This projects aims at investigating basic mechanisms how the body can successfully eliminate persisting viruses, and how “killer T cells” cause disease of the central nervous system. A better understanding of these processes and the governing principles may help in the future design of preventive and therapeutic interventions in viral and autoimmune diseases.
Context and significance of the project:
In persistent viral infection, interactions between the virus and the infected body (host) are multifaceted, and different levels of balance can establish between the host and its intruder. Accordingly, persisting viruses can cause a broad range of diseases. Examples are:
a) In sub-Saharan Africa up to 30% of the human population are infected with human immunodeficiency virus (HIV), the causative agent of the AIDS syndrome. Similarly, an estimated global number of 170 million people are carriers of hepatitis C virus (HCV) that can cause liver cancer and end-stage liver disease. Yet, protective vaccines against HIV or HCV remain unavailable, and we lack a clear understanding how the immune system can prevail in such infections.
b) Neurons represent an irreplaceable population of highly differentiated cells in our brain and spinal cord, and therefore viruses preferentially take refuge in these cells. A growing body of evidence suggests that in multiple sclerosis (MS) and other inflammatory diseases of the central nervous system, neurons become a target of “killer T cells”, possibly as a result of viral infection. This process ultimately accounts for long-term disease progression and disability. MS affects up to 0.2% of the human population in high-risk areas, but the therapeutic options in MS remain unsatisfactory.
Taken together, viral and autoimmune diseases have a tremendous impact on global health. Therefore a better general understanding of the underlying mechanisms is urgently needed, including better knowledge about successful strategies of defense as well as about mechanisms of disease.
Scientific approach, methodology and expected insights:
This project applies newly developed gene technology (reverse genetics) to one of the best-characterized animal models for persistent viral infection (lymphocytic choriomeningitis virus). The combination thereof with genetically engineered mice, multi-parameter immune cell characterization (flow cytometry), tissue and gene expression analysis and disease parameters may help shedding light on the complex interactions between virus and host in persistent infection, and on the interactions of “killer T cells” with neurons. Specifically, this project aims to understand how antibodies and “killer T cells” can succeed in controlling persistent viral infection and whether specific qualitative thresholds exist that govern “killer T cell” interactions with neurons in the context of autoimmune disease.