanisms to evade immune surveillance and to persist in the infected host. To understand the interaction of viruses with the adaptive immune response, the characterization of the cellular immunity during acute and chronic infection with retroviruses and HCV is one of the main research areas of the Transregio. In new animal models and collaborative studies on infected patients this research is broadened to HBV infection. Whereas the HCV studies are mainly focused on patients, the HBV and retrovirus projects were initiated as animal experiments but will now be extended to patient studies. After the detailed characterization of cellular immune responses against the three viruses, the mechanisms of immune evasion in chronic infections will be studied in animal models and patients with special focus on mutational escape, regulatory T cells and inhibitory receptors. We already initiated a number of new therapeutic approaches that aim to overcome immune evasion or immune dysfunction by experimentally activating the immune system to fight chronic virus. The studies are focusing on HBV and retroviruses and will be continued and extended using different pre-clinical animal models. Successful concepts shall be converted into first clinical trials in the next couple of years.
C) Prophylactic and therapeutic vaccination
Prophylactic vaccines are the most effective mode to prevent viral infections. However, it has not been possible so far to develop effective vaccines against a number of viruses inducing chronic infections, including HIV and HCV. Vaccine development against HIV and HCV is especially difficult because these two RNA viruses are extremely variable. Thus, the aim of the projects in area C is to develop novel basic strategies to optimize the delivery of viral antigens, define broadly recognized antigens, or to characterize optimal adjuvants for inducing potent immune responses against chronic viruses. These are the initial important steps to overcome current problems in the area of vaccine development against persisting pathogens, which may lead to novel pharmaceutical products in the future. Several animal models can be used to perform vaccine experiments and such studies can be supported by the central vaccine unit Z4N. Although there are different immunological requirements for prophylactic and therapeutic vaccines, successful prophylactic vaccines shall also be tested for therapeutic vaccination during chronic infections. In these experiments, using animal models of chronic HBV or retrovirus infection, the vaccine shall be combined with potent immunomodulating treatment to overcome the common immunosuppression during persistent viral infections. Immunomodulatory treatments will include TLR activation, Treg manipulation, or inhibitory receptor blockade. Basic aspects of vaccine design are in the focus of the projects in area C for this funding period.