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Abstract
Humans are frequently exposed to potentially chronic virus infections throughout their lifetime. In some cases these virus infections are cleared through innate and adaptive immune responses, while in other cases they persist and can lead to disease. Theiler's Murine Encephalomyelitis Virus (TMEV) is a potentially persistent virus that causes acute encephalitis in the central nervous system of C57B6 (B6) mice that is cleared by both innate and adaptive immune responses. As a consequence of this immune mediate clearance of TMEV B6 mice exhibit damaged hippocampal regions of the brain. In contrast, susceptible strains of mice fail to clear the virus, develop a persistent infection and chronic neurological disease. An understanding of immune-mediated mechanisms that prevent chronic infection and disease in B6 mice could aid in developing preventions and therapies for potentially persistent viruses in humans. In addition, it is possible that these immune-mediated interventions could also aid in the therapy of non-infectious diseases, such as cancer. The following chapters describe studies of the role of interferon regulatory factor 3 (IRF3) in immune responses against TMEV. In addition, these studies identify genetic differences in IRF3 between TMEV-susceptible and resistant mice that could confer differential function. The following studies also indicate that IRF3 deficiency impacts both innate and adaptive responses to TMEV and prevents clearance of TMEV from the CNS but protects from immune-mediated damage to the CNS. Furthermore, IRF3 deficiency accelerates the growth of malignant melanoma of mice. Altogether, these results indicate that IRF3 is an important factor for innate and adaptive immune responses against both viruses and cancer and that IRF3 could be an important target for future therapeutics in humans.
