About 10% of the world population suffers from chronic virus infections such as infections with hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Chronic virus infection is associated with the loss of functional cytotoxic T cells. Recent studies uncovered several mechanisms that play a central role in T cell exhaustion and thus development of chronic infections. The role of the innate immune system in the development of chronic virus infections remains unclear. Here we show that type I interferons trigger not only inhibition of virus replication but also immunoregulatory functions. The antiviral effects of type I interferons in the liver were dependent on the presence of macrophages. Macrophage depletion led to excessive virus replication and the development of chronic infection. Moreover, specific deletion of the type I interferon receptor on macrophages led to a decreased innate immune response. The regulatory functions of type I interferons were carried out by natural killer cells. Activated natural killer cells inhibited the virus specific cytotoxic T cell response and therefore delayed virus control. Depletion of natural killer cells prevented development of chronic infections and immunopathology. Moreover, type I interferons acted directly on the cytotoxic T cell response. Treatment with interferon 3 lead to increased T cell function. This resulted in induction of autoimmune diabetes in transgenic mice.
In conclusion, the nature of the innate immune response triggers the development of chronic virus infection. These results uncover new mechanisms that might provide the foundation for new therapeutic approaches for patients with chronic infections.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/29711 |
| Date | 30 August 2011 |
| Creators | Lang, Philipp |
| Contributors | Ohashi, Pamela |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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