Innate immune recognition of rabies virus: Defining the role of the inflammasome and interferon stimulated genes
Rabies virus (RABV) causes more than 70,000 deaths worldwide per year, despite the availability of vaccines and post exposure prophylaxis (PEP) following infection. Therefore, novel treatments and improved vaccines for RABV are still in need of being developed. To develop improved therapies we must first understand the activation of the immune system. The objective of this thesis was to examine how the immune system detects and prevents RABV infect. To address this we sought to determine: 1) the mechanism by which the inflammasome recognizes RNA viruses and its role in RABV pathogenicity and immunogenicity and 2) to examine the role of IFIT proteins in the restriction of RABV infection. The use of genetically modified mice have enabled the examination, both in vitro and in vivo, of the immunological effects and consequences on survival after the loss of specific genes. We demonstrate that inflammasome activation is important for the development of an effective host defense against RABV. Our results indicate that the infection of bone marrow-derived dendritic cells (BMDCs) induces both the IPS-1 dependent production of pro-interleukin-1β (IL-1β) as well as its processing, resulting in the secretion of mature IL-1β through activation of the NLRP3-, ASC-, and caspase-1- dependent inflammasome. We demonstrate that both the production of pro-IL-β and activation of the inflammasome requires viral replication. Additionally, IL-1 receptor-deficient mice show an increase in RABV pathogenicity. Furthermore, we characterize the RABV pathogenesis of mice deficient in ISG54/Ifit2, ISG56/Ifit1, and IFNAR in an effort to define their role in RABV replication and spread in vivo. We found that ISG54/Ifit2 was important for controlling not only pathogenicity after i.n. infection, but also RABV invasion into the CNS after i.m. infection. In contrast, we found that the role of ISG56/Ifit1 in RABV infection was limited to controlling RABV in the CNS. This thesis analyzed the mechanisms of an activated immune system that play an important role as the body's first line of defense against many invading pathogens. Our findings will not only contribute to the current knowledge on innate immune recognition of viral infection, but also translate into strategies for improving prevention and treatment of rabies.
Lawrence, Tessa M, "Innate immune recognition of rabies virus: Defining the role of the inflammasome and interferon stimulated genes" (2013). ETD Collection for Thomas Jefferson University. AAI3557314.